Case Reports

Hydralazine-induced antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is a complex entity characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement. Although it is an established entity, a PubMed search of articles indexed for MEDLINE using the terms hydralazine vasculitis, ANCA positive vasculitis, and hydralazine associated vasculitis revealed a limited number of cases reported in the dermatologic literature (Table 1).^1-6 We report a rare case of hydralazine-induced vasculitis associated with airway compromise and severe gastrointestinal tract bleeding.

RELATED ARTICLE: Sweet Syndrome Associated With Hydralazine-Induced Lupus Erythematosus

Case Report

A 71-year-old woman with a history of end-stage renal disease treated with hemodialysis, as well as hypertension, diabetes mellitus, and ischemic cardiomyopathy, presented to our emergency department with odynophagia, muscle weakness, shortness of breath, and a distinctive mucocutaneous eruption on the left eyelid, lips, and tongue of 2 days’ duration. Physical examination revealed an ill-appearing, afebrile, dyspneic woman with swelling of the left upper eyelid, conjunctival injection, ulcerations on the lips and tongue, and tense hemorrhagic vesicles, as well as vesiculopustules on the elbows, palms, fingers, lower legs, and toes (Figure 1). Given her dyspnea, flexible laryngoscopy was performed and revealed ulceration and edema involving the epiglottis, aryepiglottic folds, and arytenoids. The patient was intubated for airway protection and started on intravenous dexamethasone.

An extensive diagnostic workup commenced. Bacterial, viral, and fungal cultures of blood, skin tissue, and respiratory secretions, as well as human immunodeficiency virus screening, were all negative. Specifically, a tissue culture was performed on skin from the left thigh, viral culture and direct fluorescent antibody were performed on a vesicle on the right knee for herpes simplex virus and herpes zoster, and a superficial wound culture was taken from the left arm, all showing no growth. The patient’s home medications were reviewed and revealed she was currently taking hydralazine (100 mg 3 times daily), which was started approximately 2 years prior. Laboratory results revealed a positive antinuclear antibody titer of 1:320 (diffuse pattern), positive antihistone antibody, and positive ANCA with cytoplasmic and perinuclear accentuation (Table 2). Enzyme-linked immunosorbent assays showed IgG antibodies to myeloperoxidase (MPO) and proteinase 3 (Table 2). Skin biopsies from the right lower leg and right upper arm were compatible with necrotizing leukocytoclastic vasculitis characterized by mural and luminal fibrin deposition involving capillaries and venules of the superficial and deep dermis (Figure 2). The vessel walls were infiltrated by neutrophils with concomitant leukocytoclasia. Vessels in the mid dermis were occluded by cellular fibrin thrombi. Foci of neutrophilic interface dermatitis with subepidermal bulla formation were observed. Infectious stains were negative. On direct immunofluorescence, striking homogeneous mantles of staining of IgG were present within the cutaneous vasculature.

Because the infectious workup was negative and there was no other known instigating factor of vasculitis, concern for a drug-induced process prompted thorough review of the patient’s home medications and discontinuation of hydralazine. A diagnosis of hydralazine-associated cutaneous vasculitis was made when laboratory workup confirmed no underlying infectious process or rheumatologic condition and the medication known to cause her symptoms was on her medication list. The dexamethasone dose was increased, leading to rapid improvement of her mucocutaneous findings; however, on initiation of a steroid taper, she developed substantial gastrointestinal tract bleeding. An esophageal biopsy revealed a neutrophil-rich necrotizing process that essentially mirrored the cutaneous biopsy consistent with vasculitic involvement of the gastrointestinal tract. Steroids were again increased with resolution in gastrointestinal tract bleeding.

 

Comment

Our case highlights a distinct clinical presentation of hydralazine-induced ANCA-positive cutaneous vasculitis associated with severe involvement of the aerodigestive tract with gastrointestinal tract bleeding and airway compromise requiring intubation. Although discontinuation of hydralazine and in certain cases the addition of immunosuppressive agents may be adequate for resolution of symptoms, some cases progress despite treatment, leading to skin grafting, amputation, and death.^3,4 Therefore, early recognition of hydralazine-induced cutaneous vasculitis and discontinuation of hydralazine are of paramount importance.

Reporting hydralazine-induced vasculitis is valuable because of its unique cutaneous, extracutaneous, and serologic findings. In our case, the cutaneous vasculitis presented clinically with acral hemorrhagic vesiculopustules and necrotic ulcerations resembling septic emboli, as opposed to classic lesions of palpable purpura typical of drug-induced leukocytoclastic vasculitis. Similar cutaneous findings have been described in other cases of hydralazine-induced vasculitis, indicating that this pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration is characteristic of this entity.^1,3,6 In addition, involvement of the oral cavity, larynx, and gastrointestinal tract have been reported in cases of hydralazine-induced vasculitis, indicating mucosal involvement is an important feature of this disease.^3,6 Although involvement of the oral mucosa, larynx, and acral sites appears to be characteristic, the exact basis for this site localization remains elusive. A precedent has been established for a similar pattern of intraoral and laryngeal involvement in other ANCA-positive vasculitic syndromes, most notably Wegener granulomatosis.⁷ Similarly, there are certain occlusive vasculitic syndromes that show acral localization including chronic septic vasculitis and vasculitis of collagen vascular disease.

Serologic trends can aid in diagnosing hydralazine-induced vasculitis. In theory, the nonspecific cutaneous findings, often in association with joint pain and positive antinuclear antibodies, may lead clinicians to the misdiagnosis of a connective tissue disease, such as systemic lupus erythematosus (SLE). However, unlike SLE, hydralazine-induced vasculitis is associated with positive ANCAs, while antibodies against double-stranded DNA, a highly specific antibody for SLE, are uncommon.^8,9 Our patient had both positive perinuclear ANCA with cytoplasmic ANCA as well as a positive antihistone antibodies, a combination highly suggestive of a drug-induced process.

Despite the often acute presentation of hydralazine-induced ANCA-positive vasculitis, afflicted patients have characteristically been on the drug for a long period of time. Our patient is exemplary of most reported cases, as the time from initiation of hydralazine to onset of vasculitis was 2 years.⁴

The mechanism by which hydralazine causes this reaction is still a matter of debate. It seems clear that there are certain at-risk populations, such as slow acetylators and patients with an underlying hypercoagulable state. There are several theories by which hydralazine induces autoantibody formation. The first involves hydralazine metabolization by MPO released from activated neutrophils to form reactive intermediate metabolites. Such metabolites can be cytotoxic and may cause abnormal degradation of chromatin in susceptible individuals, leading to an autoimmune response against histone-DNA complexes. Alternatively, hydralazine may act as a hapten and bind to MPO, inducing an immune response against the hydralazine-MPO complex, with resultant formation of anti-MPO antibodies in susceptible individuals.¹⁰

Conclusion

Hydralazine-induced ANCA-positive vasculitis is a syndromic complex characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement along with a characteristic ANCA-positive serologic profile. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. Older age of onset, female gender, and underlying autoimmune diatheses likely define important risk factors. With more recognition and reporting of this disease, further trends in both clinical and serological presentation will emerge.

Hydralazine-induced antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is a complex entity characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement. Although it is an established entity, a PubMed search of articles indexed for MEDLINE using the terms hydralazine vasculitis, ANCA positive vasculitis, and hydralazine associated vasculitis revealed a limited number of cases reported in the dermatologic literature (Table 1).^1-6 We report a rare case of hydralazine-induced vasculitis associated with airway compromise and severe gastrointestinal tract bleeding.

RELATED ARTICLE: Sweet Syndrome Associated With Hydralazine-Induced Lupus Erythematosus

Case Report

A 71-year-old woman with a history of end-stage renal disease treated with hemodialysis, as well as hypertension, diabetes mellitus, and ischemic cardiomyopathy, presented to our emergency department with odynophagia, muscle weakness, shortness of breath, and a distinctive mucocutaneous eruption on the left eyelid, lips, and tongue of 2 days’ duration. Physical examination revealed an ill-appearing, afebrile, dyspneic woman with swelling of the left upper eyelid, conjunctival injection, ulcerations on the lips and tongue, and tense hemorrhagic vesicles, as well as vesiculopustules on the elbows, palms, fingers, lower legs, and toes (Figure 1). Given her dyspnea, flexible laryngoscopy was performed and revealed ulceration and edema involving the epiglottis, aryepiglottic folds, and arytenoids. The patient was intubated for airway protection and started on intravenous dexamethasone.

An extensive diagnostic workup commenced. Bacterial, viral, and fungal cultures of blood, skin tissue, and respiratory secretions, as well as human immunodeficiency virus screening, were all negative. Specifically, a tissue culture was performed on skin from the left thigh, viral culture and direct fluorescent antibody were performed on a vesicle on the right knee for herpes simplex virus and herpes zoster, and a superficial wound culture was taken from the left arm, all showing no growth. The patient’s home medications were reviewed and revealed she was currently taking hydralazine (100 mg 3 times daily), which was started approximately 2 years prior. Laboratory results revealed a positive antinuclear antibody titer of 1:320 (diffuse pattern), positive antihistone antibody, and positive ANCA with cytoplasmic and perinuclear accentuation (Table 2). Enzyme-linked immunosorbent assays showed IgG antibodies to myeloperoxidase (MPO) and proteinase 3 (Table 2). Skin biopsies from the right lower leg and right upper arm were compatible with necrotizing leukocytoclastic vasculitis characterized by mural and luminal fibrin deposition involving capillaries and venules of the superficial and deep dermis (Figure 2). The vessel walls were infiltrated by neutrophils with concomitant leukocytoclasia. Vessels in the mid dermis were occluded by cellular fibrin thrombi. Foci of neutrophilic interface dermatitis with subepidermal bulla formation were observed. Infectious stains were negative. On direct immunofluorescence, striking homogeneous mantles of staining of IgG were present within the cutaneous vasculature.

Because the infectious workup was negative and there was no other known instigating factor of vasculitis, concern for a drug-induced process prompted thorough review of the patient’s home medications and discontinuation of hydralazine. A diagnosis of hydralazine-associated cutaneous vasculitis was made when laboratory workup confirmed no underlying infectious process or rheumatologic condition and the medication known to cause her symptoms was on her medication list. The dexamethasone dose was increased, leading to rapid improvement of her mucocutaneous findings; however, on initiation of a steroid taper, she developed substantial gastrointestinal tract bleeding. An esophageal biopsy revealed a neutrophil-rich necrotizing process that essentially mirrored the cutaneous biopsy consistent with vasculitic involvement of the gastrointestinal tract. Steroids were again increased with resolution in gastrointestinal tract bleeding.

 

Comment

Our case highlights a distinct clinical presentation of hydralazine-induced ANCA-positive cutaneous vasculitis associated with severe involvement of the aerodigestive tract with gastrointestinal tract bleeding and airway compromise requiring intubation. Although discontinuation of hydralazine and in certain cases the addition of immunosuppressive agents may be adequate for resolution of symptoms, some cases progress despite treatment, leading to skin grafting, amputation, and death.^3,4 Therefore, early recognition of hydralazine-induced cutaneous vasculitis and discontinuation of hydralazine are of paramount importance.

Reporting hydralazine-induced vasculitis is valuable because of its unique cutaneous, extracutaneous, and serologic findings. In our case, the cutaneous vasculitis presented clinically with acral hemorrhagic vesiculopustules and necrotic ulcerations resembling septic emboli, as opposed to classic lesions of palpable purpura typical of drug-induced leukocytoclastic vasculitis. Similar cutaneous findings have been described in other cases of hydralazine-induced vasculitis, indicating that this pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration is characteristic of this entity.^1,3,6 In addition, involvement of the oral cavity, larynx, and gastrointestinal tract have been reported in cases of hydralazine-induced vasculitis, indicating mucosal involvement is an important feature of this disease.^3,6 Although involvement of the oral mucosa, larynx, and acral sites appears to be characteristic, the exact basis for this site localization remains elusive. A precedent has been established for a similar pattern of intraoral and laryngeal involvement in other ANCA-positive vasculitic syndromes, most notably Wegener granulomatosis.⁷ Similarly, there are certain occlusive vasculitic syndromes that show acral localization including chronic septic vasculitis and vasculitis of collagen vascular disease.

Serologic trends can aid in diagnosing hydralazine-induced vasculitis. In theory, the nonspecific cutaneous findings, often in association with joint pain and positive antinuclear antibodies, may lead clinicians to the misdiagnosis of a connective tissue disease, such as systemic lupus erythematosus (SLE). However, unlike SLE, hydralazine-induced vasculitis is associated with positive ANCAs, while antibodies against double-stranded DNA, a highly specific antibody for SLE, are uncommon.^8,9 Our patient had both positive perinuclear ANCA with cytoplasmic ANCA as well as a positive antihistone antibodies, a combination highly suggestive of a drug-induced process.

Despite the often acute presentation of hydralazine-induced ANCA-positive vasculitis, afflicted patients have characteristically been on the drug for a long period of time. Our patient is exemplary of most reported cases, as the time from initiation of hydralazine to onset of vasculitis was 2 years.⁴

The mechanism by which hydralazine causes this reaction is still a matter of debate. It seems clear that there are certain at-risk populations, such as slow acetylators and patients with an underlying hypercoagulable state. There are several theories by which hydralazine induces autoantibody formation. The first involves hydralazine metabolization by MPO released from activated neutrophils to form reactive intermediate metabolites. Such metabolites can be cytotoxic and may cause abnormal degradation of chromatin in susceptible individuals, leading to an autoimmune response against histone-DNA complexes. Alternatively, hydralazine may act as a hapten and bind to MPO, inducing an immune response against the hydralazine-MPO complex, with resultant formation of anti-MPO antibodies in susceptible individuals.¹⁰

Conclusion

Hydralazine-induced ANCA-positive vasculitis is a syndromic complex characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement along with a characteristic ANCA-positive serologic profile. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. Older age of onset, female gender, and underlying autoimmune diatheses likely define important risk factors. With more recognition and reporting of this disease, further trends in both clinical and serological presentation will emerge.

Hydralazine-induced antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is a complex entity characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement. Although it is an established entity, a PubMed search of articles indexed for MEDLINE using the terms hydralazine vasculitis, ANCA positive vasculitis, and hydralazine associated vasculitis revealed a limited number of cases reported in the dermatologic literature (Table 1).^1-6 We report a rare case of hydralazine-induced vasculitis associated with airway compromise and severe gastrointestinal tract bleeding.

RELATED ARTICLE: Sweet Syndrome Associated With Hydralazine-Induced Lupus Erythematosus

Case Report

A 71-year-old woman with a history of end-stage renal disease treated with hemodialysis, as well as hypertension, diabetes mellitus, and ischemic cardiomyopathy, presented to our emergency department with odynophagia, muscle weakness, shortness of breath, and a distinctive mucocutaneous eruption on the left eyelid, lips, and tongue of 2 days’ duration. Physical examination revealed an ill-appearing, afebrile, dyspneic woman with swelling of the left upper eyelid, conjunctival injection, ulcerations on the lips and tongue, and tense hemorrhagic vesicles, as well as vesiculopustules on the elbows, palms, fingers, lower legs, and toes (Figure 1). Given her dyspnea, flexible laryngoscopy was performed and revealed ulceration and edema involving the epiglottis, aryepiglottic folds, and arytenoids. The patient was intubated for airway protection and started on intravenous dexamethasone.

An extensive diagnostic workup commenced. Bacterial, viral, and fungal cultures of blood, skin tissue, and respiratory secretions, as well as human immunodeficiency virus screening, were all negative. Specifically, a tissue culture was performed on skin from the left thigh, viral culture and direct fluorescent antibody were performed on a vesicle on the right knee for herpes simplex virus and herpes zoster, and a superficial wound culture was taken from the left arm, all showing no growth. The patient’s home medications were reviewed and revealed she was currently taking hydralazine (100 mg 3 times daily), which was started approximately 2 years prior. Laboratory results revealed a positive antinuclear antibody titer of 1:320 (diffuse pattern), positive antihistone antibody, and positive ANCA with cytoplasmic and perinuclear accentuation (Table 2). Enzyme-linked immunosorbent assays showed IgG antibodies to myeloperoxidase (MPO) and proteinase 3 (Table 2). Skin biopsies from the right lower leg and right upper arm were compatible with necrotizing leukocytoclastic vasculitis characterized by mural and luminal fibrin deposition involving capillaries and venules of the superficial and deep dermis (Figure 2). The vessel walls were infiltrated by neutrophils with concomitant leukocytoclasia. Vessels in the mid dermis were occluded by cellular fibrin thrombi. Foci of neutrophilic interface dermatitis with subepidermal bulla formation were observed. Infectious stains were negative. On direct immunofluorescence, striking homogeneous mantles of staining of IgG were present within the cutaneous vasculature.

Because the infectious workup was negative and there was no other known instigating factor of vasculitis, concern for a drug-induced process prompted thorough review of the patient’s home medications and discontinuation of hydralazine. A diagnosis of hydralazine-associated cutaneous vasculitis was made when laboratory workup confirmed no underlying infectious process or rheumatologic condition and the medication known to cause her symptoms was on her medication list. The dexamethasone dose was increased, leading to rapid improvement of her mucocutaneous findings; however, on initiation of a steroid taper, she developed substantial gastrointestinal tract bleeding. An esophageal biopsy revealed a neutrophil-rich necrotizing process that essentially mirrored the cutaneous biopsy consistent with vasculitic involvement of the gastrointestinal tract. Steroids were again increased with resolution in gastrointestinal tract bleeding.

 

Comment

Our case highlights a distinct clinical presentation of hydralazine-induced ANCA-positive cutaneous vasculitis associated with severe involvement of the aerodigestive tract with gastrointestinal tract bleeding and airway compromise requiring intubation. Although discontinuation of hydralazine and in certain cases the addition of immunosuppressive agents may be adequate for resolution of symptoms, some cases progress despite treatment, leading to skin grafting, amputation, and death.^3,4 Therefore, early recognition of hydralazine-induced cutaneous vasculitis and discontinuation of hydralazine are of paramount importance.

Reporting hydralazine-induced vasculitis is valuable because of its unique cutaneous, extracutaneous, and serologic findings. In our case, the cutaneous vasculitis presented clinically with acral hemorrhagic vesiculopustules and necrotic ulcerations resembling septic emboli, as opposed to classic lesions of palpable purpura typical of drug-induced leukocytoclastic vasculitis. Similar cutaneous findings have been described in other cases of hydralazine-induced vasculitis, indicating that this pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration is characteristic of this entity.^1,3,6 In addition, involvement of the oral cavity, larynx, and gastrointestinal tract have been reported in cases of hydralazine-induced vasculitis, indicating mucosal involvement is an important feature of this disease.^3,6 Although involvement of the oral mucosa, larynx, and acral sites appears to be characteristic, the exact basis for this site localization remains elusive. A precedent has been established for a similar pattern of intraoral and laryngeal involvement in other ANCA-positive vasculitic syndromes, most notably Wegener granulomatosis.⁷ Similarly, there are certain occlusive vasculitic syndromes that show acral localization including chronic septic vasculitis and vasculitis of collagen vascular disease.

Serologic trends can aid in diagnosing hydralazine-induced vasculitis. In theory, the nonspecific cutaneous findings, often in association with joint pain and positive antinuclear antibodies, may lead clinicians to the misdiagnosis of a connective tissue disease, such as systemic lupus erythematosus (SLE). However, unlike SLE, hydralazine-induced vasculitis is associated with positive ANCAs, while antibodies against double-stranded DNA, a highly specific antibody for SLE, are uncommon.^8,9 Our patient had both positive perinuclear ANCA with cytoplasmic ANCA as well as a positive antihistone antibodies, a combination highly suggestive of a drug-induced process.

Despite the often acute presentation of hydralazine-induced ANCA-positive vasculitis, afflicted patients have characteristically been on the drug for a long period of time. Our patient is exemplary of most reported cases, as the time from initiation of hydralazine to onset of vasculitis was 2 years.⁴

The mechanism by which hydralazine causes this reaction is still a matter of debate. It seems clear that there are certain at-risk populations, such as slow acetylators and patients with an underlying hypercoagulable state. There are several theories by which hydralazine induces autoantibody formation. The first involves hydralazine metabolization by MPO released from activated neutrophils to form reactive intermediate metabolites. Such metabolites can be cytotoxic and may cause abnormal degradation of chromatin in susceptible individuals, leading to an autoimmune response against histone-DNA complexes. Alternatively, hydralazine may act as a hapten and bind to MPO, inducing an immune response against the hydralazine-MPO complex, with resultant formation of anti-MPO antibodies in susceptible individuals.¹⁰

Conclusion

Hydralazine-induced ANCA-positive vasculitis is a syndromic complex characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement along with a characteristic ANCA-positive serologic profile. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. Older age of onset, female gender, and underlying autoimmune diatheses likely define important risk factors. With more recognition and reporting of this disease, further trends in both clinical and serological presentation will emerge.

Take-Home Points

• Preoperative orthogonal radiographs need to be carefully scrutinized in irreducible fractures.
• Open reduction is often necessary when soft-tissue or bone is interposed in a fracture site.
• The fibula’s size and interosseous connection to the tibia can lead to entrapment.
• High-energy mechanisms can lead to significant deformity at time of injury, with spontaneous partial reduction prior to initial assessment.
• Consider intramedullary entrapment of adjacent long bones.

The tibia is the most commonly fractured long bone; each year, almost 500,000 tibia fractures occur in the United States alone.¹ Low-energy mechanisms of injury usually result from torsional forces and produce less comminuted fractures. Very high-energy injuries apply direct forces to the shin and are often highly comminuted or open, owing to the limited soft-tissue envelope. The extent of soft-tissue injury occurring with these fractures is the best predictor of the development of a complication, particularly nonunion or infection.¹ Low-energy closed fractures with limited comminution and sufficient cortical apposition may be treated with closed reduction and casting, but the most common treatment for tibial shaft fractures is intramedullary nailing.²

In the acute setting, closed reduction allows for temporization of soft tissues and prevention of further damage to neurovascular structures. Whether eventual treatment consists of casting or intramedullary fixation, closed reduction must first be achieved.

In this article, we report a unique case of tibial shaft fracture irreducibility caused by telescoping of the distal fibula within the proximal tibial diaphysis. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 23-year-old unrestrained driver of a tow truck rear-ended another vehicle at high speed (~45 mph) and became trapped in the vehicle. Extrication time was prolonged. The driver was brought to the emergency department at a level I trauma center, where he was found to have an obvious closed deformity of the right lower leg but remained neurovascularly intact. Radiographs showed a highly comminuted fracture of the right tibial and fibular midshaft with more than 100% medial displacement of the distal fragment (Figure 1).

Immediate closed reduction was performed in the emergency department, with the patient under sedation. The procedure improved gross realignment and reduced tension from the overlying soft tissue. Postreduction radiographs showed improved alignment that, with some displacement and angulation remaining, was deemed sufficient to temporize the injury until surgery the next morning.

The next morning, the patient was taken to the operating room for planned closed intramedullary nailing through a suprapatellar approach. After entry to the tibial medullary canal was obtained, a ball-tipped guide wire was advanced proximal to the fracture site, until significant resistance was met. With the aid of intraoperative fluoroscopic imaging, it was determined that the distal fibula fracture segment was entrapped in the medullary canal of the proximal tibia (Figure 2).

Closed reduction and removal of the fibula fragment were attempted multiple times, to no avail. A limited open approach was deemed necessary, and an incision was made anterior to the fracture site. The soft tissue over the fracture segment was bluntly dissected until the point of intussusception was palpated and visualized. A bone hook was used to dislodge the fibula from the tibial diaphysis (Figure 3).

After the fibula was liberated, additional closed manipulative reduction techniques were used on the tibia to restore length, alignment, and rotation, and an appropriately sized nail was advanced distally past the fracture segment and fixed with interlocking screws proximally and distally (Figure 4).

The postoperative course was uncomplicated. At most recent follow-up, radiographs showed near anatomical alignment, and the patient was back to normal activities without use of any pain medication or assistive device.

Discussion

Although other irreducible tibia fracture patterns have been described, midshaft tibia fracture irreducibility caused by entrapment of the fibula within the intramedullary space was a previously unreported difficulty of this very common fracture. More commonly, irreducible tibia fractures are caused by entrapment of soft-tissue structures or fracture fragments.^3,4

There are no previous documented cases of fracture patterns in which one long bone telescopes into another. Although not previously reported as occurring traumatically, the fibula was previously used as a vascularized graft in the intramedullary canal of the tibia and elsewhere.

The most well described irreducible fracture-dislocation of the lower leg is the Bosworth type, in which the proximal fragment of the fibula becomes displaced behind the tibia at the ankle joint. In addition, because of the torsional nature of most ankle fractures and the multitude of accompanying soft-tissue structures crossing at the joint, entrapment leading to irreducibility has had several different causes. These soft-tissue entrapment injures are often difficult to distinguish on plain radiographs and require further definition by computed tomography.

The high-energy mechanism of injury we have described is thought to result from lateral translation of the upper portion of the leg with the foot and lower leg fixed in place. We can posit that momentary hypervarus angulation of the tibia and the fibula with subsequent spontaneous partial reduction caused by tissue elasticity could lead to this unique injury pattern.

Although this is the first reported case of entrapment of the fibula within the intramedullary canal of the tibia, the injury should be considered when difficult closed reductions are encountered. It was only after attempted reduction for intramedullary nailing in the operating room that the telescoping fibula and the irreducibility were identified, and open reduction performed. There were no soft-tissue or neurovascular complications, but, had there been, they could have become of urgent concern and altered treatment.

In this case report, we have described a unique fracture pattern that could cause significant morbidity if not appropriately identified and treated in a timely manner.

Am J Orthop. 2017;46(3):E160-E162. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

 

Take-Home Points

• Preoperative orthogonal radiographs need to be carefully scrutinized in irreducible fractures.
• Open reduction is often necessary when soft-tissue or bone is interposed in a fracture site.
• The fibula’s size and interosseous connection to the tibia can lead to entrapment.
• High-energy mechanisms can lead to significant deformity at time of injury, with spontaneous partial reduction prior to initial assessment.
• Consider intramedullary entrapment of adjacent long bones.

The tibia is the most commonly fractured long bone; each year, almost 500,000 tibia fractures occur in the United States alone.¹ Low-energy mechanisms of injury usually result from torsional forces and produce less comminuted fractures. Very high-energy injuries apply direct forces to the shin and are often highly comminuted or open, owing to the limited soft-tissue envelope. The extent of soft-tissue injury occurring with these fractures is the best predictor of the development of a complication, particularly nonunion or infection.¹ Low-energy closed fractures with limited comminution and sufficient cortical apposition may be treated with closed reduction and casting, but the most common treatment for tibial shaft fractures is intramedullary nailing.²

In the acute setting, closed reduction allows for temporization of soft tissues and prevention of further damage to neurovascular structures. Whether eventual treatment consists of casting or intramedullary fixation, closed reduction must first be achieved.

In this article, we report a unique case of tibial shaft fracture irreducibility caused by telescoping of the distal fibula within the proximal tibial diaphysis. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 23-year-old unrestrained driver of a tow truck rear-ended another vehicle at high speed (~45 mph) and became trapped in the vehicle. Extrication time was prolonged. The driver was brought to the emergency department at a level I trauma center, where he was found to have an obvious closed deformity of the right lower leg but remained neurovascularly intact. Radiographs showed a highly comminuted fracture of the right tibial and fibular midshaft with more than 100% medial displacement of the distal fragment (Figure 1).

Immediate closed reduction was performed in the emergency department, with the patient under sedation. The procedure improved gross realignment and reduced tension from the overlying soft tissue. Postreduction radiographs showed improved alignment that, with some displacement and angulation remaining, was deemed sufficient to temporize the injury until surgery the next morning.

The next morning, the patient was taken to the operating room for planned closed intramedullary nailing through a suprapatellar approach. After entry to the tibial medullary canal was obtained, a ball-tipped guide wire was advanced proximal to the fracture site, until significant resistance was met. With the aid of intraoperative fluoroscopic imaging, it was determined that the distal fibula fracture segment was entrapped in the medullary canal of the proximal tibia (Figure 2).

Closed reduction and removal of the fibula fragment were attempted multiple times, to no avail. A limited open approach was deemed necessary, and an incision was made anterior to the fracture site. The soft tissue over the fracture segment was bluntly dissected until the point of intussusception was palpated and visualized. A bone hook was used to dislodge the fibula from the tibial diaphysis (Figure 3).

After the fibula was liberated, additional closed manipulative reduction techniques were used on the tibia to restore length, alignment, and rotation, and an appropriately sized nail was advanced distally past the fracture segment and fixed with interlocking screws proximally and distally (Figure 4).

The postoperative course was uncomplicated. At most recent follow-up, radiographs showed near anatomical alignment, and the patient was back to normal activities without use of any pain medication or assistive device.

Discussion

Although other irreducible tibia fracture patterns have been described, midshaft tibia fracture irreducibility caused by entrapment of the fibula within the intramedullary space was a previously unreported difficulty of this very common fracture. More commonly, irreducible tibia fractures are caused by entrapment of soft-tissue structures or fracture fragments.^3,4

There are no previous documented cases of fracture patterns in which one long bone telescopes into another. Although not previously reported as occurring traumatically, the fibula was previously used as a vascularized graft in the intramedullary canal of the tibia and elsewhere.

The most well described irreducible fracture-dislocation of the lower leg is the Bosworth type, in which the proximal fragment of the fibula becomes displaced behind the tibia at the ankle joint. In addition, because of the torsional nature of most ankle fractures and the multitude of accompanying soft-tissue structures crossing at the joint, entrapment leading to irreducibility has had several different causes. These soft-tissue entrapment injures are often difficult to distinguish on plain radiographs and require further definition by computed tomography.

The high-energy mechanism of injury we have described is thought to result from lateral translation of the upper portion of the leg with the foot and lower leg fixed in place. We can posit that momentary hypervarus angulation of the tibia and the fibula with subsequent spontaneous partial reduction caused by tissue elasticity could lead to this unique injury pattern.

Although this is the first reported case of entrapment of the fibula within the intramedullary canal of the tibia, the injury should be considered when difficult closed reductions are encountered. It was only after attempted reduction for intramedullary nailing in the operating room that the telescoping fibula and the irreducibility were identified, and open reduction performed. There were no soft-tissue or neurovascular complications, but, had there been, they could have become of urgent concern and altered treatment.

In this case report, we have described a unique fracture pattern that could cause significant morbidity if not appropriately identified and treated in a timely manner.

Am J Orthop. 2017;46(3):E160-E162. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

 

Take-Home Points

• Preoperative orthogonal radiographs need to be carefully scrutinized in irreducible fractures.
• Open reduction is often necessary when soft-tissue or bone is interposed in a fracture site.
• The fibula’s size and interosseous connection to the tibia can lead to entrapment.
• High-energy mechanisms can lead to significant deformity at time of injury, with spontaneous partial reduction prior to initial assessment.
• Consider intramedullary entrapment of adjacent long bones.

The tibia is the most commonly fractured long bone; each year, almost 500,000 tibia fractures occur in the United States alone.¹ Low-energy mechanisms of injury usually result from torsional forces and produce less comminuted fractures. Very high-energy injuries apply direct forces to the shin and are often highly comminuted or open, owing to the limited soft-tissue envelope. The extent of soft-tissue injury occurring with these fractures is the best predictor of the development of a complication, particularly nonunion or infection.¹ Low-energy closed fractures with limited comminution and sufficient cortical apposition may be treated with closed reduction and casting, but the most common treatment for tibial shaft fractures is intramedullary nailing.²

In the acute setting, closed reduction allows for temporization of soft tissues and prevention of further damage to neurovascular structures. Whether eventual treatment consists of casting or intramedullary fixation, closed reduction must first be achieved.

In this article, we report a unique case of tibial shaft fracture irreducibility caused by telescoping of the distal fibula within the proximal tibial diaphysis. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 23-year-old unrestrained driver of a tow truck rear-ended another vehicle at high speed (~45 mph) and became trapped in the vehicle. Extrication time was prolonged. The driver was brought to the emergency department at a level I trauma center, where he was found to have an obvious closed deformity of the right lower leg but remained neurovascularly intact. Radiographs showed a highly comminuted fracture of the right tibial and fibular midshaft with more than 100% medial displacement of the distal fragment (Figure 1).

Immediate closed reduction was performed in the emergency department, with the patient under sedation. The procedure improved gross realignment and reduced tension from the overlying soft tissue. Postreduction radiographs showed improved alignment that, with some displacement and angulation remaining, was deemed sufficient to temporize the injury until surgery the next morning.

The next morning, the patient was taken to the operating room for planned closed intramedullary nailing through a suprapatellar approach. After entry to the tibial medullary canal was obtained, a ball-tipped guide wire was advanced proximal to the fracture site, until significant resistance was met. With the aid of intraoperative fluoroscopic imaging, it was determined that the distal fibula fracture segment was entrapped in the medullary canal of the proximal tibia (Figure 2).

Closed reduction and removal of the fibula fragment were attempted multiple times, to no avail. A limited open approach was deemed necessary, and an incision was made anterior to the fracture site. The soft tissue over the fracture segment was bluntly dissected until the point of intussusception was palpated and visualized. A bone hook was used to dislodge the fibula from the tibial diaphysis (Figure 3).

After the fibula was liberated, additional closed manipulative reduction techniques were used on the tibia to restore length, alignment, and rotation, and an appropriately sized nail was advanced distally past the fracture segment and fixed with interlocking screws proximally and distally (Figure 4).

The postoperative course was uncomplicated. At most recent follow-up, radiographs showed near anatomical alignment, and the patient was back to normal activities without use of any pain medication or assistive device.

Discussion

Although other irreducible tibia fracture patterns have been described, midshaft tibia fracture irreducibility caused by entrapment of the fibula within the intramedullary space was a previously unreported difficulty of this very common fracture. More commonly, irreducible tibia fractures are caused by entrapment of soft-tissue structures or fracture fragments.^3,4

There are no previous documented cases of fracture patterns in which one long bone telescopes into another. Although not previously reported as occurring traumatically, the fibula was previously used as a vascularized graft in the intramedullary canal of the tibia and elsewhere.

The most well described irreducible fracture-dislocation of the lower leg is the Bosworth type, in which the proximal fragment of the fibula becomes displaced behind the tibia at the ankle joint. In addition, because of the torsional nature of most ankle fractures and the multitude of accompanying soft-tissue structures crossing at the joint, entrapment leading to irreducibility has had several different causes. These soft-tissue entrapment injures are often difficult to distinguish on plain radiographs and require further definition by computed tomography.

The high-energy mechanism of injury we have described is thought to result from lateral translation of the upper portion of the leg with the foot and lower leg fixed in place. We can posit that momentary hypervarus angulation of the tibia and the fibula with subsequent spontaneous partial reduction caused by tissue elasticity could lead to this unique injury pattern.

Although this is the first reported case of entrapment of the fibula within the intramedullary canal of the tibia, the injury should be considered when difficult closed reductions are encountered. It was only after attempted reduction for intramedullary nailing in the operating room that the telescoping fibula and the irreducibility were identified, and open reduction performed. There were no soft-tissue or neurovascular complications, but, had there been, they could have become of urgent concern and altered treatment.

In this case report, we have described a unique fracture pattern that could cause significant morbidity if not appropriately identified and treated in a timely manner.

Am J Orthop. 2017;46(3):E160-E162. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

 

Pulmonary sarcomatoid carcinoma (PSC) is a rare histological subtype that has an aggressive course with average survival of 11-13 months.¹ In clinical practice, the possible presentations of this rare cancer are not widely known, resulting in a misdiagnosis. That is what happened with our patient, who presented with necrotizing cavitary lung lesion and soft tissue necrotizing lymphadenitis. The clinical picture was reminiscent of tuberculosis or granulomatosis with polyangiitis and was further confounded by negative computed-tomography (CT)-guided biopsy and bronchoscopy findings, which added to the delay in diagnosis. With the currently available knowledge, the diagnosis of PSC depends largely on evaluation of the surgically resected specimen, which in most cases is avoided until there is a high suspicion of PSC. Biopsy is not useful due to extensive necrosis, as will be seen in our case. Consequently, most of the data in the literature is based on case series of autopsy specimen, and the clinical characteristics of PSC remain unclear. The rarity of PSC has prevented its characterization in literature. We report here a rare presentation of PSC with necrotizing lung lesion, to add to the paucity of the current data.

Case presentation and summary

A 58-year-old homeless man presented to the Upstate University Hospital, Syracuse, New York, with a 25-pound weight loss during the previous month and associated productive cough and hemoptysis for a week and a painful mass in the nape of his neck. He denied any fever, chest pain, sick contacts, or joint pain. He had a history of about 40 pack-years of smoking, and his brother had recently been diagnosed with lung cancer. A tender fluctuant mass was detected in the nape of his neck on examination (Figure 1).

The patient had presented 9 months earlier with persistent cough and hemoptysis, and at that visit was found to have a cavitary lesion in the right lung measuring 2 cm (0.8 in). He had undergone a computed-tomograpghy (CT)-guided biopsy of the lesion, which had shown acute and chronic inflammation with fibrosis, and he had negative bronchoscopy findings. The patient tested negative for tuberculosis during the first visit but he left the hospital against the medical advice of the physicians and he was lost to follow-up until his re-presentation.

On physical examination at his re-presentation, the patient seemed cachectic, with a blood pressure of 94/62 mm of Hg. The mass in the nape of his neck was about 3 cm (1.2 in) long, with erythema of the surrounding skin (Figure 1). Bronchial breath sounds were heard in the right upper lobe of the lung, likely due to the underlying cavitary lesion (Figure 2).

Relevant lab findings included a negative HIV test and repeat AFB (acid-fast bacilli) sputum cultures. A CT-guided biopsy with contrast of the thorax showed an interval increase in the size of the cavitary lesion in the patient’s right upper lobe, now measuring about 10 cm (4 in). Also seen were multiple nodules elsewhere in both lungs, with the largest measuring 8 mm (0.3 in). A CT scan of the neck showed 3 cm cystic mass within the posterior subcutaneous soft tissue of the C3 level, confirming the examination finding of the neck mass (Figure 2) with peripheral enhancement and surrounding infiltrative changes, likely abscess or malignant lymph node versus necrotic infection. He underwent bronchoscopy, which again failed to reveal any endobronchial lesions. Bronchoalveolar lavage was sent for microbiological analysis, including AFB and fungus, but came back negative. Transbronchial biopsy cytology revealed fragments of tumor composed of large pleomorphic cells without glandular or squamous differentiation, within large areas of necrosis (Figure 3).

Immunohistochemical studies showed strong reactivity with cytokeratin CAM5.2 (Figure 4), weak and focal reactivity with cytokeratin AE1/AE3 (Figure 5), and lack of reactivity with CD20, CD3, CD30, S-100, MART-1, TTF-1 and p63, all findings consistent with sarcomatoid carcinoma.

The patient underwent fine-needle aspiration and drainage of the neck lesion and the culture grew mixed organisms. The results of a bone scan, which was done within a week, showed multiple foci of uptake in the ribs and cervical spine.

Given the patient’s advanced disease, he was started on palliative radiotherapy with radiosensitizing chemotherapy with carboplatin (target AUC 6) and paclitaxel (135 mg/m² over 24 hours). His symptoms of hemoptysis improved transiently after the first cycle, but he became hypotensive and drowsy during the second cycle of therapy, and the family decided to make the patient comfort care and withdraw all further treatment. He was discharged to hospice.

 

Discussion

PSC is a rare variant of non-small-cell carcinoma lung cancer, accounting for up to 0.4% of lung malignancy.¹ It was recently subtyped by the World Health Organization as a non-small cell lung carcinoma with certain amount of differentiation resembling sarcoma or containing elements of sarcoma.^2-4 It is not known why both elements co-exist in the tumor, but Franks and colleagues some theories have been postulated in the literature, including possible origin from a single, aberrant stem cell with progenies differentiating in two separate pathways.³

Sarcomatoid carcinoma consists of spectrum of tumors including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and blastoma.^3,4 It usually shows male preponderance, and association with smoking.³ The diagnosis commonly occurs in the sixth decade of life, except for pulmonary blastoma, which is more common in the fourth decade and with equal gender distribution.⁴

The presenting symptoms can be variable and nonspecific, but predominantly include chest pain, cough, hemoptysis, and/or weight loss.⁵ Radiologically, pulmonary sarcomatoid cancer presenting as a necrotizing cavitary lesion in the lung is a rare finding, seldom reported in the past.^6,7 The presentation in our case, with necrotizing lymphadenitis, was reminiscent of an infectious or autoimmune etiology such as tuberculosis or granulomatosis with polyangiitis. The presence of extensive necrosis in the lesion and the characteristic heterogeneity of the tumor had resulted in inconclusive biopsy findings during the previous presentation. In clinical practice, there is over-reliance on biopsy findings to make the distinction between cancer and other mimicking conditions. This is especially true for rare tumors such as PSC, which often results in misdiagnosis and a delay in administering the proper treatment.

Transbronchial biopsy in cases such as the present case, carries little benefit because the diagnosis depends on the site from which the biopsy is taken and whether the biopsied tissue is representative of the entire mass. The diagnosis can be suspected based on the clinical and radiological findings but confirmation requires a surgical resection to delineate the accurate cytology and architecture.^5,6,8 Huang and colleagues showed a misdiagnosis rate of PSC of >70% preoperatively.⁴ Resective surgery is feasible only in patients with high index of suspicion for a malignancy, which in most cases requires previous confirmation with a biopsy. The rarity of this cancer, its unusual presentations, and the lack of specific testing preclude early diagnosis and timely treatment of this fatal condition.

Initial treatment options for localized or with limited spread disease is resective surgery. The role of chemo- or radiation therapy is not known, but they have not previously shown promising results,^6,8 except in some cases when they are used as postoperative adjuvant chemotherapy⁴ or in bulky, locally invasive tumors.¹ The recurrence rate after surgery is very high, resulting in a poor 5-year survival rate.^1,8 Experimental therapies, such as antibodies that target epidermal growth factor receptor mutations, have not shown much success either.⁸ In conclusion, the outlook for patients with PSC with the current available knowledge and treatment protocols, is dismal.

Most of the current knowledge and data in the literature is based on cases from autopsy or early-stage surgical resections rather than on patients with advanced cancer.⁵ Moreover, the role of surgical resection in PSC is questionable, given the high recurrence rate. Subsequently, the clinical and pathological manifestations have yet to be well characterized.⁴ There has been advance with the publication of more studies recently. Cytokeratin markers such as CAM 5.2 and AE1/AE3 are commonly useful to support the diagnosis when suspected.³ Other markers, including the carcinoembryonic antigen, CD15, and thyroid transcription factor-1 may be variably positive, based on the differentiation of the cancer. Other exciting prospects in the study of PSC include the suggestion of a modified vimentin histologic score for better characterization of the cancer and the discovery of high platelet-derived growth factor receptor beta immunohistochemistry expression in PSC as a potential target for future therapy.

Conclusion

Pulmonary sarcomatoid lung cancer can present with a predominant necrotizing picture that mimics diseases such as tuberculosis. In such case, transbronchial biopsy carries little benefit because the diagnosis depends on whether the biopsied tissue is representative of the entire mass, often confounded by the extensive necrosis. More data is needed to determine prognostic factors and appropriate therapeutic strategies.

Pulmonary sarcomatoid carcinoma (PSC) is a rare histological subtype that has an aggressive course with average survival of 11-13 months.¹ In clinical practice, the possible presentations of this rare cancer are not widely known, resulting in a misdiagnosis. That is what happened with our patient, who presented with necrotizing cavitary lung lesion and soft tissue necrotizing lymphadenitis. The clinical picture was reminiscent of tuberculosis or granulomatosis with polyangiitis and was further confounded by negative computed-tomography (CT)-guided biopsy and bronchoscopy findings, which added to the delay in diagnosis. With the currently available knowledge, the diagnosis of PSC depends largely on evaluation of the surgically resected specimen, which in most cases is avoided until there is a high suspicion of PSC. Biopsy is not useful due to extensive necrosis, as will be seen in our case. Consequently, most of the data in the literature is based on case series of autopsy specimen, and the clinical characteristics of PSC remain unclear. The rarity of PSC has prevented its characterization in literature. We report here a rare presentation of PSC with necrotizing lung lesion, to add to the paucity of the current data.

Case presentation and summary

A 58-year-old homeless man presented to the Upstate University Hospital, Syracuse, New York, with a 25-pound weight loss during the previous month and associated productive cough and hemoptysis for a week and a painful mass in the nape of his neck. He denied any fever, chest pain, sick contacts, or joint pain. He had a history of about 40 pack-years of smoking, and his brother had recently been diagnosed with lung cancer. A tender fluctuant mass was detected in the nape of his neck on examination (Figure 1).

The patient had presented 9 months earlier with persistent cough and hemoptysis, and at that visit was found to have a cavitary lesion in the right lung measuring 2 cm (0.8 in). He had undergone a computed-tomograpghy (CT)-guided biopsy of the lesion, which had shown acute and chronic inflammation with fibrosis, and he had negative bronchoscopy findings. The patient tested negative for tuberculosis during the first visit but he left the hospital against the medical advice of the physicians and he was lost to follow-up until his re-presentation.

On physical examination at his re-presentation, the patient seemed cachectic, with a blood pressure of 94/62 mm of Hg. The mass in the nape of his neck was about 3 cm (1.2 in) long, with erythema of the surrounding skin (Figure 1). Bronchial breath sounds were heard in the right upper lobe of the lung, likely due to the underlying cavitary lesion (Figure 2).

Relevant lab findings included a negative HIV test and repeat AFB (acid-fast bacilli) sputum cultures. A CT-guided biopsy with contrast of the thorax showed an interval increase in the size of the cavitary lesion in the patient’s right upper lobe, now measuring about 10 cm (4 in). Also seen were multiple nodules elsewhere in both lungs, with the largest measuring 8 mm (0.3 in). A CT scan of the neck showed 3 cm cystic mass within the posterior subcutaneous soft tissue of the C3 level, confirming the examination finding of the neck mass (Figure 2) with peripheral enhancement and surrounding infiltrative changes, likely abscess or malignant lymph node versus necrotic infection. He underwent bronchoscopy, which again failed to reveal any endobronchial lesions. Bronchoalveolar lavage was sent for microbiological analysis, including AFB and fungus, but came back negative. Transbronchial biopsy cytology revealed fragments of tumor composed of large pleomorphic cells without glandular or squamous differentiation, within large areas of necrosis (Figure 3).

Immunohistochemical studies showed strong reactivity with cytokeratin CAM5.2 (Figure 4), weak and focal reactivity with cytokeratin AE1/AE3 (Figure 5), and lack of reactivity with CD20, CD3, CD30, S-100, MART-1, TTF-1 and p63, all findings consistent with sarcomatoid carcinoma.

The patient underwent fine-needle aspiration and drainage of the neck lesion and the culture grew mixed organisms. The results of a bone scan, which was done within a week, showed multiple foci of uptake in the ribs and cervical spine.

Given the patient’s advanced disease, he was started on palliative radiotherapy with radiosensitizing chemotherapy with carboplatin (target AUC 6) and paclitaxel (135 mg/m² over 24 hours). His symptoms of hemoptysis improved transiently after the first cycle, but he became hypotensive and drowsy during the second cycle of therapy, and the family decided to make the patient comfort care and withdraw all further treatment. He was discharged to hospice.

 

Discussion

PSC is a rare variant of non-small-cell carcinoma lung cancer, accounting for up to 0.4% of lung malignancy.¹ It was recently subtyped by the World Health Organization as a non-small cell lung carcinoma with certain amount of differentiation resembling sarcoma or containing elements of sarcoma.^2-4 It is not known why both elements co-exist in the tumor, but Franks and colleagues some theories have been postulated in the literature, including possible origin from a single, aberrant stem cell with progenies differentiating in two separate pathways.³

Sarcomatoid carcinoma consists of spectrum of tumors including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and blastoma.^3,4 It usually shows male preponderance, and association with smoking.³ The diagnosis commonly occurs in the sixth decade of life, except for pulmonary blastoma, which is more common in the fourth decade and with equal gender distribution.⁴

The presenting symptoms can be variable and nonspecific, but predominantly include chest pain, cough, hemoptysis, and/or weight loss.⁵ Radiologically, pulmonary sarcomatoid cancer presenting as a necrotizing cavitary lesion in the lung is a rare finding, seldom reported in the past.^6,7 The presentation in our case, with necrotizing lymphadenitis, was reminiscent of an infectious or autoimmune etiology such as tuberculosis or granulomatosis with polyangiitis. The presence of extensive necrosis in the lesion and the characteristic heterogeneity of the tumor had resulted in inconclusive biopsy findings during the previous presentation. In clinical practice, there is over-reliance on biopsy findings to make the distinction between cancer and other mimicking conditions. This is especially true for rare tumors such as PSC, which often results in misdiagnosis and a delay in administering the proper treatment.

Transbronchial biopsy in cases such as the present case, carries little benefit because the diagnosis depends on the site from which the biopsy is taken and whether the biopsied tissue is representative of the entire mass. The diagnosis can be suspected based on the clinical and radiological findings but confirmation requires a surgical resection to delineate the accurate cytology and architecture.^5,6,8 Huang and colleagues showed a misdiagnosis rate of PSC of >70% preoperatively.⁴ Resective surgery is feasible only in patients with high index of suspicion for a malignancy, which in most cases requires previous confirmation with a biopsy. The rarity of this cancer, its unusual presentations, and the lack of specific testing preclude early diagnosis and timely treatment of this fatal condition.

Initial treatment options for localized or with limited spread disease is resective surgery. The role of chemo- or radiation therapy is not known, but they have not previously shown promising results,^6,8 except in some cases when they are used as postoperative adjuvant chemotherapy⁴ or in bulky, locally invasive tumors.¹ The recurrence rate after surgery is very high, resulting in a poor 5-year survival rate.^1,8 Experimental therapies, such as antibodies that target epidermal growth factor receptor mutations, have not shown much success either.⁸ In conclusion, the outlook for patients with PSC with the current available knowledge and treatment protocols, is dismal.

Most of the current knowledge and data in the literature is based on cases from autopsy or early-stage surgical resections rather than on patients with advanced cancer.⁵ Moreover, the role of surgical resection in PSC is questionable, given the high recurrence rate. Subsequently, the clinical and pathological manifestations have yet to be well characterized.⁴ There has been advance with the publication of more studies recently. Cytokeratin markers such as CAM 5.2 and AE1/AE3 are commonly useful to support the diagnosis when suspected.³ Other markers, including the carcinoembryonic antigen, CD15, and thyroid transcription factor-1 may be variably positive, based on the differentiation of the cancer. Other exciting prospects in the study of PSC include the suggestion of a modified vimentin histologic score for better characterization of the cancer and the discovery of high platelet-derived growth factor receptor beta immunohistochemistry expression in PSC as a potential target for future therapy.

Conclusion

Pulmonary sarcomatoid lung cancer can present with a predominant necrotizing picture that mimics diseases such as tuberculosis. In such case, transbronchial biopsy carries little benefit because the diagnosis depends on whether the biopsied tissue is representative of the entire mass, often confounded by the extensive necrosis. More data is needed to determine prognostic factors and appropriate therapeutic strategies.

Pulmonary sarcomatoid carcinoma (PSC) is a rare histological subtype that has an aggressive course with average survival of 11-13 months.¹ In clinical practice, the possible presentations of this rare cancer are not widely known, resulting in a misdiagnosis. That is what happened with our patient, who presented with necrotizing cavitary lung lesion and soft tissue necrotizing lymphadenitis. The clinical picture was reminiscent of tuberculosis or granulomatosis with polyangiitis and was further confounded by negative computed-tomography (CT)-guided biopsy and bronchoscopy findings, which added to the delay in diagnosis. With the currently available knowledge, the diagnosis of PSC depends largely on evaluation of the surgically resected specimen, which in most cases is avoided until there is a high suspicion of PSC. Biopsy is not useful due to extensive necrosis, as will be seen in our case. Consequently, most of the data in the literature is based on case series of autopsy specimen, and the clinical characteristics of PSC remain unclear. The rarity of PSC has prevented its characterization in literature. We report here a rare presentation of PSC with necrotizing lung lesion, to add to the paucity of the current data.

Case presentation and summary

A 58-year-old homeless man presented to the Upstate University Hospital, Syracuse, New York, with a 25-pound weight loss during the previous month and associated productive cough and hemoptysis for a week and a painful mass in the nape of his neck. He denied any fever, chest pain, sick contacts, or joint pain. He had a history of about 40 pack-years of smoking, and his brother had recently been diagnosed with lung cancer. A tender fluctuant mass was detected in the nape of his neck on examination (Figure 1).

The patient had presented 9 months earlier with persistent cough and hemoptysis, and at that visit was found to have a cavitary lesion in the right lung measuring 2 cm (0.8 in). He had undergone a computed-tomograpghy (CT)-guided biopsy of the lesion, which had shown acute and chronic inflammation with fibrosis, and he had negative bronchoscopy findings. The patient tested negative for tuberculosis during the first visit but he left the hospital against the medical advice of the physicians and he was lost to follow-up until his re-presentation.

On physical examination at his re-presentation, the patient seemed cachectic, with a blood pressure of 94/62 mm of Hg. The mass in the nape of his neck was about 3 cm (1.2 in) long, with erythema of the surrounding skin (Figure 1). Bronchial breath sounds were heard in the right upper lobe of the lung, likely due to the underlying cavitary lesion (Figure 2).

Relevant lab findings included a negative HIV test and repeat AFB (acid-fast bacilli) sputum cultures. A CT-guided biopsy with contrast of the thorax showed an interval increase in the size of the cavitary lesion in the patient’s right upper lobe, now measuring about 10 cm (4 in). Also seen were multiple nodules elsewhere in both lungs, with the largest measuring 8 mm (0.3 in). A CT scan of the neck showed 3 cm cystic mass within the posterior subcutaneous soft tissue of the C3 level, confirming the examination finding of the neck mass (Figure 2) with peripheral enhancement and surrounding infiltrative changes, likely abscess or malignant lymph node versus necrotic infection. He underwent bronchoscopy, which again failed to reveal any endobronchial lesions. Bronchoalveolar lavage was sent for microbiological analysis, including AFB and fungus, but came back negative. Transbronchial biopsy cytology revealed fragments of tumor composed of large pleomorphic cells without glandular or squamous differentiation, within large areas of necrosis (Figure 3).

Immunohistochemical studies showed strong reactivity with cytokeratin CAM5.2 (Figure 4), weak and focal reactivity with cytokeratin AE1/AE3 (Figure 5), and lack of reactivity with CD20, CD3, CD30, S-100, MART-1, TTF-1 and p63, all findings consistent with sarcomatoid carcinoma.

The patient underwent fine-needle aspiration and drainage of the neck lesion and the culture grew mixed organisms. The results of a bone scan, which was done within a week, showed multiple foci of uptake in the ribs and cervical spine.

Given the patient’s advanced disease, he was started on palliative radiotherapy with radiosensitizing chemotherapy with carboplatin (target AUC 6) and paclitaxel (135 mg/m² over 24 hours). His symptoms of hemoptysis improved transiently after the first cycle, but he became hypotensive and drowsy during the second cycle of therapy, and the family decided to make the patient comfort care and withdraw all further treatment. He was discharged to hospice.

 

Discussion

PSC is a rare variant of non-small-cell carcinoma lung cancer, accounting for up to 0.4% of lung malignancy.¹ It was recently subtyped by the World Health Organization as a non-small cell lung carcinoma with certain amount of differentiation resembling sarcoma or containing elements of sarcoma.^2-4 It is not known why both elements co-exist in the tumor, but Franks and colleagues some theories have been postulated in the literature, including possible origin from a single, aberrant stem cell with progenies differentiating in two separate pathways.³

Sarcomatoid carcinoma consists of spectrum of tumors including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and blastoma.^3,4 It usually shows male preponderance, and association with smoking.³ The diagnosis commonly occurs in the sixth decade of life, except for pulmonary blastoma, which is more common in the fourth decade and with equal gender distribution.⁴

The presenting symptoms can be variable and nonspecific, but predominantly include chest pain, cough, hemoptysis, and/or weight loss.⁵ Radiologically, pulmonary sarcomatoid cancer presenting as a necrotizing cavitary lesion in the lung is a rare finding, seldom reported in the past.^6,7 The presentation in our case, with necrotizing lymphadenitis, was reminiscent of an infectious or autoimmune etiology such as tuberculosis or granulomatosis with polyangiitis. The presence of extensive necrosis in the lesion and the characteristic heterogeneity of the tumor had resulted in inconclusive biopsy findings during the previous presentation. In clinical practice, there is over-reliance on biopsy findings to make the distinction between cancer and other mimicking conditions. This is especially true for rare tumors such as PSC, which often results in misdiagnosis and a delay in administering the proper treatment.

Transbronchial biopsy in cases such as the present case, carries little benefit because the diagnosis depends on the site from which the biopsy is taken and whether the biopsied tissue is representative of the entire mass. The diagnosis can be suspected based on the clinical and radiological findings but confirmation requires a surgical resection to delineate the accurate cytology and architecture.^5,6,8 Huang and colleagues showed a misdiagnosis rate of PSC of >70% preoperatively.⁴ Resective surgery is feasible only in patients with high index of suspicion for a malignancy, which in most cases requires previous confirmation with a biopsy. The rarity of this cancer, its unusual presentations, and the lack of specific testing preclude early diagnosis and timely treatment of this fatal condition.

Initial treatment options for localized or with limited spread disease is resective surgery. The role of chemo- or radiation therapy is not known, but they have not previously shown promising results,^6,8 except in some cases when they are used as postoperative adjuvant chemotherapy⁴ or in bulky, locally invasive tumors.¹ The recurrence rate after surgery is very high, resulting in a poor 5-year survival rate.^1,8 Experimental therapies, such as antibodies that target epidermal growth factor receptor mutations, have not shown much success either.⁸ In conclusion, the outlook for patients with PSC with the current available knowledge and treatment protocols, is dismal.

Most of the current knowledge and data in the literature is based on cases from autopsy or early-stage surgical resections rather than on patients with advanced cancer.⁵ Moreover, the role of surgical resection in PSC is questionable, given the high recurrence rate. Subsequently, the clinical and pathological manifestations have yet to be well characterized.⁴ There has been advance with the publication of more studies recently. Cytokeratin markers such as CAM 5.2 and AE1/AE3 are commonly useful to support the diagnosis when suspected.³ Other markers, including the carcinoembryonic antigen, CD15, and thyroid transcription factor-1 may be variably positive, based on the differentiation of the cancer. Other exciting prospects in the study of PSC include the suggestion of a modified vimentin histologic score for better characterization of the cancer and the discovery of high platelet-derived growth factor receptor beta immunohistochemistry expression in PSC as a potential target for future therapy.

Conclusion

Pulmonary sarcomatoid lung cancer can present with a predominant necrotizing picture that mimics diseases such as tuberculosis. In such case, transbronchial biopsy carries little benefit because the diagnosis depends on whether the biopsied tissue is representative of the entire mass, often confounded by the extensive necrosis. More data is needed to determine prognostic factors and appropriate therapeutic strategies.

Nivolumab is a full human immunoglobulin antibody to the programmed cell death 1 (PD-1) immune checkpoint receptor on T cells. This programmed cell death inhibitor is a targeted immunotherapy used to treat patients with melanoma, among other malignancies.¹ More recently, nivolumab has been used for advanced non-small-cell lung cancer (NSCLC) after failure of previous chemotherapeutic agents. It was approved by the US Food and Drug Administration for the NSCLC indication in 2015.²

PD-1 inhibitors are efficacious in treating advanced malignancies, although their immune-mediated functions can lead to undesirable side effects. Patients treated with nivolumab have been reported to develop thyroid disease,^1,3,4 diabetes,³ hypophysitis,^1,3 hypopituitarism,³ and pneumonitis,^4,2 as well as other autoimmune conditions.³ Although nivolumab is often used to treat skin diseases such as melanoma, it can have many cutaneous side effects including pruritus,^1,3-6 rash,^1,3,4,6,7 vitiligo,^1,3,7,6 mouth sores,³ injection site reactions,^3,6 and alopecia.⁵ Herein, we describe a patient who was treated with nivolumab and developed an exacerbation of pre-existing psoriasis.

Case presentation and summary

A 57-year-old man with metastatic NSCLC and a history of plaque psoriasis presented to the dermatology clinic for evaluation of new lesions on his palms and soles. The patient had been previously treated with numerous therapies for NSCLC, including chemotherapy and radiation. Previous chemotherapeutic agents included the cisplatin plus etoposide combination, with doxetaxel and pemetrexed. The patient was not able to tolerate the chemotherapy and instead opted for hospice care. After several months, he chose to restart therapy, and was started on the programmed cell death (PD)-1 inhibitor, nivolumab, at a dose of 3 mg/kg for a total of 6 cycles. He received his first dose 5 weeks before his current presentation to the clinic, and his second dose 2 weeks before.

The patient reported a 20-year history of plaque psoriasis, characterized by psoriatic plaques on the elbows and shins and for which he was treated with topical therapies with good effect. Every few months, he would develop one or two small plaques of psoriasis on his palms and soles. The lesions were inconsequential to the patient, as he never experienced more than one or two small palmoplantar lesions at a time. One week after his second cycle of nivolumab, the patient developed an eruption of lesions on his palms and soles. He observed that the lesions seemed to be similar to his previous palmoplantar psoriatic plaques but with significantly greater skin involvement. The patient denied any new-onset joint pain.

The results of a physical examination revealed a cachectic man in no acute distress, with more than 30 erythematous circular to oval circumscribed plaques with yellow to whitish scales on the bilateral palms (Figure 1) and soles (Figure 2).

The patient also had well-demarcated, thick oval erythematous plaques with micaceous scales on the bilateral elbows (Figure 3), and thin scaly erythematous plaques on the anterior shins (Figure 4). There were no psoriatic plaques on the remainder of the trunk or extremities. Mucosal surfaces, scalp, and nails were uninvolved.

A clinical diagnosis of exacerbation of pre-existing psoriasis owing to nivolumab therapy was made. The patient was started on clobetasol 0.05% ointment twice daily under occlusion with plastic wrap to the affected areas, and he was continued on nivolumab for his NSCLC.

Discussion

Treatment with nivolumab can lead to a range of autoimmune side effects, and as shown in this case, psoriasis is one of the cutaneous findings that could be exacerbated by treatment with nivolumab. To date, two cases of exacerbation of psoriasis in patients treated with nivolumab for melanoma have been reported in the literature.^8,9 In the first case, the patient had well-controlled plaque psoriasis at baseline and he subsequently developed psoriatic plaques on the trunk and extremities after the second infusion of nivolumab for metastatic melanoma. A biopsy showed regular acanthosis with hyperkeratosis and parakeratosis in addition to dilated vessels in the papillary dermis.⁸ In the second case, the patient had a history of psoriasis vulgaris with no active lesions. Three weeks after his first course of nivolumab for metastatic oral mucosal melanoma, he developed new, well-circumscribed erythematous scaly plaques on the trunk and extremities that were clinically diagnosed as psoriasis.⁹ In a third case, a patient without a prior history of psoriasis experienced a psoriasiform eruption on the trunk and extremities after the fourth dose of nivolumab for oral mucosal melanoma.¹⁰ Thus, our case is the third reported case of exacerbation of preexisting psoriasis in a patient treated with nivolumab. Furthermore, our patient is the first reported case of a patient treated with nivolumab for NSCLC to develop this adverse event. Whereas the previously reported cases were characterized by widespread trunk and extremity involvement, our patient developed focal exacerbation of the palmoplantar areas.

 

Additional studies are needed to more clearly characterize the specific cutaneous toxicities of nivolumab and to determine if particular skin reactions may indicate a better response to the anticancer agent. Side effects such as psoriasis can often be managed with topical therapies and may not require withdrawal of the medication. We encourage the collaboration of dermatologists and oncologists to enhance the diagnosis and management of these cutaneous side effects in cancer patients.

Nivolumab is a full human immunoglobulin antibody to the programmed cell death 1 (PD-1) immune checkpoint receptor on T cells. This programmed cell death inhibitor is a targeted immunotherapy used to treat patients with melanoma, among other malignancies.¹ More recently, nivolumab has been used for advanced non-small-cell lung cancer (NSCLC) after failure of previous chemotherapeutic agents. It was approved by the US Food and Drug Administration for the NSCLC indication in 2015.²

PD-1 inhibitors are efficacious in treating advanced malignancies, although their immune-mediated functions can lead to undesirable side effects. Patients treated with nivolumab have been reported to develop thyroid disease,^1,3,4 diabetes,³ hypophysitis,^1,3 hypopituitarism,³ and pneumonitis,^4,2 as well as other autoimmune conditions.³ Although nivolumab is often used to treat skin diseases such as melanoma, it can have many cutaneous side effects including pruritus,^1,3-6 rash,^1,3,4,6,7 vitiligo,^1,3,7,6 mouth sores,³ injection site reactions,^3,6 and alopecia.⁵ Herein, we describe a patient who was treated with nivolumab and developed an exacerbation of pre-existing psoriasis.

Case presentation and summary

A 57-year-old man with metastatic NSCLC and a history of plaque psoriasis presented to the dermatology clinic for evaluation of new lesions on his palms and soles. The patient had been previously treated with numerous therapies for NSCLC, including chemotherapy and radiation. Previous chemotherapeutic agents included the cisplatin plus etoposide combination, with doxetaxel and pemetrexed. The patient was not able to tolerate the chemotherapy and instead opted for hospice care. After several months, he chose to restart therapy, and was started on the programmed cell death (PD)-1 inhibitor, nivolumab, at a dose of 3 mg/kg for a total of 6 cycles. He received his first dose 5 weeks before his current presentation to the clinic, and his second dose 2 weeks before.

The patient reported a 20-year history of plaque psoriasis, characterized by psoriatic plaques on the elbows and shins and for which he was treated with topical therapies with good effect. Every few months, he would develop one or two small plaques of psoriasis on his palms and soles. The lesions were inconsequential to the patient, as he never experienced more than one or two small palmoplantar lesions at a time. One week after his second cycle of nivolumab, the patient developed an eruption of lesions on his palms and soles. He observed that the lesions seemed to be similar to his previous palmoplantar psoriatic plaques but with significantly greater skin involvement. The patient denied any new-onset joint pain.

The results of a physical examination revealed a cachectic man in no acute distress, with more than 30 erythematous circular to oval circumscribed plaques with yellow to whitish scales on the bilateral palms (Figure 1) and soles (Figure 2).

The patient also had well-demarcated, thick oval erythematous plaques with micaceous scales on the bilateral elbows (Figure 3), and thin scaly erythematous plaques on the anterior shins (Figure 4). There were no psoriatic plaques on the remainder of the trunk or extremities. Mucosal surfaces, scalp, and nails were uninvolved.

A clinical diagnosis of exacerbation of pre-existing psoriasis owing to nivolumab therapy was made. The patient was started on clobetasol 0.05% ointment twice daily under occlusion with plastic wrap to the affected areas, and he was continued on nivolumab for his NSCLC.

Discussion

Treatment with nivolumab can lead to a range of autoimmune side effects, and as shown in this case, psoriasis is one of the cutaneous findings that could be exacerbated by treatment with nivolumab. To date, two cases of exacerbation of psoriasis in patients treated with nivolumab for melanoma have been reported in the literature.^8,9 In the first case, the patient had well-controlled plaque psoriasis at baseline and he subsequently developed psoriatic plaques on the trunk and extremities after the second infusion of nivolumab for metastatic melanoma. A biopsy showed regular acanthosis with hyperkeratosis and parakeratosis in addition to dilated vessels in the papillary dermis.⁸ In the second case, the patient had a history of psoriasis vulgaris with no active lesions. Three weeks after his first course of nivolumab for metastatic oral mucosal melanoma, he developed new, well-circumscribed erythematous scaly plaques on the trunk and extremities that were clinically diagnosed as psoriasis.⁹ In a third case, a patient without a prior history of psoriasis experienced a psoriasiform eruption on the trunk and extremities after the fourth dose of nivolumab for oral mucosal melanoma.¹⁰ Thus, our case is the third reported case of exacerbation of preexisting psoriasis in a patient treated with nivolumab. Furthermore, our patient is the first reported case of a patient treated with nivolumab for NSCLC to develop this adverse event. Whereas the previously reported cases were characterized by widespread trunk and extremity involvement, our patient developed focal exacerbation of the palmoplantar areas.

 

Additional studies are needed to more clearly characterize the specific cutaneous toxicities of nivolumab and to determine if particular skin reactions may indicate a better response to the anticancer agent. Side effects such as psoriasis can often be managed with topical therapies and may not require withdrawal of the medication. We encourage the collaboration of dermatologists and oncologists to enhance the diagnosis and management of these cutaneous side effects in cancer patients.

Nivolumab is a full human immunoglobulin antibody to the programmed cell death 1 (PD-1) immune checkpoint receptor on T cells. This programmed cell death inhibitor is a targeted immunotherapy used to treat patients with melanoma, among other malignancies.¹ More recently, nivolumab has been used for advanced non-small-cell lung cancer (NSCLC) after failure of previous chemotherapeutic agents. It was approved by the US Food and Drug Administration for the NSCLC indication in 2015.²

PD-1 inhibitors are efficacious in treating advanced malignancies, although their immune-mediated functions can lead to undesirable side effects. Patients treated with nivolumab have been reported to develop thyroid disease,^1,3,4 diabetes,³ hypophysitis,^1,3 hypopituitarism,³ and pneumonitis,^4,2 as well as other autoimmune conditions.³ Although nivolumab is often used to treat skin diseases such as melanoma, it can have many cutaneous side effects including pruritus,^1,3-6 rash,^1,3,4,6,7 vitiligo,^1,3,7,6 mouth sores,³ injection site reactions,^3,6 and alopecia.⁵ Herein, we describe a patient who was treated with nivolumab and developed an exacerbation of pre-existing psoriasis.

Case presentation and summary

A 57-year-old man with metastatic NSCLC and a history of plaque psoriasis presented to the dermatology clinic for evaluation of new lesions on his palms and soles. The patient had been previously treated with numerous therapies for NSCLC, including chemotherapy and radiation. Previous chemotherapeutic agents included the cisplatin plus etoposide combination, with doxetaxel and pemetrexed. The patient was not able to tolerate the chemotherapy and instead opted for hospice care. After several months, he chose to restart therapy, and was started on the programmed cell death (PD)-1 inhibitor, nivolumab, at a dose of 3 mg/kg for a total of 6 cycles. He received his first dose 5 weeks before his current presentation to the clinic, and his second dose 2 weeks before.

The patient reported a 20-year history of plaque psoriasis, characterized by psoriatic plaques on the elbows and shins and for which he was treated with topical therapies with good effect. Every few months, he would develop one or two small plaques of psoriasis on his palms and soles. The lesions were inconsequential to the patient, as he never experienced more than one or two small palmoplantar lesions at a time. One week after his second cycle of nivolumab, the patient developed an eruption of lesions on his palms and soles. He observed that the lesions seemed to be similar to his previous palmoplantar psoriatic plaques but with significantly greater skin involvement. The patient denied any new-onset joint pain.

The results of a physical examination revealed a cachectic man in no acute distress, with more than 30 erythematous circular to oval circumscribed plaques with yellow to whitish scales on the bilateral palms (Figure 1) and soles (Figure 2).

The patient also had well-demarcated, thick oval erythematous plaques with micaceous scales on the bilateral elbows (Figure 3), and thin scaly erythematous plaques on the anterior shins (Figure 4). There were no psoriatic plaques on the remainder of the trunk or extremities. Mucosal surfaces, scalp, and nails were uninvolved.

A clinical diagnosis of exacerbation of pre-existing psoriasis owing to nivolumab therapy was made. The patient was started on clobetasol 0.05% ointment twice daily under occlusion with plastic wrap to the affected areas, and he was continued on nivolumab for his NSCLC.

Discussion

Treatment with nivolumab can lead to a range of autoimmune side effects, and as shown in this case, psoriasis is one of the cutaneous findings that could be exacerbated by treatment with nivolumab. To date, two cases of exacerbation of psoriasis in patients treated with nivolumab for melanoma have been reported in the literature.^8,9 In the first case, the patient had well-controlled plaque psoriasis at baseline and he subsequently developed psoriatic plaques on the trunk and extremities after the second infusion of nivolumab for metastatic melanoma. A biopsy showed regular acanthosis with hyperkeratosis and parakeratosis in addition to dilated vessels in the papillary dermis.⁸ In the second case, the patient had a history of psoriasis vulgaris with no active lesions. Three weeks after his first course of nivolumab for metastatic oral mucosal melanoma, he developed new, well-circumscribed erythematous scaly plaques on the trunk and extremities that were clinically diagnosed as psoriasis.⁹ In a third case, a patient without a prior history of psoriasis experienced a psoriasiform eruption on the trunk and extremities after the fourth dose of nivolumab for oral mucosal melanoma.¹⁰ Thus, our case is the third reported case of exacerbation of preexisting psoriasis in a patient treated with nivolumab. Furthermore, our patient is the first reported case of a patient treated with nivolumab for NSCLC to develop this adverse event. Whereas the previously reported cases were characterized by widespread trunk and extremity involvement, our patient developed focal exacerbation of the palmoplantar areas.

 

Additional studies are needed to more clearly characterize the specific cutaneous toxicities of nivolumab and to determine if particular skin reactions may indicate a better response to the anticancer agent. Side effects such as psoriasis can often be managed with topical therapies and may not require withdrawal of the medication. We encourage the collaboration of dermatologists and oncologists to enhance the diagnosis and management of these cutaneous side effects in cancer patients.

Age-related macular degeneration (AMD) is a common condition that affects the elderly white population. About 6.5% of Americans have been diagnosed with AMD, and 0.8% have received an end-stage AMD diagnosis.¹ Exudative AMD is typically more visually debilitating and comprises between 10% and 15% of all AMD cases, with conversion from dry to wet about 10%.¹

A thorough examination of the posterior pole is of utmost importance in patients with dry AMD in order to ensure there is no conversion to the exudative form. However, it also is imperative to perform a peripheral evaluation in these patients due to the incidence of peripheral choroidal neovascular membrane (CNVM) and its potential visual significance.

Case Report 1

An 80-year-old white male with type 2 diabetes mellitus (DM) without retinopathy, dry AMD, and epiretinal membranes (ERM) in both eyes presented to the eye clinic for a 6-month follow-up. On examination, he had visual acuity (VA) of 20/25 in both eyes and reported no ocular problems. The intraocular pressures were 17 mm Hg in the right eye and 20 mm Hg in the left eye. Slit-lamp examination of the anterior segment of both eyes was significant for 2+ nuclear sclerotic cataracts.

On dilated fundus exam, there were macular drusen and ERM in both eyes; peripherally in the right eye, there was cobblestone degeneration and pigmentary changes. Peripherally in the left eye, there was a large retinal pigment epithelial detachment (PED) with subretinal hemorrhage in the inferior temporal quadrant (Figure 1) along with cobblestone degeneration and pigmentary changes. Peripheral optical coherence tomography (OCT) in the left eye showed a large PED in the location of the hemorrhage (Figure 2).

 

Case Report 2

An 88-year-old white male presented to the eye clinic reporting blurred vision at distance and dry eyes. The patient’s medical history was remarkable for vascular and heart disease, treated with warfarin. The patient also had insulin controlled DM, with no prior history of retinopathy. His past ocular history included hard drusen in the macula, peripheral drusen, pavingstone degeneration, and a fibrotic scar temporally in the right eye.

At his annual eye examination, the patient’s vision was correctable to 20/25 in both eyes. His anterior segment slit-lamp exam was remarkable for posterior chamber intraocular lenses, clear and centered in each eye. His posterior pole exam was remarkable for small hard drusen at the macula in both eyes. Peripherally in the right eye, there was a large disciform fibrotic scar temporally (Figure 3) as well as cobblestone degeneration and peripheral drusen. The left eye revealed a large disciform hemorrhage temporally (Figure 4) with cobblestone degeneration and peripheral drusen.

Both patients currently are being closely monitored for any encroachment of the peripheral lesions into the posterior poles.

Discussion

Peripheral exudative hemorrhagic chorioretinopathy (PEHCR), also referred to in the literature as eccentric disciform CNVM, peripheral CNVM, and peripheral age-related degeneration, is a rare condition more prevalent in elderly white females.^2-4 Mean age ranges from 70 to 82 years, with bilateral involvement ranging from 18% to 37%.^2-4 The mid-periphery or periphery is the most common location for these lesions, more specifically, in the inferior temporal quadrant.^2,3,5,6

Age-related macular degeneration is not pathognomonic for PEHCR. Mantel and colleagues reported that 68.9% of the patients in their study had AMD.³ Visual acuity ranges from 20/20 to light perception, dependent upon ocular comorbidities.^2,3 As reported by Mantel and colleagues, patients with symptomatic PEHCR commonly experience visual loss, floaters, photopsias, metamorphopsia, and scotoma.³

Peripheral exudative hemorrhagic chorioretinopathy is a hemorrhagic or exudative process that can occur either as an isolated lesion or as multiple lesions that consist of a PED along with hemorrhage, subretinal fluid and/or fibrotic scarring.^2-5 Peripheral exudative hemorrhagic chorioretinopathy is not visually significant unless a vitreous hemorrhage is evident or the blood and/or fluid extends to the macular region.^2,5

The exact etiology of peripheral CNVM remains unknown; however, ischemia, mechanical forces, and defects in Bruch’s membrane all have been speculated as causative factors.^2,3,6 Others have hypothesized that PEHCR is a form of polypoidal choroidal vasculopathy.^3,7,8 A rupture in Bruch’s membrane with a vascular complex contributes to the pathophysiology and histology of this condition.^3,6

Given the propensity for cardiovascular diseases, such as DM and hypertension, to lead to retinal ischemia, it is important to take a good case history.^2,4,6 Additionally, anticoagulants have been shown to exacerbate bleeding.^2,5 Due to PEHCR’s location in the periphery, as well as its appearance as an elevated dark mass, it is important to differentiate these lesions from a choroidal melanoma.^2,6 Recognition of PEHCR can save the patient from unnecessary treatment with radiation or enucleation.

Peripheral exudative hemorrhagic chorioretinopathy is a self-limiting condition that generally requires close observation only. Long-term follow-up studies show resolution, regression, or stability of the peripheral lesions.^4,5,8 If a hemorrhage is present, the blood will resolve and leave a disciform scar with pigmentary changes.^2-4 In cases where vision is threatened, CNVM has been treated with photocoagulation, cryopexy, and more recently, intravitreal anti-VEGF injections.^4,5,9,10 Given that VEGF is more prevalent in the presence of a choroidal neovascular complex, the goal of anti-VEGF therapy is to prevent the growth of and further damage from these abnormal blood vessels.⁵

 

Conclusion

The authors have described 2 cases of asymptomatic PEHCR in elderly white males who are both currently being observed closely. Peripheral exudative hemorrhagic chorioretinopathy is an uncommon finding; therefore, knowledge of this condition also may be rare. Through this article and these cases, the importance of routine peripheral fundus examination to detect PEHCR should be stressed. It also is important to include PEHCR as a differential diagnosis when evaluating a peripheral dark elevated lesion to distinguish from peripheral melanomas and avoid unnecessary treatments. If identified, these lesions often require close observation only, and a retina referral is warranted if there is macular involvement or a rapidly progressive lesion.⁵

Age-related macular degeneration (AMD) is a common condition that affects the elderly white population. About 6.5% of Americans have been diagnosed with AMD, and 0.8% have received an end-stage AMD diagnosis.¹ Exudative AMD is typically more visually debilitating and comprises between 10% and 15% of all AMD cases, with conversion from dry to wet about 10%.¹

A thorough examination of the posterior pole is of utmost importance in patients with dry AMD in order to ensure there is no conversion to the exudative form. However, it also is imperative to perform a peripheral evaluation in these patients due to the incidence of peripheral choroidal neovascular membrane (CNVM) and its potential visual significance.

Case Report 1

An 80-year-old white male with type 2 diabetes mellitus (DM) without retinopathy, dry AMD, and epiretinal membranes (ERM) in both eyes presented to the eye clinic for a 6-month follow-up. On examination, he had visual acuity (VA) of 20/25 in both eyes and reported no ocular problems. The intraocular pressures were 17 mm Hg in the right eye and 20 mm Hg in the left eye. Slit-lamp examination of the anterior segment of both eyes was significant for 2+ nuclear sclerotic cataracts.

On dilated fundus exam, there were macular drusen and ERM in both eyes; peripherally in the right eye, there was cobblestone degeneration and pigmentary changes. Peripherally in the left eye, there was a large retinal pigment epithelial detachment (PED) with subretinal hemorrhage in the inferior temporal quadrant (Figure 1) along with cobblestone degeneration and pigmentary changes. Peripheral optical coherence tomography (OCT) in the left eye showed a large PED in the location of the hemorrhage (Figure 2).

 

Case Report 2

An 88-year-old white male presented to the eye clinic reporting blurred vision at distance and dry eyes. The patient’s medical history was remarkable for vascular and heart disease, treated with warfarin. The patient also had insulin controlled DM, with no prior history of retinopathy. His past ocular history included hard drusen in the macula, peripheral drusen, pavingstone degeneration, and a fibrotic scar temporally in the right eye.

At his annual eye examination, the patient’s vision was correctable to 20/25 in both eyes. His anterior segment slit-lamp exam was remarkable for posterior chamber intraocular lenses, clear and centered in each eye. His posterior pole exam was remarkable for small hard drusen at the macula in both eyes. Peripherally in the right eye, there was a large disciform fibrotic scar temporally (Figure 3) as well as cobblestone degeneration and peripheral drusen. The left eye revealed a large disciform hemorrhage temporally (Figure 4) with cobblestone degeneration and peripheral drusen.

Both patients currently are being closely monitored for any encroachment of the peripheral lesions into the posterior poles.

Discussion

Peripheral exudative hemorrhagic chorioretinopathy (PEHCR), also referred to in the literature as eccentric disciform CNVM, peripheral CNVM, and peripheral age-related degeneration, is a rare condition more prevalent in elderly white females.^2-4 Mean age ranges from 70 to 82 years, with bilateral involvement ranging from 18% to 37%.^2-4 The mid-periphery or periphery is the most common location for these lesions, more specifically, in the inferior temporal quadrant.^2,3,5,6

Age-related macular degeneration is not pathognomonic for PEHCR. Mantel and colleagues reported that 68.9% of the patients in their study had AMD.³ Visual acuity ranges from 20/20 to light perception, dependent upon ocular comorbidities.^2,3 As reported by Mantel and colleagues, patients with symptomatic PEHCR commonly experience visual loss, floaters, photopsias, metamorphopsia, and scotoma.³

Peripheral exudative hemorrhagic chorioretinopathy is a hemorrhagic or exudative process that can occur either as an isolated lesion or as multiple lesions that consist of a PED along with hemorrhage, subretinal fluid and/or fibrotic scarring.^2-5 Peripheral exudative hemorrhagic chorioretinopathy is not visually significant unless a vitreous hemorrhage is evident or the blood and/or fluid extends to the macular region.^2,5

The exact etiology of peripheral CNVM remains unknown; however, ischemia, mechanical forces, and defects in Bruch’s membrane all have been speculated as causative factors.^2,3,6 Others have hypothesized that PEHCR is a form of polypoidal choroidal vasculopathy.^3,7,8 A rupture in Bruch’s membrane with a vascular complex contributes to the pathophysiology and histology of this condition.^3,6

Given the propensity for cardiovascular diseases, such as DM and hypertension, to lead to retinal ischemia, it is important to take a good case history.^2,4,6 Additionally, anticoagulants have been shown to exacerbate bleeding.^2,5 Due to PEHCR’s location in the periphery, as well as its appearance as an elevated dark mass, it is important to differentiate these lesions from a choroidal melanoma.^2,6 Recognition of PEHCR can save the patient from unnecessary treatment with radiation or enucleation.

Peripheral exudative hemorrhagic chorioretinopathy is a self-limiting condition that generally requires close observation only. Long-term follow-up studies show resolution, regression, or stability of the peripheral lesions.^4,5,8 If a hemorrhage is present, the blood will resolve and leave a disciform scar with pigmentary changes.^2-4 In cases where vision is threatened, CNVM has been treated with photocoagulation, cryopexy, and more recently, intravitreal anti-VEGF injections.^4,5,9,10 Given that VEGF is more prevalent in the presence of a choroidal neovascular complex, the goal of anti-VEGF therapy is to prevent the growth of and further damage from these abnormal blood vessels.⁵

 

Conclusion

The authors have described 2 cases of asymptomatic PEHCR in elderly white males who are both currently being observed closely. Peripheral exudative hemorrhagic chorioretinopathy is an uncommon finding; therefore, knowledge of this condition also may be rare. Through this article and these cases, the importance of routine peripheral fundus examination to detect PEHCR should be stressed. It also is important to include PEHCR as a differential diagnosis when evaluating a peripheral dark elevated lesion to distinguish from peripheral melanomas and avoid unnecessary treatments. If identified, these lesions often require close observation only, and a retina referral is warranted if there is macular involvement or a rapidly progressive lesion.⁵

Age-related macular degeneration (AMD) is a common condition that affects the elderly white population. About 6.5% of Americans have been diagnosed with AMD, and 0.8% have received an end-stage AMD diagnosis.¹ Exudative AMD is typically more visually debilitating and comprises between 10% and 15% of all AMD cases, with conversion from dry to wet about 10%.¹

A thorough examination of the posterior pole is of utmost importance in patients with dry AMD in order to ensure there is no conversion to the exudative form. However, it also is imperative to perform a peripheral evaluation in these patients due to the incidence of peripheral choroidal neovascular membrane (CNVM) and its potential visual significance.

Case Report 1

An 80-year-old white male with type 2 diabetes mellitus (DM) without retinopathy, dry AMD, and epiretinal membranes (ERM) in both eyes presented to the eye clinic for a 6-month follow-up. On examination, he had visual acuity (VA) of 20/25 in both eyes and reported no ocular problems. The intraocular pressures were 17 mm Hg in the right eye and 20 mm Hg in the left eye. Slit-lamp examination of the anterior segment of both eyes was significant for 2+ nuclear sclerotic cataracts.

On dilated fundus exam, there were macular drusen and ERM in both eyes; peripherally in the right eye, there was cobblestone degeneration and pigmentary changes. Peripherally in the left eye, there was a large retinal pigment epithelial detachment (PED) with subretinal hemorrhage in the inferior temporal quadrant (Figure 1) along with cobblestone degeneration and pigmentary changes. Peripheral optical coherence tomography (OCT) in the left eye showed a large PED in the location of the hemorrhage (Figure 2).

 

Case Report 2

An 88-year-old white male presented to the eye clinic reporting blurred vision at distance and dry eyes. The patient’s medical history was remarkable for vascular and heart disease, treated with warfarin. The patient also had insulin controlled DM, with no prior history of retinopathy. His past ocular history included hard drusen in the macula, peripheral drusen, pavingstone degeneration, and a fibrotic scar temporally in the right eye.

At his annual eye examination, the patient’s vision was correctable to 20/25 in both eyes. His anterior segment slit-lamp exam was remarkable for posterior chamber intraocular lenses, clear and centered in each eye. His posterior pole exam was remarkable for small hard drusen at the macula in both eyes. Peripherally in the right eye, there was a large disciform fibrotic scar temporally (Figure 3) as well as cobblestone degeneration and peripheral drusen. The left eye revealed a large disciform hemorrhage temporally (Figure 4) with cobblestone degeneration and peripheral drusen.

Both patients currently are being closely monitored for any encroachment of the peripheral lesions into the posterior poles.

Discussion

Peripheral exudative hemorrhagic chorioretinopathy (PEHCR), also referred to in the literature as eccentric disciform CNVM, peripheral CNVM, and peripheral age-related degeneration, is a rare condition more prevalent in elderly white females.^2-4 Mean age ranges from 70 to 82 years, with bilateral involvement ranging from 18% to 37%.^2-4 The mid-periphery or periphery is the most common location for these lesions, more specifically, in the inferior temporal quadrant.^2,3,5,6

Age-related macular degeneration is not pathognomonic for PEHCR. Mantel and colleagues reported that 68.9% of the patients in their study had AMD.³ Visual acuity ranges from 20/20 to light perception, dependent upon ocular comorbidities.^2,3 As reported by Mantel and colleagues, patients with symptomatic PEHCR commonly experience visual loss, floaters, photopsias, metamorphopsia, and scotoma.³

Peripheral exudative hemorrhagic chorioretinopathy is a hemorrhagic or exudative process that can occur either as an isolated lesion or as multiple lesions that consist of a PED along with hemorrhage, subretinal fluid and/or fibrotic scarring.^2-5 Peripheral exudative hemorrhagic chorioretinopathy is not visually significant unless a vitreous hemorrhage is evident or the blood and/or fluid extends to the macular region.^2,5

The exact etiology of peripheral CNVM remains unknown; however, ischemia, mechanical forces, and defects in Bruch’s membrane all have been speculated as causative factors.^2,3,6 Others have hypothesized that PEHCR is a form of polypoidal choroidal vasculopathy.^3,7,8 A rupture in Bruch’s membrane with a vascular complex contributes to the pathophysiology and histology of this condition.^3,6

Given the propensity for cardiovascular diseases, such as DM and hypertension, to lead to retinal ischemia, it is important to take a good case history.^2,4,6 Additionally, anticoagulants have been shown to exacerbate bleeding.^2,5 Due to PEHCR’s location in the periphery, as well as its appearance as an elevated dark mass, it is important to differentiate these lesions from a choroidal melanoma.^2,6 Recognition of PEHCR can save the patient from unnecessary treatment with radiation or enucleation.

Peripheral exudative hemorrhagic chorioretinopathy is a self-limiting condition that generally requires close observation only. Long-term follow-up studies show resolution, regression, or stability of the peripheral lesions.^4,5,8 If a hemorrhage is present, the blood will resolve and leave a disciform scar with pigmentary changes.^2-4 In cases where vision is threatened, CNVM has been treated with photocoagulation, cryopexy, and more recently, intravitreal anti-VEGF injections.^4,5,9,10 Given that VEGF is more prevalent in the presence of a choroidal neovascular complex, the goal of anti-VEGF therapy is to prevent the growth of and further damage from these abnormal blood vessels.⁵

 

Conclusion

The authors have described 2 cases of asymptomatic PEHCR in elderly white males who are both currently being observed closely. Peripheral exudative hemorrhagic chorioretinopathy is an uncommon finding; therefore, knowledge of this condition also may be rare. Through this article and these cases, the importance of routine peripheral fundus examination to detect PEHCR should be stressed. It also is important to include PEHCR as a differential diagnosis when evaluating a peripheral dark elevated lesion to distinguish from peripheral melanomas and avoid unnecessary treatments. If identified, these lesions often require close observation only, and a retina referral is warranted if there is macular involvement or a rapidly progressive lesion.⁵

Acquired epidermodysplasia verruciformis (EDV) is a rare disorder occurring in patients with depressed cellular immunity, particularly individuals with human immunodeficiency virus (HIV). Rare cases of acquired EDV have been reported in stem cell or solid organ transplant recipients. Weakened cellular immunity predisposes the patient to human papillomavirus (HPV) infections, with 92% of renal transplant recipients developing warts within 5 years posttransplantation.¹ Specific EDV-HPV subtypes have been isolated from lesions in several immunosuppressed individuals, with HPV-5 and HPV-8 being the most commonly isolated subtypes.^2,3 Herein, we present the clinical findings of a renal transplant recipient who presented for evaluation of multiple skin lesions characteristic of EDV 5 years following transplantation and initiation of immunosuppressive therapy. Additionally, we review the current diagnostic findings, management, and treatment of acquired EDV.

A 44-year-old white woman presented for evaluation of several pruritic cutaneous lesions that had developed on the chest and neck of 1 month’s duration. The patient had been on the immunosuppressant medications cyclosporine and mycophenolate mofetil for more than 5 years following renal transplantation 7 years prior to the current presentation. She also was on low-dose prednisone for chronic systemic lupus erythematosus. Her family history was negative for any pertinent skin conditions.

On physical examination the patient exhibited several grouped 0.5-cm, shiny, pink lichenoid macules located on the upper mid chest, anterior neck, and left leg clinically resembling the lesions of pityriasis versicolor (Figure 1). A shave biopsy was taken from one of the newest lesions on the left leg. Histopathology revealed viral epidermal cytopathic changes, blue cytoplasm, and coarse hypergranulosis characteristic of EDV (Figure 2). A diagnosis of acquired EDV was made based on the clinical and histopathologic findings.

The patient’s skin lesions became more widespread despite several different treatment regimens, including cryosurgery; tazarotene cream 0.05% nightly; imiquimod cream 5% once weekly; and intermittent short courses of 5-fluorouracil cream 5%, which provided the best response. At her most recent clinic visit 8 years after initial presentation, she continued to have more widespread lesions on the trunk, arms, and legs, but no evidence of malignant transformation.

 

Comment

Epidermodysplasia verruciformis was first recognized as an inherited condition, most commonly inherited in an autosomal-dominant fashion; however, X-linked recessive cases have been reported.^4,5 Patients with the inherited forms of this condition are prone to recurrent HPV infections secondary to a missense mutation in the epidermodysplasia verruciformis 1 and 2 genes, EVER1 and EVER2, on the EV1 locus located on chromosome 17q25.⁶ Because of this mutation, the patient’s cellular immunity becomes weakened. Cellular presentation of the EDV-HPV antigen to T lymphocytes becomes impaired, thereby inhibiting the body’s ability to successfully clear itself of the virus.^5,6 The most commonly isolated EDV-HPV subtypes are HPV-5 and HPV-8, but HPV types 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, and 50 also have been associated with EDV.^1,3,7

Patients who have suppressed cellular immunity, such as transplant recipients on long-term immunosuppressant medications and individuals with HIV, graft-vs-host disease, systemic lupus erythematosus, and hematologic malignancies, are susceptible to EDV, as well as patients with atopic dermatitis being treated with topical calcineurin inhibitors.^2,3,8-15 These patients acquire depressed cellular immunity and become increasingly susceptible to infections with the EDV-HPV subtypes. When clinical and histopathologic findings are consistent with EDV, a diagnosis of acquired EDV is given, which was further confirmed in a study conducted by Harwood et al.¹⁶ They found immunocompromised patients carry more EDV-HPV subtypes in skin lesions analyzed by polymerase chain reaction than immunocompetent individuals.¹⁶ Additionally, there is a positive correlation between the length of immunosuppression and the development of HPV lesions, with a majority of patients developing lesions within 5 years following initial immunosuppression.^1,7,10,17

Epidermodysplasia verruciformis commonly presents with multiple hypopigmented to red macules that may coalesce into patches with a fine scale, clinically resembling the lesions of pityriasis versicolor.^2,3,8-15 Epidermodysplasia verruciformis also may present as multiple flesh-colored, flat-topped, verrucous papules that clinically resemble the lesions of verruca plana on sun-exposed areas such as the face, arms, and legs.⁹ The characteristic histopathologic findings are enlarged keratinocytes with perinuclear halos and blue-gray cytoplasm as well as hypergranulosis.¹⁸ Immunocompromised hosts infected with EDV-HPV histologically tend to display more severe dysplasia than immunocompetent individuals.¹⁹ The differential diagnosis includes pityriasis versicolor, squamous cell carcinoma (SCC), and verruca plana. Tissue cultures and potassium hydroxide scrapings for microorganisms should be negative.

The specific EDV-HPV strains 5, 8, and 41 carry the highest oncogenic potential, with more than 60% of inherited EDV patients developing SCC by the fourth and fifth decades of life.¹⁶ Unlike inherited EDV, the clinical course of acquired EDV is less well known; however, UV light is thought to act synergistically with the EDV-HPV in oncogenic transformation of the lesions, as most of the SCCs develop on sun-exposed areas, and darker-skinned patients seem to have a decreased risk for malignant transformation of EDV lesions.^4,9,20,21 Preventative measures such as strict sun protection and annual surveillance of lesions can help to prevent oncogenic progression of the lesions; however, several single- and multiple-agent regimens have been used in the treatment of EDV with variable results. Topical imiquimod, 5-fluorouracil, tretinoin, and tazarotene have been used with variable success. Acitretin alone and in combination with interferon alfa-2a also has been used.^22,23 Highly active antiretroviral therapy in patients with HIV has effectively decreased the number of lesions in a subset of patients.²⁴ We (anecdotal) and others²⁵ also have had success using photodynamic therapy. Squamous cell carcinoma arising in patients with EDV can be managed by excision or by Mohs micrographic surgery.

Conclusion

We report a rare case of acquired EDV in a solid organ transplant recipient. Epidermodysplasia verruciformis can be acquired in immunosuppressed patients such as ours, and these patients should be followed closely due to the potential for malignant transformation. More studies regarding the anticipated clinical course of skin lesions in patients with acquired EDV are needed to better predict the time frame for malignant transformation.

Acquired epidermodysplasia verruciformis (EDV) is a rare disorder occurring in patients with depressed cellular immunity, particularly individuals with human immunodeficiency virus (HIV). Rare cases of acquired EDV have been reported in stem cell or solid organ transplant recipients. Weakened cellular immunity predisposes the patient to human papillomavirus (HPV) infections, with 92% of renal transplant recipients developing warts within 5 years posttransplantation.¹ Specific EDV-HPV subtypes have been isolated from lesions in several immunosuppressed individuals, with HPV-5 and HPV-8 being the most commonly isolated subtypes.^2,3 Herein, we present the clinical findings of a renal transplant recipient who presented for evaluation of multiple skin lesions characteristic of EDV 5 years following transplantation and initiation of immunosuppressive therapy. Additionally, we review the current diagnostic findings, management, and treatment of acquired EDV.

A 44-year-old white woman presented for evaluation of several pruritic cutaneous lesions that had developed on the chest and neck of 1 month’s duration. The patient had been on the immunosuppressant medications cyclosporine and mycophenolate mofetil for more than 5 years following renal transplantation 7 years prior to the current presentation. She also was on low-dose prednisone for chronic systemic lupus erythematosus. Her family history was negative for any pertinent skin conditions.

On physical examination the patient exhibited several grouped 0.5-cm, shiny, pink lichenoid macules located on the upper mid chest, anterior neck, and left leg clinically resembling the lesions of pityriasis versicolor (Figure 1). A shave biopsy was taken from one of the newest lesions on the left leg. Histopathology revealed viral epidermal cytopathic changes, blue cytoplasm, and coarse hypergranulosis characteristic of EDV (Figure 2). A diagnosis of acquired EDV was made based on the clinical and histopathologic findings.

The patient’s skin lesions became more widespread despite several different treatment regimens, including cryosurgery; tazarotene cream 0.05% nightly; imiquimod cream 5% once weekly; and intermittent short courses of 5-fluorouracil cream 5%, which provided the best response. At her most recent clinic visit 8 years after initial presentation, she continued to have more widespread lesions on the trunk, arms, and legs, but no evidence of malignant transformation.

 

Comment

Epidermodysplasia verruciformis was first recognized as an inherited condition, most commonly inherited in an autosomal-dominant fashion; however, X-linked recessive cases have been reported.^4,5 Patients with the inherited forms of this condition are prone to recurrent HPV infections secondary to a missense mutation in the epidermodysplasia verruciformis 1 and 2 genes, EVER1 and EVER2, on the EV1 locus located on chromosome 17q25.⁶ Because of this mutation, the patient’s cellular immunity becomes weakened. Cellular presentation of the EDV-HPV antigen to T lymphocytes becomes impaired, thereby inhibiting the body’s ability to successfully clear itself of the virus.^5,6 The most commonly isolated EDV-HPV subtypes are HPV-5 and HPV-8, but HPV types 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, and 50 also have been associated with EDV.^1,3,7

Patients who have suppressed cellular immunity, such as transplant recipients on long-term immunosuppressant medications and individuals with HIV, graft-vs-host disease, systemic lupus erythematosus, and hematologic malignancies, are susceptible to EDV, as well as patients with atopic dermatitis being treated with topical calcineurin inhibitors.^2,3,8-15 These patients acquire depressed cellular immunity and become increasingly susceptible to infections with the EDV-HPV subtypes. When clinical and histopathologic findings are consistent with EDV, a diagnosis of acquired EDV is given, which was further confirmed in a study conducted by Harwood et al.¹⁶ They found immunocompromised patients carry more EDV-HPV subtypes in skin lesions analyzed by polymerase chain reaction than immunocompetent individuals.¹⁶ Additionally, there is a positive correlation between the length of immunosuppression and the development of HPV lesions, with a majority of patients developing lesions within 5 years following initial immunosuppression.^1,7,10,17

Epidermodysplasia verruciformis commonly presents with multiple hypopigmented to red macules that may coalesce into patches with a fine scale, clinically resembling the lesions of pityriasis versicolor.^2,3,8-15 Epidermodysplasia verruciformis also may present as multiple flesh-colored, flat-topped, verrucous papules that clinically resemble the lesions of verruca plana on sun-exposed areas such as the face, arms, and legs.⁹ The characteristic histopathologic findings are enlarged keratinocytes with perinuclear halos and blue-gray cytoplasm as well as hypergranulosis.¹⁸ Immunocompromised hosts infected with EDV-HPV histologically tend to display more severe dysplasia than immunocompetent individuals.¹⁹ The differential diagnosis includes pityriasis versicolor, squamous cell carcinoma (SCC), and verruca plana. Tissue cultures and potassium hydroxide scrapings for microorganisms should be negative.

The specific EDV-HPV strains 5, 8, and 41 carry the highest oncogenic potential, with more than 60% of inherited EDV patients developing SCC by the fourth and fifth decades of life.¹⁶ Unlike inherited EDV, the clinical course of acquired EDV is less well known; however, UV light is thought to act synergistically with the EDV-HPV in oncogenic transformation of the lesions, as most of the SCCs develop on sun-exposed areas, and darker-skinned patients seem to have a decreased risk for malignant transformation of EDV lesions.^4,9,20,21 Preventative measures such as strict sun protection and annual surveillance of lesions can help to prevent oncogenic progression of the lesions; however, several single- and multiple-agent regimens have been used in the treatment of EDV with variable results. Topical imiquimod, 5-fluorouracil, tretinoin, and tazarotene have been used with variable success. Acitretin alone and in combination with interferon alfa-2a also has been used.^22,23 Highly active antiretroviral therapy in patients with HIV has effectively decreased the number of lesions in a subset of patients.²⁴ We (anecdotal) and others²⁵ also have had success using photodynamic therapy. Squamous cell carcinoma arising in patients with EDV can be managed by excision or by Mohs micrographic surgery.

Conclusion

We report a rare case of acquired EDV in a solid organ transplant recipient. Epidermodysplasia verruciformis can be acquired in immunosuppressed patients such as ours, and these patients should be followed closely due to the potential for malignant transformation. More studies regarding the anticipated clinical course of skin lesions in patients with acquired EDV are needed to better predict the time frame for malignant transformation.

Acquired epidermodysplasia verruciformis (EDV) is a rare disorder occurring in patients with depressed cellular immunity, particularly individuals with human immunodeficiency virus (HIV). Rare cases of acquired EDV have been reported in stem cell or solid organ transplant recipients. Weakened cellular immunity predisposes the patient to human papillomavirus (HPV) infections, with 92% of renal transplant recipients developing warts within 5 years posttransplantation.¹ Specific EDV-HPV subtypes have been isolated from lesions in several immunosuppressed individuals, with HPV-5 and HPV-8 being the most commonly isolated subtypes.^2,3 Herein, we present the clinical findings of a renal transplant recipient who presented for evaluation of multiple skin lesions characteristic of EDV 5 years following transplantation and initiation of immunosuppressive therapy. Additionally, we review the current diagnostic findings, management, and treatment of acquired EDV.

A 44-year-old white woman presented for evaluation of several pruritic cutaneous lesions that had developed on the chest and neck of 1 month’s duration. The patient had been on the immunosuppressant medications cyclosporine and mycophenolate mofetil for more than 5 years following renal transplantation 7 years prior to the current presentation. She also was on low-dose prednisone for chronic systemic lupus erythematosus. Her family history was negative for any pertinent skin conditions.

On physical examination the patient exhibited several grouped 0.5-cm, shiny, pink lichenoid macules located on the upper mid chest, anterior neck, and left leg clinically resembling the lesions of pityriasis versicolor (Figure 1). A shave biopsy was taken from one of the newest lesions on the left leg. Histopathology revealed viral epidermal cytopathic changes, blue cytoplasm, and coarse hypergranulosis characteristic of EDV (Figure 2). A diagnosis of acquired EDV was made based on the clinical and histopathologic findings.

The patient’s skin lesions became more widespread despite several different treatment regimens, including cryosurgery; tazarotene cream 0.05% nightly; imiquimod cream 5% once weekly; and intermittent short courses of 5-fluorouracil cream 5%, which provided the best response. At her most recent clinic visit 8 years after initial presentation, she continued to have more widespread lesions on the trunk, arms, and legs, but no evidence of malignant transformation.

 

Comment

Epidermodysplasia verruciformis was first recognized as an inherited condition, most commonly inherited in an autosomal-dominant fashion; however, X-linked recessive cases have been reported.^4,5 Patients with the inherited forms of this condition are prone to recurrent HPV infections secondary to a missense mutation in the epidermodysplasia verruciformis 1 and 2 genes, EVER1 and EVER2, on the EV1 locus located on chromosome 17q25.⁶ Because of this mutation, the patient’s cellular immunity becomes weakened. Cellular presentation of the EDV-HPV antigen to T lymphocytes becomes impaired, thereby inhibiting the body’s ability to successfully clear itself of the virus.^5,6 The most commonly isolated EDV-HPV subtypes are HPV-5 and HPV-8, but HPV types 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, and 50 also have been associated with EDV.^1,3,7

Patients who have suppressed cellular immunity, such as transplant recipients on long-term immunosuppressant medications and individuals with HIV, graft-vs-host disease, systemic lupus erythematosus, and hematologic malignancies, are susceptible to EDV, as well as patients with atopic dermatitis being treated with topical calcineurin inhibitors.^2,3,8-15 These patients acquire depressed cellular immunity and become increasingly susceptible to infections with the EDV-HPV subtypes. When clinical and histopathologic findings are consistent with EDV, a diagnosis of acquired EDV is given, which was further confirmed in a study conducted by Harwood et al.¹⁶ They found immunocompromised patients carry more EDV-HPV subtypes in skin lesions analyzed by polymerase chain reaction than immunocompetent individuals.¹⁶ Additionally, there is a positive correlation between the length of immunosuppression and the development of HPV lesions, with a majority of patients developing lesions within 5 years following initial immunosuppression.^1,7,10,17

Epidermodysplasia verruciformis commonly presents with multiple hypopigmented to red macules that may coalesce into patches with a fine scale, clinically resembling the lesions of pityriasis versicolor.^2,3,8-15 Epidermodysplasia verruciformis also may present as multiple flesh-colored, flat-topped, verrucous papules that clinically resemble the lesions of verruca plana on sun-exposed areas such as the face, arms, and legs.⁹ The characteristic histopathologic findings are enlarged keratinocytes with perinuclear halos and blue-gray cytoplasm as well as hypergranulosis.¹⁸ Immunocompromised hosts infected with EDV-HPV histologically tend to display more severe dysplasia than immunocompetent individuals.¹⁹ The differential diagnosis includes pityriasis versicolor, squamous cell carcinoma (SCC), and verruca plana. Tissue cultures and potassium hydroxide scrapings for microorganisms should be negative.

The specific EDV-HPV strains 5, 8, and 41 carry the highest oncogenic potential, with more than 60% of inherited EDV patients developing SCC by the fourth and fifth decades of life.¹⁶ Unlike inherited EDV, the clinical course of acquired EDV is less well known; however, UV light is thought to act synergistically with the EDV-HPV in oncogenic transformation of the lesions, as most of the SCCs develop on sun-exposed areas, and darker-skinned patients seem to have a decreased risk for malignant transformation of EDV lesions.^4,9,20,21 Preventative measures such as strict sun protection and annual surveillance of lesions can help to prevent oncogenic progression of the lesions; however, several single- and multiple-agent regimens have been used in the treatment of EDV with variable results. Topical imiquimod, 5-fluorouracil, tretinoin, and tazarotene have been used with variable success. Acitretin alone and in combination with interferon alfa-2a also has been used.^22,23 Highly active antiretroviral therapy in patients with HIV has effectively decreased the number of lesions in a subset of patients.²⁴ We (anecdotal) and others²⁵ also have had success using photodynamic therapy. Squamous cell carcinoma arising in patients with EDV can be managed by excision or by Mohs micrographic surgery.

Conclusion

We report a rare case of acquired EDV in a solid organ transplant recipient. Epidermodysplasia verruciformis can be acquired in immunosuppressed patients such as ours, and these patients should be followed closely due to the potential for malignant transformation. More studies regarding the anticipated clinical course of skin lesions in patients with acquired EDV are needed to better predict the time frame for malignant transformation.

Case Report

A 72-year-old white man with a history of pancreatic adenocarcinoma presented for Mohs micrographic surgery of a basal cell carcinoma on the right helix. On the day of the surgery, the patient reported a new, rapidly growing, exquisitely painful lesion on the cheek of 3 to 4 weeks’ duration. Physical examination revealed a 0.8×0.8×0.8-cm, extremely tender, firm, pink papule on the right preauricular cheek. A horizontal deep shave excision was done and the histopathology was remarkable for neoplastic cells with necrosis in the dermis. We observed dermal cellular infiltrates in the form of sheets and nodules, some showing central necrosis (Figure 1). At higher magnification, a trabecular arrangement of cells was seen. These cells had a moderate amount of cytoplasm with eccentric nuclei and rare nucleoli (Figure 2). Mitotic figures were seen at higher magnification (Figure 3). Immunohistochemistry of the neoplastic cells exhibited similar positive staining for the neuroendocrine markers chromogranin A and synaptophysin (Figure 4). Staining of the neoplastic cells also was positive for thyroid transcription factor 1 (TTF-1) and cancer antigen 19-9. Villin and caudal type homeobox 2 stains were negative. These results were consistent with cutaneous metastasis from a known pulmonary carcinoid tumor.

On further review of the patient’s medical history, it was discovered that he had undergone a Whipple procedure with adjuvant chemotherapy and radiation for pancreatic adenocarcinoma approximately 4 years prior to the current presentation. He was then followed by oncology, and 3 years later a chest computed tomography suggested possible disease progression with a new pulmonary metastasis. This pulmonary lesion was biopsied and immunologic staining was consistent with a primary neuroendocrine neoplasm of the lung, a new carcinoid tumor. The tissue was positive for cytokeratin (CK) 7,TTF-1, cancer antigen 19-9, CD56, synaptophysin, and chromogranin A, and was negative for villin and CK20. By the time he was seen in our clinic, several trials of chemotherapy had failed. Serial computed tomography subsequently demonstrated progression of the lung disease and he later developed malignant pleural effusions. Approximately 6 months after the cutaneous carcinoid metastasis was diagnosed, the patient died of respiratory failure.

 

Comment

Carcinoid tumors are uncommon neoplasms of neuroendocrine origin that generally arise in the gastrointestinal or bronchopulmonary tracts. Metastases from these primary neoplasms more commonly affect the regional lymph nodes or viscera, with rare reports of cutaneous metastases to the skin. The true incidence of carcinoid tumors with metastasis to the skin is unknown because it is limited to single case reports in the literature.

The clinical presentation of cutaneous carcinoid metastases has been reported most commonly as firm papules of varying sizes with no specific site predilection.¹ The color of these lesions has ranged from erythematous to violaceous to brown.² Several of the reported cases were noted to be extremely tender and painful, while other reports of lesions were noted to be asymptomatic or only mildly pruritic.^3-7

Carcinoid syndrome is more common with neoplasms present within the gastrointestinal tract, but it also has been reported with large bronchial carcinoid tumors and with metastatic disease.^8,9 Paroxysmal flushing is the most prominent cutaneous manifestation of this syndrome, occurring in 75% of patients.^10,11 Other common symptoms include patchy cyanosis, telangiectasia, and pellagralike skin lesions.³ Carcinoid syndrome secondary to bronchial adenomas is thought to differ from gastrointestinal carcinoid neoplasms in that it has prolonged flushing (hours to days instead of minutes) and is characterized by marked anxiety, fever, disorientation, sweating, and lacrimation.^8,9

Many cases of cutaneous carcinoid metastases have been accompanied by reports of exquisite tenderness,⁷ similar to our patient. The pathogenesis of the pain in these lesions is still unclear, but several hypotheses have been established. It has been postulated that perineural invasion by the tumor is responsible for the pain; however, this finding has been inconsistent, as neural involvement also has been present in nonpainful lesions.^2,5,7,12 Another theory for the pain is that it is secondary to the release of vasoactive substances and peptide hormones from the carcinoid cells, such as kallikrein and serotonin. Lastly, local tissue necrosis and fibrosis also have been suggested as possible etiologies.⁷

The histology of cutaneous carcinoid metastases typically resembles the primary lesion and may demonstrate fascicles of spindle cells with focal areas of necrosis, mild atypia, and a relatively low mitotic rate.¹⁰ Other neoplasms such as Merkel cell carcinoma and carcinoidlike sebaceous carcinoma should be considered in the differential diagnosis. A primary malignant peripheral primitive neuroectodermal tumor or a primary cutaneous carcinoid tumor is less common but should be considered. Differing from carcinoid tumors, Merkel cell carcinomas usually have a higher mitotic rate and positive staining for CK20. The sebaceous neoplasms with a carcinoidlike pattern may appear histologically similar, requiring immunohistochemical evaluation with monoclonal antibodies such as D2-40.¹³ A diffuse granular cytoplasmic reaction to chromogranin A is characteristic of carcinoid tumors. Synaptophysin and TTF-1 also are positive in carcinoid tumors, with TTF-1 being highly specific for neuroendocrine tumors of the lung.¹⁰

Cutaneous metastases of internal malignancies are more common from carcinomas of the lungs, gastrointestinal tract, and breasts.⁵ Occasionally, the cutaneous metastasis will develop directly over the underlying malignancy. Our case of cutaneous metastasis of a carcinoid tumor presented as an exquisitely tender and painful papule on the cheek. The histology of the lesion was consistent with the known carcinoid tumor of the lung. Because these lesions are extremely uncommon, it is imperative to obtain an accurate clinical history and use the appropriate immunohistochemical panel to correctly diagnose these metastases.

Case Report

A 72-year-old white man with a history of pancreatic adenocarcinoma presented for Mohs micrographic surgery of a basal cell carcinoma on the right helix. On the day of the surgery, the patient reported a new, rapidly growing, exquisitely painful lesion on the cheek of 3 to 4 weeks’ duration. Physical examination revealed a 0.8×0.8×0.8-cm, extremely tender, firm, pink papule on the right preauricular cheek. A horizontal deep shave excision was done and the histopathology was remarkable for neoplastic cells with necrosis in the dermis. We observed dermal cellular infiltrates in the form of sheets and nodules, some showing central necrosis (Figure 1). At higher magnification, a trabecular arrangement of cells was seen. These cells had a moderate amount of cytoplasm with eccentric nuclei and rare nucleoli (Figure 2). Mitotic figures were seen at higher magnification (Figure 3). Immunohistochemistry of the neoplastic cells exhibited similar positive staining for the neuroendocrine markers chromogranin A and synaptophysin (Figure 4). Staining of the neoplastic cells also was positive for thyroid transcription factor 1 (TTF-1) and cancer antigen 19-9. Villin and caudal type homeobox 2 stains were negative. These results were consistent with cutaneous metastasis from a known pulmonary carcinoid tumor.

On further review of the patient’s medical history, it was discovered that he had undergone a Whipple procedure with adjuvant chemotherapy and radiation for pancreatic adenocarcinoma approximately 4 years prior to the current presentation. He was then followed by oncology, and 3 years later a chest computed tomography suggested possible disease progression with a new pulmonary metastasis. This pulmonary lesion was biopsied and immunologic staining was consistent with a primary neuroendocrine neoplasm of the lung, a new carcinoid tumor. The tissue was positive for cytokeratin (CK) 7,TTF-1, cancer antigen 19-9, CD56, synaptophysin, and chromogranin A, and was negative for villin and CK20. By the time he was seen in our clinic, several trials of chemotherapy had failed. Serial computed tomography subsequently demonstrated progression of the lung disease and he later developed malignant pleural effusions. Approximately 6 months after the cutaneous carcinoid metastasis was diagnosed, the patient died of respiratory failure.

 

Comment

Carcinoid tumors are uncommon neoplasms of neuroendocrine origin that generally arise in the gastrointestinal or bronchopulmonary tracts. Metastases from these primary neoplasms more commonly affect the regional lymph nodes or viscera, with rare reports of cutaneous metastases to the skin. The true incidence of carcinoid tumors with metastasis to the skin is unknown because it is limited to single case reports in the literature.

The clinical presentation of cutaneous carcinoid metastases has been reported most commonly as firm papules of varying sizes with no specific site predilection.¹ The color of these lesions has ranged from erythematous to violaceous to brown.² Several of the reported cases were noted to be extremely tender and painful, while other reports of lesions were noted to be asymptomatic or only mildly pruritic.^3-7

Carcinoid syndrome is more common with neoplasms present within the gastrointestinal tract, but it also has been reported with large bronchial carcinoid tumors and with metastatic disease.^8,9 Paroxysmal flushing is the most prominent cutaneous manifestation of this syndrome, occurring in 75% of patients.^10,11 Other common symptoms include patchy cyanosis, telangiectasia, and pellagralike skin lesions.³ Carcinoid syndrome secondary to bronchial adenomas is thought to differ from gastrointestinal carcinoid neoplasms in that it has prolonged flushing (hours to days instead of minutes) and is characterized by marked anxiety, fever, disorientation, sweating, and lacrimation.^8,9

Many cases of cutaneous carcinoid metastases have been accompanied by reports of exquisite tenderness,⁷ similar to our patient. The pathogenesis of the pain in these lesions is still unclear, but several hypotheses have been established. It has been postulated that perineural invasion by the tumor is responsible for the pain; however, this finding has been inconsistent, as neural involvement also has been present in nonpainful lesions.^2,5,7,12 Another theory for the pain is that it is secondary to the release of vasoactive substances and peptide hormones from the carcinoid cells, such as kallikrein and serotonin. Lastly, local tissue necrosis and fibrosis also have been suggested as possible etiologies.⁷

The histology of cutaneous carcinoid metastases typically resembles the primary lesion and may demonstrate fascicles of spindle cells with focal areas of necrosis, mild atypia, and a relatively low mitotic rate.¹⁰ Other neoplasms such as Merkel cell carcinoma and carcinoidlike sebaceous carcinoma should be considered in the differential diagnosis. A primary malignant peripheral primitive neuroectodermal tumor or a primary cutaneous carcinoid tumor is less common but should be considered. Differing from carcinoid tumors, Merkel cell carcinomas usually have a higher mitotic rate and positive staining for CK20. The sebaceous neoplasms with a carcinoidlike pattern may appear histologically similar, requiring immunohistochemical evaluation with monoclonal antibodies such as D2-40.¹³ A diffuse granular cytoplasmic reaction to chromogranin A is characteristic of carcinoid tumors. Synaptophysin and TTF-1 also are positive in carcinoid tumors, with TTF-1 being highly specific for neuroendocrine tumors of the lung.¹⁰

Cutaneous metastases of internal malignancies are more common from carcinomas of the lungs, gastrointestinal tract, and breasts.⁵ Occasionally, the cutaneous metastasis will develop directly over the underlying malignancy. Our case of cutaneous metastasis of a carcinoid tumor presented as an exquisitely tender and painful papule on the cheek. The histology of the lesion was consistent with the known carcinoid tumor of the lung. Because these lesions are extremely uncommon, it is imperative to obtain an accurate clinical history and use the appropriate immunohistochemical panel to correctly diagnose these metastases.

Case Report

A 72-year-old white man with a history of pancreatic adenocarcinoma presented for Mohs micrographic surgery of a basal cell carcinoma on the right helix. On the day of the surgery, the patient reported a new, rapidly growing, exquisitely painful lesion on the cheek of 3 to 4 weeks’ duration. Physical examination revealed a 0.8×0.8×0.8-cm, extremely tender, firm, pink papule on the right preauricular cheek. A horizontal deep shave excision was done and the histopathology was remarkable for neoplastic cells with necrosis in the dermis. We observed dermal cellular infiltrates in the form of sheets and nodules, some showing central necrosis (Figure 1). At higher magnification, a trabecular arrangement of cells was seen. These cells had a moderate amount of cytoplasm with eccentric nuclei and rare nucleoli (Figure 2). Mitotic figures were seen at higher magnification (Figure 3). Immunohistochemistry of the neoplastic cells exhibited similar positive staining for the neuroendocrine markers chromogranin A and synaptophysin (Figure 4). Staining of the neoplastic cells also was positive for thyroid transcription factor 1 (TTF-1) and cancer antigen 19-9. Villin and caudal type homeobox 2 stains were negative. These results were consistent with cutaneous metastasis from a known pulmonary carcinoid tumor.

On further review of the patient’s medical history, it was discovered that he had undergone a Whipple procedure with adjuvant chemotherapy and radiation for pancreatic adenocarcinoma approximately 4 years prior to the current presentation. He was then followed by oncology, and 3 years later a chest computed tomography suggested possible disease progression with a new pulmonary metastasis. This pulmonary lesion was biopsied and immunologic staining was consistent with a primary neuroendocrine neoplasm of the lung, a new carcinoid tumor. The tissue was positive for cytokeratin (CK) 7,TTF-1, cancer antigen 19-9, CD56, synaptophysin, and chromogranin A, and was negative for villin and CK20. By the time he was seen in our clinic, several trials of chemotherapy had failed. Serial computed tomography subsequently demonstrated progression of the lung disease and he later developed malignant pleural effusions. Approximately 6 months after the cutaneous carcinoid metastasis was diagnosed, the patient died of respiratory failure.

 

Comment

Carcinoid tumors are uncommon neoplasms of neuroendocrine origin that generally arise in the gastrointestinal or bronchopulmonary tracts. Metastases from these primary neoplasms more commonly affect the regional lymph nodes or viscera, with rare reports of cutaneous metastases to the skin. The true incidence of carcinoid tumors with metastasis to the skin is unknown because it is limited to single case reports in the literature.

The clinical presentation of cutaneous carcinoid metastases has been reported most commonly as firm papules of varying sizes with no specific site predilection.¹ The color of these lesions has ranged from erythematous to violaceous to brown.² Several of the reported cases were noted to be extremely tender and painful, while other reports of lesions were noted to be asymptomatic or only mildly pruritic.^3-7

Carcinoid syndrome is more common with neoplasms present within the gastrointestinal tract, but it also has been reported with large bronchial carcinoid tumors and with metastatic disease.^8,9 Paroxysmal flushing is the most prominent cutaneous manifestation of this syndrome, occurring in 75% of patients.^10,11 Other common symptoms include patchy cyanosis, telangiectasia, and pellagralike skin lesions.³ Carcinoid syndrome secondary to bronchial adenomas is thought to differ from gastrointestinal carcinoid neoplasms in that it has prolonged flushing (hours to days instead of minutes) and is characterized by marked anxiety, fever, disorientation, sweating, and lacrimation.^8,9

Many cases of cutaneous carcinoid metastases have been accompanied by reports of exquisite tenderness,⁷ similar to our patient. The pathogenesis of the pain in these lesions is still unclear, but several hypotheses have been established. It has been postulated that perineural invasion by the tumor is responsible for the pain; however, this finding has been inconsistent, as neural involvement also has been present in nonpainful lesions.^2,5,7,12 Another theory for the pain is that it is secondary to the release of vasoactive substances and peptide hormones from the carcinoid cells, such as kallikrein and serotonin. Lastly, local tissue necrosis and fibrosis also have been suggested as possible etiologies.⁷

The histology of cutaneous carcinoid metastases typically resembles the primary lesion and may demonstrate fascicles of spindle cells with focal areas of necrosis, mild atypia, and a relatively low mitotic rate.¹⁰ Other neoplasms such as Merkel cell carcinoma and carcinoidlike sebaceous carcinoma should be considered in the differential diagnosis. A primary malignant peripheral primitive neuroectodermal tumor or a primary cutaneous carcinoid tumor is less common but should be considered. Differing from carcinoid tumors, Merkel cell carcinomas usually have a higher mitotic rate and positive staining for CK20. The sebaceous neoplasms with a carcinoidlike pattern may appear histologically similar, requiring immunohistochemical evaluation with monoclonal antibodies such as D2-40.¹³ A diffuse granular cytoplasmic reaction to chromogranin A is characteristic of carcinoid tumors. Synaptophysin and TTF-1 also are positive in carcinoid tumors, with TTF-1 being highly specific for neuroendocrine tumors of the lung.¹⁰

Cutaneous metastases of internal malignancies are more common from carcinomas of the lungs, gastrointestinal tract, and breasts.⁵ Occasionally, the cutaneous metastasis will develop directly over the underlying malignancy. Our case of cutaneous metastasis of a carcinoid tumor presented as an exquisitely tender and painful papule on the cheek. The histology of the lesion was consistent with the known carcinoid tumor of the lung. Because these lesions are extremely uncommon, it is imperative to obtain an accurate clinical history and use the appropriate immunohistochemical panel to correctly diagnose these metastases.

Take-Home Points

• AIPD of DM-THA is defined by dissociation within 1 year of implantation resulting from component impingement or closed reduction maneuvers.
• This is a distinct entity from “late” IPD (>1 year) from implantation as this is associated most often with polyethylene wear, component loosening, and arthrofibrosis.
• A history of DM dislocation followed by subjective “clunking,” instability, and a series of more frequent dislocations should raise concern for AIPD.
• Classic radiographic findings of AIPD include eccentric hip reduction and soft tissue radiolucency (ie, halo sign) from dissociated polyethylene component.

• Treating practitioners of AIPD should consider closed reduction with general anesthesia and sedation in the operating room to limit risk of dissociation.

Dual-mobility (DM) components were invented in the 1970s and have been used in primary and revision total hip arthroplasty (THA) in Europe ever since.¹ However, DM components are most commonly used in the treatment of recurrent hip instability, and early results have been promising.² In DM-THAs, a smaller (22-mm or 28-mm) metal femoral head snap-fits into a larger polyethylene ball (inner articulation), which articulates with a highly polished metal shell (outer articulation), which is either implanted directly in the acetabulum or placed in an uncemented acetabular cup. The 2 articulations used in these devices theoretically increase hip range of motion (ROM) and increase the inferior head displacement distance (jump distance) required for dislocation.³

However, this DM articulation with increased ROM may also cause chronic impingement of the femoral component neck or Morse taper against the outer polyethylene bearing, resulting in polyethylene wear and late intraprosthetic dissociation (IPD) (separation of inner articulation between femoral head and polyethylene liner). In 2004, Lecuire and colleagues⁴ reported 7 cases of IPD occurring a mean of 10 years after implantation during the period 1989 to 1997. In 2013, Philippot and colleagues⁵ reported that 81 of 1960 primary THAs developed IPD a mean of 9 years after implantation. These IPD cases were attributed to polyethylene wear or outer articulation blockage caused by arthrofibrosis or heterotopic ossification. Reports of acute IPD (AIPD), however, are rare. In 2011, Stigbrand and Ullmark⁶ reported 3 cases in which the DM prosthesis dislocated within 1 year after implantation. It was suggested that the inner metal head dissociated from the larger polyethylene component after attempted closed reduction for dislocation (separation of larger polyethylene component from acetabulum or acetabular liner).

DM components were unavailable to surgeons in the United States until 2011. The first US Food and Drug Administration (FDA)-approved DM device was the MDM (Modular Dual Mobility, Stryker). To our knowledge, 2 cases of AIPD with this prosthesis have been reported.^{7, 8} As with the cases in Europe, closed reduction was the suspected cause, but there was no explanation for the initial dislocation event.

In this article, we present the case of a nondemented man who developed AIPD of a THA with the MDM component and a 28-mm femoral head with a skirted neck (StelKast). His operative findings suggest a poor head-to-neck ratio caused by a larger diameter femoral neck or a skirted prosthesis, or a forceful reduction maneuver, may predispose DM components to AIPD. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In 2012, a 63-year-old man with a history of drug abuse underwent left primary THA. Seven posterior dislocations and 3 years later, the acetabular component was revised to the MDM prosthesis; the well-fixed StelKast femoral component was retained (Figure 1).

Within 3 months after revision surgery, the left hip dislocated 3 times in 1 week, when the patient bent over to retrieve an object on the ground. The first 2 dislocations were treated with closed reduction under conscious sedation at an outside emergency department.

Shortly after, the patient, with complaints of left hip pain and clunking, was seen by a physician assistant, but the treating team did not notice the eccentric reduction on radiographs. The third dislocation was treated with closed reduction under conscious sedation in the emergency department at our institution (Figure 2). Postreduction radiographs still showed the eccentric reduction, and a radiolucent halo was visible superior to the greater trochanter (Figure 3).

With the patient’s erythrocyte sedimentation rate and C-reactive protein level both normal, a second revision was performed. During surgery, the polyethylene head was found beneath the gluteus maximus (Figure 4).

Gross inspection revealed a small amount of eccentric polyethylene wear and metal debris of the inner articulation (Figure 5). As the abductor muscles were intact, it was decided to proceed with revision to a larger DM component and to downsize the femoral head to a skirtless component (Table, Figure 6).

 

Discussion

Recurrent dislocation and instability accounts for 22.5% of THA revisions in the United States.⁹ Until 2011, options for managing recurrent dislocation in the United States included modular component exchange, component revision for malposition, and use of constrained components.¹⁰

However, the decreased motion of constrained components may produce excess stress that eventually results in failure.^11-13

In 1974, Bousquet first reported use of the DM prosthesis in primary THA; the prosthesis allowed increased stability without sacrificing motion or fixation.¹ However, longer-term studies of DM components disclosed a new complication, IPD. In 2004, Lecuire and colleagues⁴ reported 7 cases of IPD occurring a mean of 10 years after implantation of the Bousquet prosthesis.

Philippot and colleagues⁵ reported that 81 of 1960 primary THAs with DM components developed IPD a mean of 9 years after implantation. They described 3 types of IPD based on mechanism of injury: type I, caused by wear of the inner articulation without arthrofibrosis or cup loosening (n = 26); type II, resulting from blocked outer articulation motion, caused by arthrofibrosis, nonunion, calcification, or heterotopic ossification (n = 41); and type III, associated with acetabular component loosening (n = 14). IPD occurred an average of 11 years (type I), 8 years (type II), and 9 years (type III) after implantation.

AIPD, which occurs within 1 year after implantation, has been reported much less often than late IPD. Stigbrand and Ullmark⁶ reported 3 cases of AIPD that developed within 7 months after implantation of Amplitude and Advantage (Zimmer Biomet) DM prostheses.

The authors proposed that AIPD is related to incomplete coupling of the metal head and the inner polyethylene liner or to shearing of the large polyethylene component on the acetabular rim during a closed reduction maneuver. According to their description, the femoral head in the acetabulum had an “eccentric” radiographic appearance. The authors recommended administering muscle relaxants during closed reduction to avoid dissociation of the liner during the reduction.

This unusual complication apparently is not confined to a specific implant or region. Since the MDM component was introduced in the United States, 2 more cases of AIPD have been identified (Table). Banzhof and colleagues⁷ reported the case of a 68-year-old woman who, 2 months after the MDM was placed for recurrent instability, dislocated the component while rising from a seated position. Her IPD most likely resulted from a closed reduction. The affected hip eventually required closed reduction in the operating room. Postreduction radiographs showed the characteristic eccentric appearance; a halo, also visible in the soft tissues, corresponded with the dissociated radiolucent polyethylene liner. The authors attributed the early failure to an eccentrically seated metal liner that separated the locking mechanism. The MDM component was revised to a conventional THA, with the femoral head upsized and length added.

Ward and colleagues⁸ reported the case of an 87-year-old woman who had a conventional THA revised to an MDM component for recurrent instability. Two months after surgery, this patient, who had dementia, experienced 2 posterior dislocations while rising from a chair. Closed reduction in the emergency department seemed successful, but later she presented to the surgeon’s office with symptoms of instability and clunking, complaints similar to our patient’s. Radiographs showed an eccentric reduction caused by IPD, and the MDM component was revised to a constrained liner. Adding a MDM component to a retained DePuy (DePuy Synthes) femoral stem and head is considered “off-label use,” which, the authors proposed, may have been related to the AIPD in their patient’s case. However, one manufacturer’s femoral component and head are often mated with another manufacturer’s acetabular component to allow for a less complex revision. Our recommendation for surgeons is that, before proceeding with this treatment option, they investigate each component’s exact dimensions to ensure there are no subtle size differences that could cause problems. For example, a 28-mm head diameter that is actually 28.2 mm may affect mating properties, with the inner polyethylene articulation causing AIPD to develop.

Other cases of earlier IPD have been described, but they do not fit the APID definition given in this article. Riviere and colleagues¹⁴ reported the case of a 42-year-old man who, because of a previous adverse reaction to metal debris, underwent revision to a DM polyethylene ball in a retained BHR (Birmingham Hip Resurfacing) acetabular shell (Birmingham Hip, Smith & Nephew). Unfortunately, IPD occurred 14 months after surgery. Banka and colleagues¹⁵ reported the case of a 70-year-old woman who underwent revision to a DM cup for recurrent instability, but they did not specify the length of time between implantation and IPD and did not offer an explanation for the complication. Finally, Odland and Sierra¹⁶ reported the case of a 77-year-old man, with previous intertrochanteric and pelvic fractures, who underwent revision to a DM cup with retention of a Waldemar femoral component (Waldemar Link). He spontaneously developed IPD with ambulation 2 years after surgery.

Certainly, our patient’s presentation course is similar to other patients’. Within 3 months after revision to the MDM component, his left hip dislocated 3 times in 1 week. We contend his AIPD resulted from closed reduction, with the polyethylene dislodged from the femoral head with contact on the acetabulum. A larger or skirted neck may increase impingement during normal activity and thereby widen the polyethylene opening excessively and/or reduce the polyethylene ball ROM to impinge during the relocation maneuver. In this case, dissociation was noted only after the third dislocation. Pathognomonic eccentric positioning of the head in the acetabulum and, less commonly, the halo sign were evident on postreduction radiographs. Optimal treatment for AIPD of a DM component is controversial. Choices are limited to a constrained liner or, if possible, repeat DM with larger components. For recurrent dislocation, our patient underwent revision to an MDM component, but a femoral head with a skirted neck was used in an attempt to increase soft-tissue tension. During the second revision, minor eccentric wear of the inner articulation of the polyethylene component (consistent with impingement) was noted, and wear was visible on inspection of the outer articulation. We think his AIPD resulted from femoral neck impingement of the skirted head against the polyethylene ball.

AIPD is a discrete entity, with sudden failure of a DM component within 1 year after implantation. AIPD is characterized by dissociation of the femoral head from the inner articulation, resulting from impingement or closed reduction. More studies are needed to determine which patients with DM components are at highest risk and which treatment is most appropriate. We recommend taking extra care when reducing hips with this articulation and adopting a low threshold for general anesthesia use in the presence of paralysis.

Am J Orthop. 2017;46(3):E154-E159. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

 

Take-Home Points

• AIPD of DM-THA is defined by dissociation within 1 year of implantation resulting from component impingement or closed reduction maneuvers.
• This is a distinct entity from “late” IPD (>1 year) from implantation as this is associated most often with polyethylene wear, component loosening, and arthrofibrosis.
• A history of DM dislocation followed by subjective “clunking,” instability, and a series of more frequent dislocations should raise concern for AIPD.
• Classic radiographic findings of AIPD include eccentric hip reduction and soft tissue radiolucency (ie, halo sign) from dissociated polyethylene component.

• Treating practitioners of AIPD should consider closed reduction with general anesthesia and sedation in the operating room to limit risk of dissociation.

Dual-mobility (DM) components were invented in the 1970s and have been used in primary and revision total hip arthroplasty (THA) in Europe ever since.¹ However, DM components are most commonly used in the treatment of recurrent hip instability, and early results have been promising.² In DM-THAs, a smaller (22-mm or 28-mm) metal femoral head snap-fits into a larger polyethylene ball (inner articulation), which articulates with a highly polished metal shell (outer articulation), which is either implanted directly in the acetabulum or placed in an uncemented acetabular cup. The 2 articulations used in these devices theoretically increase hip range of motion (ROM) and increase the inferior head displacement distance (jump distance) required for dislocation.³

However, this DM articulation with increased ROM may also cause chronic impingement of the femoral component neck or Morse taper against the outer polyethylene bearing, resulting in polyethylene wear and late intraprosthetic dissociation (IPD) (separation of inner articulation between femoral head and polyethylene liner). In 2004, Lecuire and colleagues⁴ reported 7 cases of IPD occurring a mean of 10 years after implantation during the period 1989 to 1997. In 2013, Philippot and colleagues⁵ reported that 81 of 1960 primary THAs developed IPD a mean of 9 years after implantation. These IPD cases were attributed to polyethylene wear or outer articulation blockage caused by arthrofibrosis or heterotopic ossification. Reports of acute IPD (AIPD), however, are rare. In 2011, Stigbrand and Ullmark⁶ reported 3 cases in which the DM prosthesis dislocated within 1 year after implantation. It was suggested that the inner metal head dissociated from the larger polyethylene component after attempted closed reduction for dislocation (separation of larger polyethylene component from acetabulum or acetabular liner).

DM components were unavailable to surgeons in the United States until 2011. The first US Food and Drug Administration (FDA)-approved DM device was the MDM (Modular Dual Mobility, Stryker). To our knowledge, 2 cases of AIPD with this prosthesis have been reported.^{7, 8} As with the cases in Europe, closed reduction was the suspected cause, but there was no explanation for the initial dislocation event.

In this article, we present the case of a nondemented man who developed AIPD of a THA with the MDM component and a 28-mm femoral head with a skirted neck (StelKast). His operative findings suggest a poor head-to-neck ratio caused by a larger diameter femoral neck or a skirted prosthesis, or a forceful reduction maneuver, may predispose DM components to AIPD. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In 2012, a 63-year-old man with a history of drug abuse underwent left primary THA. Seven posterior dislocations and 3 years later, the acetabular component was revised to the MDM prosthesis; the well-fixed StelKast femoral component was retained (Figure 1).

Within 3 months after revision surgery, the left hip dislocated 3 times in 1 week, when the patient bent over to retrieve an object on the ground. The first 2 dislocations were treated with closed reduction under conscious sedation at an outside emergency department.

Shortly after, the patient, with complaints of left hip pain and clunking, was seen by a physician assistant, but the treating team did not notice the eccentric reduction on radiographs. The third dislocation was treated with closed reduction under conscious sedation in the emergency department at our institution (Figure 2). Postreduction radiographs still showed the eccentric reduction, and a radiolucent halo was visible superior to the greater trochanter (Figure 3).

With the patient’s erythrocyte sedimentation rate and C-reactive protein level both normal, a second revision was performed. During surgery, the polyethylene head was found beneath the gluteus maximus (Figure 4).

Gross inspection revealed a small amount of eccentric polyethylene wear and metal debris of the inner articulation (Figure 5). As the abductor muscles were intact, it was decided to proceed with revision to a larger DM component and to downsize the femoral head to a skirtless component (Table, Figure 6).

 

Discussion

Recurrent dislocation and instability accounts for 22.5% of THA revisions in the United States.⁹ Until 2011, options for managing recurrent dislocation in the United States included modular component exchange, component revision for malposition, and use of constrained components.¹⁰

However, the decreased motion of constrained components may produce excess stress that eventually results in failure.^11-13

In 1974, Bousquet first reported use of the DM prosthesis in primary THA; the prosthesis allowed increased stability without sacrificing motion or fixation.¹ However, longer-term studies of DM components disclosed a new complication, IPD. In 2004, Lecuire and colleagues⁴ reported 7 cases of IPD occurring a mean of 10 years after implantation of the Bousquet prosthesis.

Philippot and colleagues⁵ reported that 81 of 1960 primary THAs with DM components developed IPD a mean of 9 years after implantation. They described 3 types of IPD based on mechanism of injury: type I, caused by wear of the inner articulation without arthrofibrosis or cup loosening (n = 26); type II, resulting from blocked outer articulation motion, caused by arthrofibrosis, nonunion, calcification, or heterotopic ossification (n = 41); and type III, associated with acetabular component loosening (n = 14). IPD occurred an average of 11 years (type I), 8 years (type II), and 9 years (type III) after implantation.

AIPD, which occurs within 1 year after implantation, has been reported much less often than late IPD. Stigbrand and Ullmark⁶ reported 3 cases of AIPD that developed within 7 months after implantation of Amplitude and Advantage (Zimmer Biomet) DM prostheses.

The authors proposed that AIPD is related to incomplete coupling of the metal head and the inner polyethylene liner or to shearing of the large polyethylene component on the acetabular rim during a closed reduction maneuver. According to their description, the femoral head in the acetabulum had an “eccentric” radiographic appearance. The authors recommended administering muscle relaxants during closed reduction to avoid dissociation of the liner during the reduction.

This unusual complication apparently is not confined to a specific implant or region. Since the MDM component was introduced in the United States, 2 more cases of AIPD have been identified (Table). Banzhof and colleagues⁷ reported the case of a 68-year-old woman who, 2 months after the MDM was placed for recurrent instability, dislocated the component while rising from a seated position. Her IPD most likely resulted from a closed reduction. The affected hip eventually required closed reduction in the operating room. Postreduction radiographs showed the characteristic eccentric appearance; a halo, also visible in the soft tissues, corresponded with the dissociated radiolucent polyethylene liner. The authors attributed the early failure to an eccentrically seated metal liner that separated the locking mechanism. The MDM component was revised to a conventional THA, with the femoral head upsized and length added.

Ward and colleagues⁸ reported the case of an 87-year-old woman who had a conventional THA revised to an MDM component for recurrent instability. Two months after surgery, this patient, who had dementia, experienced 2 posterior dislocations while rising from a chair. Closed reduction in the emergency department seemed successful, but later she presented to the surgeon’s office with symptoms of instability and clunking, complaints similar to our patient’s. Radiographs showed an eccentric reduction caused by IPD, and the MDM component was revised to a constrained liner. Adding a MDM component to a retained DePuy (DePuy Synthes) femoral stem and head is considered “off-label use,” which, the authors proposed, may have been related to the AIPD in their patient’s case. However, one manufacturer’s femoral component and head are often mated with another manufacturer’s acetabular component to allow for a less complex revision. Our recommendation for surgeons is that, before proceeding with this treatment option, they investigate each component’s exact dimensions to ensure there are no subtle size differences that could cause problems. For example, a 28-mm head diameter that is actually 28.2 mm may affect mating properties, with the inner polyethylene articulation causing AIPD to develop.

Other cases of earlier IPD have been described, but they do not fit the APID definition given in this article. Riviere and colleagues¹⁴ reported the case of a 42-year-old man who, because of a previous adverse reaction to metal debris, underwent revision to a DM polyethylene ball in a retained BHR (Birmingham Hip Resurfacing) acetabular shell (Birmingham Hip, Smith & Nephew). Unfortunately, IPD occurred 14 months after surgery. Banka and colleagues¹⁵ reported the case of a 70-year-old woman who underwent revision to a DM cup for recurrent instability, but they did not specify the length of time between implantation and IPD and did not offer an explanation for the complication. Finally, Odland and Sierra¹⁶ reported the case of a 77-year-old man, with previous intertrochanteric and pelvic fractures, who underwent revision to a DM cup with retention of a Waldemar femoral component (Waldemar Link). He spontaneously developed IPD with ambulation 2 years after surgery.

Certainly, our patient’s presentation course is similar to other patients’. Within 3 months after revision to the MDM component, his left hip dislocated 3 times in 1 week. We contend his AIPD resulted from closed reduction, with the polyethylene dislodged from the femoral head with contact on the acetabulum. A larger or skirted neck may increase impingement during normal activity and thereby widen the polyethylene opening excessively and/or reduce the polyethylene ball ROM to impinge during the relocation maneuver. In this case, dissociation was noted only after the third dislocation. Pathognomonic eccentric positioning of the head in the acetabulum and, less commonly, the halo sign were evident on postreduction radiographs. Optimal treatment for AIPD of a DM component is controversial. Choices are limited to a constrained liner or, if possible, repeat DM with larger components. For recurrent dislocation, our patient underwent revision to an MDM component, but a femoral head with a skirted neck was used in an attempt to increase soft-tissue tension. During the second revision, minor eccentric wear of the inner articulation of the polyethylene component (consistent with impingement) was noted, and wear was visible on inspection of the outer articulation. We think his AIPD resulted from femoral neck impingement of the skirted head against the polyethylene ball.

AIPD is a discrete entity, with sudden failure of a DM component within 1 year after implantation. AIPD is characterized by dissociation of the femoral head from the inner articulation, resulting from impingement or closed reduction. More studies are needed to determine which patients with DM components are at highest risk and which treatment is most appropriate. We recommend taking extra care when reducing hips with this articulation and adopting a low threshold for general anesthesia use in the presence of paralysis.

Am J Orthop. 2017;46(3):E154-E159. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

 

Take-Home Points

• AIPD of DM-THA is defined by dissociation within 1 year of implantation resulting from component impingement or closed reduction maneuvers.
• This is a distinct entity from “late” IPD (>1 year) from implantation as this is associated most often with polyethylene wear, component loosening, and arthrofibrosis.
• A history of DM dislocation followed by subjective “clunking,” instability, and a series of more frequent dislocations should raise concern for AIPD.
• Classic radiographic findings of AIPD include eccentric hip reduction and soft tissue radiolucency (ie, halo sign) from dissociated polyethylene component.

• Treating practitioners of AIPD should consider closed reduction with general anesthesia and sedation in the operating room to limit risk of dissociation.

Dual-mobility (DM) components were invented in the 1970s and have been used in primary and revision total hip arthroplasty (THA) in Europe ever since.¹ However, DM components are most commonly used in the treatment of recurrent hip instability, and early results have been promising.² In DM-THAs, a smaller (22-mm or 28-mm) metal femoral head snap-fits into a larger polyethylene ball (inner articulation), which articulates with a highly polished metal shell (outer articulation), which is either implanted directly in the acetabulum or placed in an uncemented acetabular cup. The 2 articulations used in these devices theoretically increase hip range of motion (ROM) and increase the inferior head displacement distance (jump distance) required for dislocation.³

However, this DM articulation with increased ROM may also cause chronic impingement of the femoral component neck or Morse taper against the outer polyethylene bearing, resulting in polyethylene wear and late intraprosthetic dissociation (IPD) (separation of inner articulation between femoral head and polyethylene liner). In 2004, Lecuire and colleagues⁴ reported 7 cases of IPD occurring a mean of 10 years after implantation during the period 1989 to 1997. In 2013, Philippot and colleagues⁵ reported that 81 of 1960 primary THAs developed IPD a mean of 9 years after implantation. These IPD cases were attributed to polyethylene wear or outer articulation blockage caused by arthrofibrosis or heterotopic ossification. Reports of acute IPD (AIPD), however, are rare. In 2011, Stigbrand and Ullmark⁶ reported 3 cases in which the DM prosthesis dislocated within 1 year after implantation. It was suggested that the inner metal head dissociated from the larger polyethylene component after attempted closed reduction for dislocation (separation of larger polyethylene component from acetabulum or acetabular liner).

DM components were unavailable to surgeons in the United States until 2011. The first US Food and Drug Administration (FDA)-approved DM device was the MDM (Modular Dual Mobility, Stryker). To our knowledge, 2 cases of AIPD with this prosthesis have been reported.^{7, 8} As with the cases in Europe, closed reduction was the suspected cause, but there was no explanation for the initial dislocation event.

In this article, we present the case of a nondemented man who developed AIPD of a THA with the MDM component and a 28-mm femoral head with a skirted neck (StelKast). His operative findings suggest a poor head-to-neck ratio caused by a larger diameter femoral neck or a skirted prosthesis, or a forceful reduction maneuver, may predispose DM components to AIPD. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In 2012, a 63-year-old man with a history of drug abuse underwent left primary THA. Seven posterior dislocations and 3 years later, the acetabular component was revised to the MDM prosthesis; the well-fixed StelKast femoral component was retained (Figure 1).

Within 3 months after revision surgery, the left hip dislocated 3 times in 1 week, when the patient bent over to retrieve an object on the ground. The first 2 dislocations were treated with closed reduction under conscious sedation at an outside emergency department.

Shortly after, the patient, with complaints of left hip pain and clunking, was seen by a physician assistant, but the treating team did not notice the eccentric reduction on radiographs. The third dislocation was treated with closed reduction under conscious sedation in the emergency department at our institution (Figure 2). Postreduction radiographs still showed the eccentric reduction, and a radiolucent halo was visible superior to the greater trochanter (Figure 3).

With the patient’s erythrocyte sedimentation rate and C-reactive protein level both normal, a second revision was performed. During surgery, the polyethylene head was found beneath the gluteus maximus (Figure 4).

Gross inspection revealed a small amount of eccentric polyethylene wear and metal debris of the inner articulation (Figure 5). As the abductor muscles were intact, it was decided to proceed with revision to a larger DM component and to downsize the femoral head to a skirtless component (Table, Figure 6).

 

Discussion

Recurrent dislocation and instability accounts for 22.5% of THA revisions in the United States.⁹ Until 2011, options for managing recurrent dislocation in the United States included modular component exchange, component revision for malposition, and use of constrained components.¹⁰

However, the decreased motion of constrained components may produce excess stress that eventually results in failure.^11-13

In 1974, Bousquet first reported use of the DM prosthesis in primary THA; the prosthesis allowed increased stability without sacrificing motion or fixation.¹ However, longer-term studies of DM components disclosed a new complication, IPD. In 2004, Lecuire and colleagues⁴ reported 7 cases of IPD occurring a mean of 10 years after implantation of the Bousquet prosthesis.

Philippot and colleagues⁵ reported that 81 of 1960 primary THAs with DM components developed IPD a mean of 9 years after implantation. They described 3 types of IPD based on mechanism of injury: type I, caused by wear of the inner articulation without arthrofibrosis or cup loosening (n = 26); type II, resulting from blocked outer articulation motion, caused by arthrofibrosis, nonunion, calcification, or heterotopic ossification (n = 41); and type III, associated with acetabular component loosening (n = 14). IPD occurred an average of 11 years (type I), 8 years (type II), and 9 years (type III) after implantation.

AIPD, which occurs within 1 year after implantation, has been reported much less often than late IPD. Stigbrand and Ullmark⁶ reported 3 cases of AIPD that developed within 7 months after implantation of Amplitude and Advantage (Zimmer Biomet) DM prostheses.

The authors proposed that AIPD is related to incomplete coupling of the metal head and the inner polyethylene liner or to shearing of the large polyethylene component on the acetabular rim during a closed reduction maneuver. According to their description, the femoral head in the acetabulum had an “eccentric” radiographic appearance. The authors recommended administering muscle relaxants during closed reduction to avoid dissociation of the liner during the reduction.

This unusual complication apparently is not confined to a specific implant or region. Since the MDM component was introduced in the United States, 2 more cases of AIPD have been identified (Table). Banzhof and colleagues⁷ reported the case of a 68-year-old woman who, 2 months after the MDM was placed for recurrent instability, dislocated the component while rising from a seated position. Her IPD most likely resulted from a closed reduction. The affected hip eventually required closed reduction in the operating room. Postreduction radiographs showed the characteristic eccentric appearance; a halo, also visible in the soft tissues, corresponded with the dissociated radiolucent polyethylene liner. The authors attributed the early failure to an eccentrically seated metal liner that separated the locking mechanism. The MDM component was revised to a conventional THA, with the femoral head upsized and length added.

Ward and colleagues⁸ reported the case of an 87-year-old woman who had a conventional THA revised to an MDM component for recurrent instability. Two months after surgery, this patient, who had dementia, experienced 2 posterior dislocations while rising from a chair. Closed reduction in the emergency department seemed successful, but later she presented to the surgeon’s office with symptoms of instability and clunking, complaints similar to our patient’s. Radiographs showed an eccentric reduction caused by IPD, and the MDM component was revised to a constrained liner. Adding a MDM component to a retained DePuy (DePuy Synthes) femoral stem and head is considered “off-label use,” which, the authors proposed, may have been related to the AIPD in their patient’s case. However, one manufacturer’s femoral component and head are often mated with another manufacturer’s acetabular component to allow for a less complex revision. Our recommendation for surgeons is that, before proceeding with this treatment option, they investigate each component’s exact dimensions to ensure there are no subtle size differences that could cause problems. For example, a 28-mm head diameter that is actually 28.2 mm may affect mating properties, with the inner polyethylene articulation causing AIPD to develop.

Other cases of earlier IPD have been described, but they do not fit the APID definition given in this article. Riviere and colleagues¹⁴ reported the case of a 42-year-old man who, because of a previous adverse reaction to metal debris, underwent revision to a DM polyethylene ball in a retained BHR (Birmingham Hip Resurfacing) acetabular shell (Birmingham Hip, Smith & Nephew). Unfortunately, IPD occurred 14 months after surgery. Banka and colleagues¹⁵ reported the case of a 70-year-old woman who underwent revision to a DM cup for recurrent instability, but they did not specify the length of time between implantation and IPD and did not offer an explanation for the complication. Finally, Odland and Sierra¹⁶ reported the case of a 77-year-old man, with previous intertrochanteric and pelvic fractures, who underwent revision to a DM cup with retention of a Waldemar femoral component (Waldemar Link). He spontaneously developed IPD with ambulation 2 years after surgery.

Certainly, our patient’s presentation course is similar to other patients’. Within 3 months after revision to the MDM component, his left hip dislocated 3 times in 1 week. We contend his AIPD resulted from closed reduction, with the polyethylene dislodged from the femoral head with contact on the acetabulum. A larger or skirted neck may increase impingement during normal activity and thereby widen the polyethylene opening excessively and/or reduce the polyethylene ball ROM to impinge during the relocation maneuver. In this case, dissociation was noted only after the third dislocation. Pathognomonic eccentric positioning of the head in the acetabulum and, less commonly, the halo sign were evident on postreduction radiographs. Optimal treatment for AIPD of a DM component is controversial. Choices are limited to a constrained liner or, if possible, repeat DM with larger components. For recurrent dislocation, our patient underwent revision to an MDM component, but a femoral head with a skirted neck was used in an attempt to increase soft-tissue tension. During the second revision, minor eccentric wear of the inner articulation of the polyethylene component (consistent with impingement) was noted, and wear was visible on inspection of the outer articulation. We think his AIPD resulted from femoral neck impingement of the skirted head against the polyethylene ball.

AIPD is a discrete entity, with sudden failure of a DM component within 1 year after implantation. AIPD is characterized by dissociation of the femoral head from the inner articulation, resulting from impingement or closed reduction. More studies are needed to determine which patients with DM components are at highest risk and which treatment is most appropriate. We recommend taking extra care when reducing hips with this articulation and adopting a low threshold for general anesthesia use in the presence of paralysis.

Am J Orthop. 2017;46(3):E154-E159. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

 

Case

A 49-year-old man with a history of hypertension, for which he was taking aspirin, carvedilol, hydralazine, and nifedipine, presented to the ED with complaints of left-sided weakness that started 3 hours before he came to the ED. Initial vital signs were: blood pressure, 158/90 mm Hg; heart rate, 74 beats/min; respiratory rate, 18 breaths/min; and temperature, 98°F. Oxygen saturation was 100% on room air, and a finger-stick glucose test was 106 mg/dL.

Physical examination revealed slowed speech with mild dysarthria, mild left facial droop, 2/5 strength in all muscle groups in the left upper and lower extremities, and decreased sensation to light touch on the left side. The patient also had left-sided sensory neglect and an abnormal gait, and dragged his left foot on the floor when walking. The rest of his examination was normal.

The stroke team was activated, and the patient was immediately transferred to the ED radiology department for imaging studies. A noncontrast head computed tomography (CT) was negative for any acute intracranial hemorrhage or cerebral edema. A CT angiogram (CTA) also was performed, which revealed atherosclerosis but no arterial occlusion. Based on these findings and the existing protocol, the patient received an intravenous (IV) bolus of tissue plasminogen activator (tPA). Approximately 17 minutes after tPA administration, the patient developed left-sided upper and lower lip swelling. There was no voice change, tongue swelling, or uvular deviation.

What is the differential diagnosis of swelling of the lip?

The differential diagnoses for lip swelling includes trauma, allergic reaction, and angioedema (hereditary, or angiotensin converting enzyme inhibitor [ACEI]-induced). The patient in this case denied any trauma to the lip, and no bleeding was noted from the lip; however, his entire left lip (upper and lower) was swollen. He was not taking any ACEIs or angiotensin-receptor blockers (ARBs). He also denied a family history of angioedema or any prior similar episodes. The patient further denied exposure to any new medications, foods, or other substances and had no respiratory distress, urticaria, or other findings consistent with an allergy.

What are the common adverse effects of tPA?

The only US Food and Drug-approved pharmacological treatment for ischemic stroke is tPA (also known as IV rtPA). Tissue plasminogen activator hydrolyzes plasminogen to plasmin, which exerts a fibrinolytic effect. Based on the ability of tPA to lyse thrombus, it is also a standard therapy for hemodynamically unstable patients with confirmed pulmonary embolism, as well as for patients with myocardial infarction in whom percutaneous intervention is contraindicated or unavailable. Despite the beneficial effects of tPA, significant adverse effects are associated with the drug. For example, thrombolysis may result in conversion of an ischemic stroke into a hemorrhagic event, resulting in generalized bleeding from mucosal surfaces.

The increase in plasmin may play a role in the development of angioedema by activating the kinin pathway, leading to the formation of the vasodilator bradykinin (Figure). Plasmin also activates the complement system and leads to the production of anaphylatoxins C₃a, C₄a, and C₅a, which also cause mast cell degranulation and histamine release.¹

When does post-tPA angioedema occur?

In the few published case reports available, tPA-induced angioedema was shown to typically occur in the stroke distribution (which was attributed to the left-sided swelling in this patient).² Following tPA administration, the onset of angioedema reportedly varies from as early as 10 to 15 minutes from initiation until about 1 hour postinfusion. The short half-life of tPA (approximately 7 minutes)² limits the outer- time window for the initial development of angioedema, but progression can continue well beyond this timeframe.

What is the treatment for tPA-induced angioedema?

The first priority of acute management of angioedema is discontinuation of the inciting substance, if possible—in this case, the tPA infusion.³ Assessment and maintenance of a patent airway are of utmost concern. Patients with posterior oropharyngeal effects or who are progressing should be admitted to an intensive care unit (ICU) for observation.^4-6

 

Endotracheal Intubation. Providers should have a low threshold for endotracheal intubation, which should ideally be performed in any patient at risk for airway compromise.⁴ Due to the extensive airway swelling that can occur in the setting of angioedema, airway intervention should optimally be performed by an available clinician with the most skill and experience in this area. It is wise to be prepared to utilize advanced airway techniques, if available, including fiberoptic laryngoscopy or potentially cricothyrotomy.

Histamine Agonists. Standard therapy for patients who develop angioedema should include histamine antagonists, such as diphenhydramine (H₁ antagonist) and famotidine (H₂ antagonist) along with corticosteroids. Although these therapies are unlikely to be helpful in the treatment of tPA-induced angioedema, the difficulty in excluding allergic angioedema and the low risk of adverse effects associated with these medications support their use.

Fresh Frozen Plasma. Fresh frozen plasma (FFP) should be considered for patients who have a history of hereditary angioedema. Fresh frozen plasma contains enzymes that degrade bradykinin. Although FFP has been used successfully in the treatment of ACEI-induced angioedema, its use (or benefit) in tPA-related cases is not clear.

Icatibant. A selective bradykinin B₂-receptor antagonist, icatibant has been used to treat patients with ACEI-induced angioedema because of its effects on bradykinin receptors. Comparison of the efficacy of icatibant to the prevailing treatment strategy of diphenhydramine, famotidine, and methylprednisolone found a shorter time to symptom relief with icatibant.⁷ However, icatibant is extremely expensive ($23,000/30 mg). As previously mentioned, based on its similar mechanism of action, lower cost, and safety profile, FFP can be given (off label) in this situation.

Case Conclusion

The patient was given diphenhydramine, famotidine, and methylprednisolone, but did not show any improvement. His upper/lower lip swelling continued to worsen, and 30 minutes after the onset of angioedema, he was unable to open his mouth more than 1 cm.

Multiple attempts to perform awake fiberoptic intubation failed due to inadequate sedation; however, intubation was successfully performed following light sedation. The patient self-extubated in the ICU on hospital day 3, and the angioedema had progressively decreased. Angioedema and weakness completely resolved by hospital day 4, and he was discharged home on hospital day 7.

Case

A 49-year-old man with a history of hypertension, for which he was taking aspirin, carvedilol, hydralazine, and nifedipine, presented to the ED with complaints of left-sided weakness that started 3 hours before he came to the ED. Initial vital signs were: blood pressure, 158/90 mm Hg; heart rate, 74 beats/min; respiratory rate, 18 breaths/min; and temperature, 98°F. Oxygen saturation was 100% on room air, and a finger-stick glucose test was 106 mg/dL.

Physical examination revealed slowed speech with mild dysarthria, mild left facial droop, 2/5 strength in all muscle groups in the left upper and lower extremities, and decreased sensation to light touch on the left side. The patient also had left-sided sensory neglect and an abnormal gait, and dragged his left foot on the floor when walking. The rest of his examination was normal.

The stroke team was activated, and the patient was immediately transferred to the ED radiology department for imaging studies. A noncontrast head computed tomography (CT) was negative for any acute intracranial hemorrhage or cerebral edema. A CT angiogram (CTA) also was performed, which revealed atherosclerosis but no arterial occlusion. Based on these findings and the existing protocol, the patient received an intravenous (IV) bolus of tissue plasminogen activator (tPA). Approximately 17 minutes after tPA administration, the patient developed left-sided upper and lower lip swelling. There was no voice change, tongue swelling, or uvular deviation.

What is the differential diagnosis of swelling of the lip?

The differential diagnoses for lip swelling includes trauma, allergic reaction, and angioedema (hereditary, or angiotensin converting enzyme inhibitor [ACEI]-induced). The patient in this case denied any trauma to the lip, and no bleeding was noted from the lip; however, his entire left lip (upper and lower) was swollen. He was not taking any ACEIs or angiotensin-receptor blockers (ARBs). He also denied a family history of angioedema or any prior similar episodes. The patient further denied exposure to any new medications, foods, or other substances and had no respiratory distress, urticaria, or other findings consistent with an allergy.

What are the common adverse effects of tPA?

The only US Food and Drug-approved pharmacological treatment for ischemic stroke is tPA (also known as IV rtPA). Tissue plasminogen activator hydrolyzes plasminogen to plasmin, which exerts a fibrinolytic effect. Based on the ability of tPA to lyse thrombus, it is also a standard therapy for hemodynamically unstable patients with confirmed pulmonary embolism, as well as for patients with myocardial infarction in whom percutaneous intervention is contraindicated or unavailable. Despite the beneficial effects of tPA, significant adverse effects are associated with the drug. For example, thrombolysis may result in conversion of an ischemic stroke into a hemorrhagic event, resulting in generalized bleeding from mucosal surfaces.

The increase in plasmin may play a role in the development of angioedema by activating the kinin pathway, leading to the formation of the vasodilator bradykinin (Figure). Plasmin also activates the complement system and leads to the production of anaphylatoxins C₃a, C₄a, and C₅a, which also cause mast cell degranulation and histamine release.¹

When does post-tPA angioedema occur?

In the few published case reports available, tPA-induced angioedema was shown to typically occur in the stroke distribution (which was attributed to the left-sided swelling in this patient).² Following tPA administration, the onset of angioedema reportedly varies from as early as 10 to 15 minutes from initiation until about 1 hour postinfusion. The short half-life of tPA (approximately 7 minutes)² limits the outer- time window for the initial development of angioedema, but progression can continue well beyond this timeframe.

What is the treatment for tPA-induced angioedema?

The first priority of acute management of angioedema is discontinuation of the inciting substance, if possible—in this case, the tPA infusion.³ Assessment and maintenance of a patent airway are of utmost concern. Patients with posterior oropharyngeal effects or who are progressing should be admitted to an intensive care unit (ICU) for observation.^4-6

 

Endotracheal Intubation. Providers should have a low threshold for endotracheal intubation, which should ideally be performed in any patient at risk for airway compromise.⁴ Due to the extensive airway swelling that can occur in the setting of angioedema, airway intervention should optimally be performed by an available clinician with the most skill and experience in this area. It is wise to be prepared to utilize advanced airway techniques, if available, including fiberoptic laryngoscopy or potentially cricothyrotomy.

Histamine Agonists. Standard therapy for patients who develop angioedema should include histamine antagonists, such as diphenhydramine (H₁ antagonist) and famotidine (H₂ antagonist) along with corticosteroids. Although these therapies are unlikely to be helpful in the treatment of tPA-induced angioedema, the difficulty in excluding allergic angioedema and the low risk of adverse effects associated with these medications support their use.

Fresh Frozen Plasma. Fresh frozen plasma (FFP) should be considered for patients who have a history of hereditary angioedema. Fresh frozen plasma contains enzymes that degrade bradykinin. Although FFP has been used successfully in the treatment of ACEI-induced angioedema, its use (or benefit) in tPA-related cases is not clear.

Icatibant. A selective bradykinin B₂-receptor antagonist, icatibant has been used to treat patients with ACEI-induced angioedema because of its effects on bradykinin receptors. Comparison of the efficacy of icatibant to the prevailing treatment strategy of diphenhydramine, famotidine, and methylprednisolone found a shorter time to symptom relief with icatibant.⁷ However, icatibant is extremely expensive ($23,000/30 mg). As previously mentioned, based on its similar mechanism of action, lower cost, and safety profile, FFP can be given (off label) in this situation.

Case Conclusion

The patient was given diphenhydramine, famotidine, and methylprednisolone, but did not show any improvement. His upper/lower lip swelling continued to worsen, and 30 minutes after the onset of angioedema, he was unable to open his mouth more than 1 cm.

Multiple attempts to perform awake fiberoptic intubation failed due to inadequate sedation; however, intubation was successfully performed following light sedation. The patient self-extubated in the ICU on hospital day 3, and the angioedema had progressively decreased. Angioedema and weakness completely resolved by hospital day 4, and he was discharged home on hospital day 7.

Case

A 49-year-old man with a history of hypertension, for which he was taking aspirin, carvedilol, hydralazine, and nifedipine, presented to the ED with complaints of left-sided weakness that started 3 hours before he came to the ED. Initial vital signs were: blood pressure, 158/90 mm Hg; heart rate, 74 beats/min; respiratory rate, 18 breaths/min; and temperature, 98°F. Oxygen saturation was 100% on room air, and a finger-stick glucose test was 106 mg/dL.

Physical examination revealed slowed speech with mild dysarthria, mild left facial droop, 2/5 strength in all muscle groups in the left upper and lower extremities, and decreased sensation to light touch on the left side. The patient also had left-sided sensory neglect and an abnormal gait, and dragged his left foot on the floor when walking. The rest of his examination was normal.

The stroke team was activated, and the patient was immediately transferred to the ED radiology department for imaging studies. A noncontrast head computed tomography (CT) was negative for any acute intracranial hemorrhage or cerebral edema. A CT angiogram (CTA) also was performed, which revealed atherosclerosis but no arterial occlusion. Based on these findings and the existing protocol, the patient received an intravenous (IV) bolus of tissue plasminogen activator (tPA). Approximately 17 minutes after tPA administration, the patient developed left-sided upper and lower lip swelling. There was no voice change, tongue swelling, or uvular deviation.

What is the differential diagnosis of swelling of the lip?

The differential diagnoses for lip swelling includes trauma, allergic reaction, and angioedema (hereditary, or angiotensin converting enzyme inhibitor [ACEI]-induced). The patient in this case denied any trauma to the lip, and no bleeding was noted from the lip; however, his entire left lip (upper and lower) was swollen. He was not taking any ACEIs or angiotensin-receptor blockers (ARBs). He also denied a family history of angioedema or any prior similar episodes. The patient further denied exposure to any new medications, foods, or other substances and had no respiratory distress, urticaria, or other findings consistent with an allergy.

What are the common adverse effects of tPA?

The only US Food and Drug-approved pharmacological treatment for ischemic stroke is tPA (also known as IV rtPA). Tissue plasminogen activator hydrolyzes plasminogen to plasmin, which exerts a fibrinolytic effect. Based on the ability of tPA to lyse thrombus, it is also a standard therapy for hemodynamically unstable patients with confirmed pulmonary embolism, as well as for patients with myocardial infarction in whom percutaneous intervention is contraindicated or unavailable. Despite the beneficial effects of tPA, significant adverse effects are associated with the drug. For example, thrombolysis may result in conversion of an ischemic stroke into a hemorrhagic event, resulting in generalized bleeding from mucosal surfaces.

The increase in plasmin may play a role in the development of angioedema by activating the kinin pathway, leading to the formation of the vasodilator bradykinin (Figure). Plasmin also activates the complement system and leads to the production of anaphylatoxins C₃a, C₄a, and C₅a, which also cause mast cell degranulation and histamine release.¹

When does post-tPA angioedema occur?

In the few published case reports available, tPA-induced angioedema was shown to typically occur in the stroke distribution (which was attributed to the left-sided swelling in this patient).² Following tPA administration, the onset of angioedema reportedly varies from as early as 10 to 15 minutes from initiation until about 1 hour postinfusion. The short half-life of tPA (approximately 7 minutes)² limits the outer- time window for the initial development of angioedema, but progression can continue well beyond this timeframe.

What is the treatment for tPA-induced angioedema?

The first priority of acute management of angioedema is discontinuation of the inciting substance, if possible—in this case, the tPA infusion.³ Assessment and maintenance of a patent airway are of utmost concern. Patients with posterior oropharyngeal effects or who are progressing should be admitted to an intensive care unit (ICU) for observation.^4-6

 

Endotracheal Intubation. Providers should have a low threshold for endotracheal intubation, which should ideally be performed in any patient at risk for airway compromise.⁴ Due to the extensive airway swelling that can occur in the setting of angioedema, airway intervention should optimally be performed by an available clinician with the most skill and experience in this area. It is wise to be prepared to utilize advanced airway techniques, if available, including fiberoptic laryngoscopy or potentially cricothyrotomy.

Histamine Agonists. Standard therapy for patients who develop angioedema should include histamine antagonists, such as diphenhydramine (H₁ antagonist) and famotidine (H₂ antagonist) along with corticosteroids. Although these therapies are unlikely to be helpful in the treatment of tPA-induced angioedema, the difficulty in excluding allergic angioedema and the low risk of adverse effects associated with these medications support their use.

Fresh Frozen Plasma. Fresh frozen plasma (FFP) should be considered for patients who have a history of hereditary angioedema. Fresh frozen plasma contains enzymes that degrade bradykinin. Although FFP has been used successfully in the treatment of ACEI-induced angioedema, its use (or benefit) in tPA-related cases is not clear.

Icatibant. A selective bradykinin B₂-receptor antagonist, icatibant has been used to treat patients with ACEI-induced angioedema because of its effects on bradykinin receptors. Comparison of the efficacy of icatibant to the prevailing treatment strategy of diphenhydramine, famotidine, and methylprednisolone found a shorter time to symptom relief with icatibant.⁷ However, icatibant is extremely expensive ($23,000/30 mg). As previously mentioned, based on its similar mechanism of action, lower cost, and safety profile, FFP can be given (off label) in this situation.

Case Conclusion

The patient was given diphenhydramine, famotidine, and methylprednisolone, but did not show any improvement. His upper/lower lip swelling continued to worsen, and 30 minutes after the onset of angioedema, he was unable to open his mouth more than 1 cm.

Multiple attempts to perform awake fiberoptic intubation failed due to inadequate sedation; however, intubation was successfully performed following light sedation. The patient self-extubated in the ICU on hospital day 3, and the angioedema had progressively decreased. Angioedema and weakness completely resolved by hospital day 4, and he was discharged home on hospital day 7.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

 

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

 

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

 

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

RELATED ARTICLE: Basal Cell Carcinoma: Analysis of Factors Associated With Incomplete Excision

Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

 

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.

Nonmelanoma skin cancer is the most common malignancy in the United States, with basal cell carcinoma (BCC) being the major histological subtype and accounting for approximately 80% of all skin cancers.^1-3 The age-adjusted incidence of BCC in the United States between 2004 and 2006 was estimated at 1019 cases per 100,000 in women and 1488 cases per 100,000 in men, and an estimated 2.8 million new cases are diagnosed in the United States each year.^3,4 Rates have been shown to increase with advancing age and are higher in males than females at all ages.³ Exposure to solar UVB radiation generally is considered to be the greatest risk factor for development of BCC.^3,5,6 Severe or frequent sunburn and recreational exposure to sun in childhood (from birth to 19 years of age), particularly in individuals who tend to burn rather than tan, have been shown to substantially increase the risk for developing BCC as an adult.⁷ Additional risk factors include light skin color, red or blonde hair color, presence of a large number of moles on the extremities, and a family history of melanoma or painful/blistering sunburn reactions.^3,7 Exposure to certain toxins, immunosuppression, and several genetic cancer syndromes also have been linked to BCC.⁵

Eighty percent of BCC cases involve the head and neck, with the trunk, arms, and legs being the next most common sites.⁵ Basal cell carcinoma can be classified by histologic subtype including nodular, superficial, nodulocystic, morpheic, metatypical, pigmented, and ulcerative, as well as other rarer forms.⁸ Elder⁹ recommended that it may be most clinically practical to divide BCC into subtypes that are known to have low (eg, nodular, nodulocystic) or relatively high risk for local recurrence (eg, infiltrating, morpheic, and metatypical).^9,10 The most common histologic subtype is nodular BCC, with an incidence of 40% to 60%, which typically presents as a red to white pearly nodule or papule with a rolled border; overlying telangiectasia; and occasionally crusting, ulceration, or a cyst.^5,11,12

Basal cell carcinoma generally is a slow-growing and highly curable form of skin cancer.^5,13,14 Compared to either squamous cell carcinoma or melanoma, BCC is generally easier to treat and carries a more favorable prognosis with a lower incidence of recurrence and metastasis.¹⁵ Malignancy in BCC is due to local growth and destruction of the primary tumor rather than metastasis, which is quite rare (estimated to occur in 0.0028% to 0.55% of cases) but carries a poor prognosis.^5,11,16 Basal cell carcinoma grows continuously along the path of least resistance, showing an affinity for the dermis, fascial planes, nerve sheaths, blood vessels, and lymphatic vessels. It is through these pathways that certain locally aggressive tumors can achieve great depths and distant spread. Tumors also are known to spread along embryonic fascial planes, which allows cells to extend in a direction perpendicular to the skin surface and achieve greater depths.¹³ Metastasis has been found to occur more frequently in white men, arising from large tumors larger than 7.5 cm on the head and neck with spread to local lymph nodes. The median survival rate in this group, even in patients receiving adjuvant chemotherapy or radiation, is 10 months but is lower in patients with larger tumors and those who neglect to seek medical care.¹⁶ Although mortality is low, its high and increasing prevalence makes BCC an important and costly health problem in the United States.^2,17

Case Report

A 60-year-old white man with a history of diabetes mellitus presented to the dermatology clinic with concerns about a nonhealing sore on the right upper back that had been present for more than 10 years and had gradually increased in size. The patient reported he did not have health insurance and thus did not seek medical care. Despite the size and location of the lesion, he was able to maintain an active lifestyle and worked as a janitor without difficulty until shortly before presentation when the lesion began to ooze and bleed, requiring him to change the dressing multiple times each day. The patient had no systemic symptoms and described himself as an otherwise healthy man.

On evaluation, the patient was noted to have a 20×15-cm ulcerated tumor on the right side of the upper back and shoulder with no satellite lesions (Figure 1). There were no palpable lymph nodes or satellite lesions and the rest of the physical examination was unremarkable. An 8-mm shave biopsy was collected on the day of presentation and sent for pathology to evaluate for suspected malignancy. On histology, BCC was present with islands of tumor cells extending from the epidermis into the dermis (Figure 2). These nests of cells displayed classic peripheral palisading of hyperchromatic, ovoid-shaped, basaloid nuclei at the periphery. Clefting around islands of tumor cells in the dermis also was apparent. Several foci suggested squamous differentiation, but the bulk of the lesion suggested a conventional nodular BCC.

The patient was referred to a surgical oncologist who recommended a wide surgical excision (SE) and delayed split-thickness skin graft (STSG) due to the size and location of the lesion. Eighteen days after receiving the diagnosis of BCC, the patient was taken to the operating room and underwent wide en bloc resection of the soft tissue tumor. Upon lifting the specimen off the underlying muscles, it was found to be penetrating into portions of the trapezius, deltoid, paraspinal, supraspinalis, and infraspinatus muscles. As such, the ulcerated tumor was removed as well as portions of the underlying musculature measuring 21×18 cm. The wound was left open until final pathology on margin clearance was available. It was covered with a wound vac to encourage granulation in anticipation of a planned delayed STSG. There were no complications, and the patient returned to the recovery unit in good condition where the dressing was replaced with a large wound vac system.

Final histologic examination showed negative deep and peripheral margins. More extensive examination of histology of the excised tumor was found to have characteristics consistent with metatypical and morpheic-type BCC. In addition to islands of tumor cells noted in the dermis on original biopsy, this sample also revealed basaloid cells arranged in thin elongated trabeculae invading deeper into the reticular dermis without peripheral palisading, suggestive of the morpheic variant (Figure 3A).^8,9,10 Other areas were found to have focal squamous differentiation with keratin pearls and intercellular bridges (Figure 3B). These findings support the diagnosis of a completely excised BCC of the metatypical (referred to by some authorities as basosquamous)^8,9 type.

The patient was seen for postoperative evaluations at 2 and 3 weeks. Each time granulation was noted to be proceeding well without signs of infection, and the wound vac was left in place. One month after the initial SE, the patient returned for the planned STSG. The skin graft was harvested from the right lateral thigh and was meshed and transferred to the recipient site on the right upper back, sewn circumferentially to the wound edges. Occlusive petrolatum gauze was placed over the graft followed by the wound vac for coverage until the graft matured.

The patient returned for follow-up approximately 7 months after his initial visit to the clinic. He reported feeling well, and his only concern was mild soreness of the scapular muscles while playing golf. The site of tumor excision showed 100% take of the STSG with no nodules in or around the site to suggest recurrence (Figure 4). The patient denied experiencing any constitutional symptoms and had no palpable lymph nodes or physical examination findings suggestive of metastatic disease or new tumor development at other sites. At 36 months after his initial clinic visit, he remained free of recurrence.

 

Comment

Typical BCC lesions are indolent and small, occurring primarily on the head and neck.^5,11,12,17 We report the case of a locally advanced, extremely large and penetrating lesion located on the trunk. This relatively unique case provides for an interesting comparison between available treatments for BCC as well as several of the generally accepted principles of management previously described in the literature.

Treatment Considerations

The approach to management of BCC considers factors related to the tumor and those related to the patient and practitioner. Telfer et al⁶ recommended that tumors be categorized as relatively low or high risk based on prognostic factors including size, site, histologic subtype and growth pattern; definition of margins; and presence or absence of prior treatment. Characteristics of high-risk tumors include size greater than 2.5 to 3 cm in diameter; location on the midface, nose, or ears; aggressive histologic subtype including morpheic, infiltrating, and metatypical; deep extension; perineural invasion; neglected or long-standing lesions; incomplete SE or Mohs micrographic surgery (MMS); and recurrence of tumor after prior treatment.^13,14,18 Although rare, tumors of the metatypical subtype are particularly important to identify, as they are known to be more aggressive and prone to spread than other forms of BCC.^19,20 The clinical appearance of metatypical BCCs often is identical to lower-risk subtypes, reinforcing the importance of careful histologic examination of an adequately deep biopsy, given that metatypical features often are present only in the deep tissue planes.¹⁹

The practitioner also must consider patient-related factors such as age, general health, immunocompromised states, coexisting medical conditions, and current medications. The skills, experience, and recommendations of the physician also are expected to influence treatment selection.^6,21

Surgical Versus Nonsurgical Treatment Approaches

Treatment of large, locally advanced, primary BCCs can be divided into surgical and nonsurgical approaches.^5,6 Surgical approaches include MMS and SE. Mohs micrographic surgery, electrodesiccation and curettage, and cryosurgery may achieve high cure rates in lesions that are low risk but generally are not recommended for use with recurrent or high-risk large and aggressive tumors.^5,6 Nonsurgical approaches include radiotherapy; chemotherapy; and vismodegib, an oral inhibitor of the hedgehog pathway involved in the development of many BCCs.^5,6,22 Topical photodynamic therapy with 5-aminolevulinic acid, topical imiquimod (immune-response modulator) and 5-fluorouracil, and intralesional interferon are other nonsurgical options that are primarily effective for small superficial BCCs. These modalities are not indicated for high-risk tumors.^5,6,23

For small tumors, MMS is regarded by most practitioners as the gold standard due to the high cure rate and cosmetic results it provides.^5,6,18,24 This procedure allows for precise mapping of tumor location on frozen sections and, unlike surgical excision, examination of close to 100% of the deep and peripheral margins.¹⁸ Excision and evaluation of thin horizontal sections for tumor extension also allows for a greater degree of tissue conservation than other modalities.^6,25 Mohs micrographic surgery is particularly useful for tumors of the midface, aggressive histologic subtype (eg, morpheic, infiltrating, basosquamous, micronodular), deep invasion, and perineural spread.^6,8,18,25 In a large review of 3 studies including a total of 7670 patients with primary BCC treated by MMS, Rowe et al²⁶ reported a 5-year recurrence rate of 1.0%, which was 8.7 times less than the weighted average of all non-MMS modalities. Similarly, in a large prospective review by Leibovitch et al,¹⁸ the 5-year recurrence rate of BCC treated with MMS was 1.4% in primary cases and 4.0% in previously recurrent cases.¹⁸ They reported that the main predictors of recurrence included longer tumor duration, more levels of excision required to obtain clear margins, notable subclinical extension, and prior recurrence. Interestingly, tumor and postexcision defect size did not predict recurrence.¹⁸ Margin-controlled excision with MMS was associated with higher success rates than modalities based on clinical margins without histologic control (eg, surgical excision, electrocautery, curettage) and potentially incomplete excision.^12,18

Although MMS has been demonstrated to have a high success rate, it has relative disadvantages. Tumors that are multicentric or have indistinct borders are more difficult to treat with MMS, and cure rates with MMS have been shown to decrease with increasing tumor diameter.^13,25 For example, reported cure rates are greater than 99% for MMS in BCCs less than 2 cm in diameter compared to 98.6% for those between 2 and 3 cm, and only 90.5% for those greater than 3 cm.²⁷ Mohs micrographic surgery requires a highly trained surgeon and can be extremely time consuming and labor intensive, particularly with large and locally aggressive tumors.^6,25 Tumors that involve fat and cartilage require modifications to standardized processing techniques, and deep wounds involving muscle and bone create technical challenges in maintaining orientation.²⁵ In the past, MMS was more expensive than other treatment modalities; however, cost analyses have demonstrated a near-equal cost of MMS compared to surgical excision with permanent section control and lower cost as compared to radiation therapy for selected cases.²⁸

Surgical excision also is considered a highly effective treatment of primary BCC and is the most commonly used treatment modality for BCC.^5,18,29 In this procedure, the peripheral and deep margins of excised tissue can be examined by a pathologist.⁶ Telfer et al⁶ recommended SE as the preferable treatment of choice for both large and small tumors in low-risk sites (ie, those that do not include the face) with nodular histology, tumors with morpheic histology in low-risk sites, and small (<2 cm) superficial tumors in high-risk sites. It is recommended that the size of surgical margins correlate with the likelihood of the presence of subclinical tumor extensions. Larger and morpheic-type BCCs require wider margins to achieve complete excision. In these cases, a 3-mm margin yields only a 66% cure rate, while 5-mm margins yield an 82% cure rate and 13- to 15-mm margins yield cure rates higher than 95%.^6,29,30 In a series examining recurrence rates of primary BCC, Rowe et al²⁶ reviewed 10 studies (2606 patients treated by SE) and calculated a 5-year recurrence rate of 10.1%. Silverman et al³¹ reviewed 5-year recurrence rates in 588 cases of BCC treated with SE. They concluded that BCC on the neck, trunk, arms, and legs of any size may be effectively treated with this modality, with 1 case of recurrence among 187 cases (0.5% recurrence rate). Multivariate analysis identified 2 independent risk factors for recurrence: anatomic site (head) and patient sex (male). Analysis of BCCs on the head distinct from other body sites demonstrated a moderately significant trend (P=.196) of increasing diameter with increasing recurrence rates. Age at treatment, duration of lesion, and length of treatment were not significantly associated with an increased risk of recurrence.³¹ Similarly, a review of 1417 cases of BCC by Dubin and Kopf²¹ demonstrated an increased risk with tumors located on the head and larger lesions.

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Radiotherapy (RT) is a commonly employed nonsurgical approach to management. Its use has been declining in recent years due to relative disadvantages and side effects. Similar to MMS, it can be extremely effective for carefully selected patients.^11,31 Radiotherapy is most effective for use with aggressive, rapidly growing BCC subtypes that are more sensitive to radiation, as replicating cells undergo mitotic death when radiation is applied.¹⁵ Radiotherapy is considered a viable option for patients who are not candidates for surgery, tumors in locations difficult to access for SE, and for rare unresectable tumors as a primary therapy.^5,11 In a randomized comparison between RT and SE approaches to the treatment of primary BCCs on the face, RT was found to be inferior to SE both in efficacy (4-year recurrence rate, 7.5% vs 0.7%) and cosmesis (rate of good results, 69% vs 87%).³²

The major disadvantages of RT as compared to other treatment modalities such as MMS or SE are the lack of control at margins and compromised inferior cosmetic outcomes. Hair loss, hyperpigmentation or hypopigmentation, telangiectasia, keloids, cutaneous necrosis, and RT-induced dermatitis have been reported as side effects of RT.^6,11,32-34 Other disadvantages of RT include the inconvenience of multiple visits to the hospital for treatment, and high cost as compared to other modalities such as MMS.³⁵ Finally, use of RT even for relatively benign disease has been linked to an increased risk for both squamous cell carcinoma, BCC, and sarcomas.^15,36

Vismodegib is an oral drug approved by the US Food and Drug Administration in 2012 for the treatment of locally advanced BCC. It is a first-in-class small-molecule systemic inhibitor of the intracellular hedgehog signaling pathway, which has been implicated in the growth and development of several types of cancer, including BCC.^36-38 Most patients with BCC carry loss-of-function mutations that affect PTCH1 and result in unregulated reactivation of the hedgehog pathway and uncontrolled cell growth.^38-40 Vismodegib is a small molecule that selectively deactivates the hedgehog pathway. It currently is indicated for the treatment of metastatic BCC or patients with locally advanced BCCs who are not candidates for SE or RT.^38-41 An open-label nonrandomized phase 2 study by Sekulic et al⁴² evaluated the effectiveness of vismodegib for treatment of metastatic or inoperable BCCs. In 33 patients with metastatic BCCs, the response rate was 30% (10/33) with a 9.5-month median progression-free survival. All responses were partial, with 73% (24/33) showing tumor shrinkage. In 63 patients with locally advanced BCCs, the response rate was 43% (27/63). Most patients demonstrated visible reductions in tumor size and improvement in appearance, but 13 patients (21%) in this group were noted to have a complete response (ie, absence of residual BCC on biopsy). Both cohorts had a median response time of 7.6 months.⁴²

 

Conclusion

Our patient presented with an extremely large and ulcerating lesion on the upper back that met the criteria for classification as a high-risk tumor. In light of the tumor location and size as well as the involvement of deep tissues and muscles, we elected to pursue SE for management. This modality proved to be extremely effective, and the patient continues to be free of residual or recurrent BCC more than 36 months after surgery. Two large systematic reviews lend support to this management approach and report excellent outcomes. In a review article by Rubin et al,⁵ SE was shown to provide cure rates greater than 99% for BCC lesions of any size on the neck, trunk, and extremities. Moreover, Thissen et al⁴³ performed a systematic meta-analysis of 18 studies reporting recurrence rates of primary BCC after treatment with various modalities and concluded that when surgery is not contraindicated, SE is the treatment of choice for nodular and superficial BCC. Both groups agree in their recommendations that MMS should be used for BCCs in cosmetically compromised zones (eg, midface), sites where tissue sparing is essential, aggressive growth patterns (eg, perineural invasion, morpheaform histology), and when high risk of recurrence is unacceptable.^5,43 In contrast, MMS is not recommended for tumors of large diameter or with indistinct borders due to decreased cure rates.^13,25,27 Vismodegib is an interesting new option in development for management of metastatic and aggressive nonresectable BCCs. It was not an option in our patient. Although consideration for use of vismodegib as a neoadjuvant treatment to shrink the tumor prior to surgery is reasonable, the decision to proceed directly with SE proved to be the superior option for our patient.