Marylee Braniecki, MD

The Diagnosis: Lichen Planus Pemphigoides

Lichen planus pemphigoides (LPP) is a rare acquired autoimmune blistering disorder with an estimated worldwide prevalence of approximately 1 in 1,000,000 individuals.¹ It often manifests with overlapping features of both LP and bullous pemphigoid (BP). The condition usually presents in the fifth decade of life and has a slight female predominance.² Although primarily idiopathic, it has been associated with certain medications and treatments, such as angiotensin-converting enzyme inhibitors, programmed cell death protein 1 inhibitors, programmed cell death ligand 1 inhibitors, labetalol, narrowband UVB, and psoralen plus UVA.^3,4

Patients initially present with lesions of classic lichen planus (LP) with pink-purple, flat-topped, pruritic, polygonal papules and plaques.⁵ After weeks to months, tense vesicles and bullae usually develop on the sites of LP as well as on uninvolved skin. One study found a mean lag time of about 8.3 months for blistering to present after LP,⁵ but concurrent presentations of both have been reported.¹ In addition, oral mucosal involvement has been seen in 36% of cases. The most commonly affected sites are the extremities; however, involvement can be widespread.²

The pathogenesis of LPP currently is unknown. It has been proposed that in LP, injury of basal keratinocytes exposes hidden basement membrane and hemidesmosome antigens including BP180, a 180 kDa transmembrane protein of the basement membrane zone (BMZ),⁶ which triggers an immune response where T cells recognize the extracellular portion of BP180 and antibodies are formed against the likely autoantigen.1 One study has suggested that the autoantigen in LPP is the MCW-4 epitope within the C-terminal end of the NC16A domain of BP180.⁷

Histopathology of LPP reveals characteristics of both LP as well as BP. Typical features of LP on hematoxylin and eosin (H&E) staining include lichenoid lymphocytic interface dermatitis, sawtooth rete ridges, wedge-shaped hypergranulosis, and colloid bodies, as demonstrated from the biopsy of our patient’s gluteal cleft lesion (quiz image 1), while the predominant feature of BP on H&E staining includes a subepidermal bulla with eosinophils.² Typically, direct immunofluorescence (DIF) shows linear deposits of IgG and/or C3 along the BMZ. Indirect immunofluorescence (IIF) often reveals IgG against the roof of the BMZ in a human split-skin substrate.¹ Antibodies against BP180 or uncommonly BP230 often are detected on enzyme-linked immunosorbent assay (ELISA). For our patient, IIF and ELISA tests were positive. Given the clinical presentation with recurrent oral and gluteal cleft erosions, histologic findings, and the results of our patient’s immunological testing, the diagnosis of LPP was made.

Topical steroids often are used to treat localized disease of LPP.8 Oral prednisone also may be given for widespread or unresponsive disease.⁹ Other treatments include azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, tetracycline in combination with nicotinamide, acitretin, ustekinumab, baricitinib, and rituximab with intravenous immunoglobulin.^3,8,10-12 Any potential medication culprits should be discontinued.⁹ Patients with oral involvement may require a soft diet to avoid further mucosal insult.¹⁰ Additionally, providers should consider dentistry, ophthalmology, and/or otolaryngology referrals depending on disease severity.

Bullous pemphigoid, the most common autoimmune blistering disease, has an estimated incidence of 10 to 43 per million individuals per year.² Classically, it presents with tense bullae on the skin of the lower abdomen, thighs, groin, forearms, and axillae. Circulating antibodies against 2 BMZ proteins—BP180 and BP230—are important factors in BP pathogenesis.² Diagnosis of BP is based on clinical features, histologic findings, and immunological studies including DIF, IIF, and ELISA. An eosinophil-rich subepidermal split typically is seen on H&E staining (Figure 1).

Direct immunofluorescence displays linear IgG and/ or C3 staining at the BMZ. Indirect immunofluorescence on a human salt-split skin substrate commonly shows linear BMZ deposition on the roof of the blister.² Indirect immunofluorescence for IgG deposition on monkey esophagus substrate shows linear BMZ deposition. Antibodies against the NC16A domain of BP180 (NC16A-BP180) are dominant, but BP230 antibodies against BP230 also are detected with ELISA.² Further studies have indicated that the NC16A epitopes of BP180 that are targeted in BP are MCW-0-3,² different from the autoantigen MCW-4 that is targeted in LPP.⁷

Paraneoplastic pemphigus (PNP) is another diagnosis to consider. Patients with PNP initially present with oral findings—most commonly chronic, erosive, and painful mucositis—followed by cutaneous involvement, which varies from the development of bullae to the formation of plaques similar to those of LP.¹³ The latter, in combination with oral erosions, may appear clinically similar to LPP. The results of DIF in conjugation with IIF and ELISA may help to further differentiate these disorders. Direct immunofluorescence in PNP typically reveals positive intercellular and/or BMZ IgG and C3, while DIF in LPP reveals depositions along the BMZ alone. Indirect immunofluorescence performed on rat bladder epithelium is particularly useful, as binding of IgG to rat bladder epithelium is characteristic of PNP and not seen in other disorders.¹⁴ Lastly, patients with PNP may develop IgG antibodies to various antigens such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, desmoglein 1, and desmoglein 3, which would not be expected in LPP patients.¹⁵ Hematoxylin and eosin staining differs from LPP, primarily with the location of the blister being intraepidermal. Acantholysis with hemorrhagic bullae can be seen (Figure 2).

Classic LP is an inflammatory disorder that mainly affects adults, with an estimated incidence of less than 1%.¹⁶ The classic form presents with purple, flat-topped, pruritic, polygonal papules and plaques of varying size that often are characterized by Wickham striae. Lichen planus possesses a broad spectrum of subtypes involving different locations, though skin lesions usually are localized to the extremities. Despite an unknown etiology, activated T cells and T helper type 1 cytokines are considered key in keratinocyte injury. Compact orthokeratosis, wedge-shaped hypergranulosis, focal dyskeratosis, and colloid bodies typically are found on H&E staining, along with a dense bandlike lymphohistiocytic infiltrate at the dermoepidermal junction (DEJ)(Figure 3). Direct immunofluorescence typically shows a shaggy band of fibrinogen along the DEJ in addition to colloid bodies that stain with various autoantibodies including IgM, IgG, IgA, and C3.¹⁶

Bullous LP is a rare variant of LP that commonly develops on the oral mucosa and the legs, with blisters confined on pre-existing LP lesions.⁹ The pathogenesis is related to an epidermal inflammatory infiltrate that leads to basal layer destruction followed by dermal-epidermal separations that cause blistering.¹⁷ Bullous LP does not have positive DIF, IIF, or ELISA because the pathophysiology does not involve autoantibody production. Histopathology typically displays an extensive inflammatory infiltrate and degeneration of the basal keratinocytes, resulting in large dermal-epidermal separations called Max-Joseph spaces (Figure 4).¹⁷ Colloid bodies are prominent in bullous LP but rarely are seen in LPP; eosinophils also are much more prominent in LPP compared to bullous LP.¹⁸ Unlike in LPP, DIF usually is negative in bullous LP, though lichenoid lesions may exhibit globular deposition of IgM, IgG, and IgA in the colloid bodies of the lower epidermis and/or papillary dermis. Similar to LP, DIF of the biopsy specimen shows linear or shaggy deposits of fibrinogen at the DEJ.¹⁷

The Diagnosis: Lichen Planus Pemphigoides

Lichen planus pemphigoides (LPP) is a rare acquired autoimmune blistering disorder with an estimated worldwide prevalence of approximately 1 in 1,000,000 individuals.¹ It often manifests with overlapping features of both LP and bullous pemphigoid (BP). The condition usually presents in the fifth decade of life and has a slight female predominance.² Although primarily idiopathic, it has been associated with certain medications and treatments, such as angiotensin-converting enzyme inhibitors, programmed cell death protein 1 inhibitors, programmed cell death ligand 1 inhibitors, labetalol, narrowband UVB, and psoralen plus UVA.^3,4

Patients initially present with lesions of classic lichen planus (LP) with pink-purple, flat-topped, pruritic, polygonal papules and plaques.⁵ After weeks to months, tense vesicles and bullae usually develop on the sites of LP as well as on uninvolved skin. One study found a mean lag time of about 8.3 months for blistering to present after LP,⁵ but concurrent presentations of both have been reported.¹ In addition, oral mucosal involvement has been seen in 36% of cases. The most commonly affected sites are the extremities; however, involvement can be widespread.²

The pathogenesis of LPP currently is unknown. It has been proposed that in LP, injury of basal keratinocytes exposes hidden basement membrane and hemidesmosome antigens including BP180, a 180 kDa transmembrane protein of the basement membrane zone (BMZ),⁶ which triggers an immune response where T cells recognize the extracellular portion of BP180 and antibodies are formed against the likely autoantigen.1 One study has suggested that the autoantigen in LPP is the MCW-4 epitope within the C-terminal end of the NC16A domain of BP180.⁷

Histopathology of LPP reveals characteristics of both LP as well as BP. Typical features of LP on hematoxylin and eosin (H&E) staining include lichenoid lymphocytic interface dermatitis, sawtooth rete ridges, wedge-shaped hypergranulosis, and colloid bodies, as demonstrated from the biopsy of our patient’s gluteal cleft lesion (quiz image 1), while the predominant feature of BP on H&E staining includes a subepidermal bulla with eosinophils.² Typically, direct immunofluorescence (DIF) shows linear deposits of IgG and/or C3 along the BMZ. Indirect immunofluorescence (IIF) often reveals IgG against the roof of the BMZ in a human split-skin substrate.¹ Antibodies against BP180 or uncommonly BP230 often are detected on enzyme-linked immunosorbent assay (ELISA). For our patient, IIF and ELISA tests were positive. Given the clinical presentation with recurrent oral and gluteal cleft erosions, histologic findings, and the results of our patient’s immunological testing, the diagnosis of LPP was made.

Topical steroids often are used to treat localized disease of LPP.8 Oral prednisone also may be given for widespread or unresponsive disease.⁹ Other treatments include azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, tetracycline in combination with nicotinamide, acitretin, ustekinumab, baricitinib, and rituximab with intravenous immunoglobulin.^3,8,10-12 Any potential medication culprits should be discontinued.⁹ Patients with oral involvement may require a soft diet to avoid further mucosal insult.¹⁰ Additionally, providers should consider dentistry, ophthalmology, and/or otolaryngology referrals depending on disease severity.

Bullous pemphigoid, the most common autoimmune blistering disease, has an estimated incidence of 10 to 43 per million individuals per year.² Classically, it presents with tense bullae on the skin of the lower abdomen, thighs, groin, forearms, and axillae. Circulating antibodies against 2 BMZ proteins—BP180 and BP230—are important factors in BP pathogenesis.² Diagnosis of BP is based on clinical features, histologic findings, and immunological studies including DIF, IIF, and ELISA. An eosinophil-rich subepidermal split typically is seen on H&E staining (Figure 1).

Direct immunofluorescence displays linear IgG and/ or C3 staining at the BMZ. Indirect immunofluorescence on a human salt-split skin substrate commonly shows linear BMZ deposition on the roof of the blister.² Indirect immunofluorescence for IgG deposition on monkey esophagus substrate shows linear BMZ deposition. Antibodies against the NC16A domain of BP180 (NC16A-BP180) are dominant, but BP230 antibodies against BP230 also are detected with ELISA.² Further studies have indicated that the NC16A epitopes of BP180 that are targeted in BP are MCW-0-3,² different from the autoantigen MCW-4 that is targeted in LPP.⁷

Paraneoplastic pemphigus (PNP) is another diagnosis to consider. Patients with PNP initially present with oral findings—most commonly chronic, erosive, and painful mucositis—followed by cutaneous involvement, which varies from the development of bullae to the formation of plaques similar to those of LP.¹³ The latter, in combination with oral erosions, may appear clinically similar to LPP. The results of DIF in conjugation with IIF and ELISA may help to further differentiate these disorders. Direct immunofluorescence in PNP typically reveals positive intercellular and/or BMZ IgG and C3, while DIF in LPP reveals depositions along the BMZ alone. Indirect immunofluorescence performed on rat bladder epithelium is particularly useful, as binding of IgG to rat bladder epithelium is characteristic of PNP and not seen in other disorders.¹⁴ Lastly, patients with PNP may develop IgG antibodies to various antigens such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, desmoglein 1, and desmoglein 3, which would not be expected in LPP patients.¹⁵ Hematoxylin and eosin staining differs from LPP, primarily with the location of the blister being intraepidermal. Acantholysis with hemorrhagic bullae can be seen (Figure 2).

Classic LP is an inflammatory disorder that mainly affects adults, with an estimated incidence of less than 1%.¹⁶ The classic form presents with purple, flat-topped, pruritic, polygonal papules and plaques of varying size that often are characterized by Wickham striae. Lichen planus possesses a broad spectrum of subtypes involving different locations, though skin lesions usually are localized to the extremities. Despite an unknown etiology, activated T cells and T helper type 1 cytokines are considered key in keratinocyte injury. Compact orthokeratosis, wedge-shaped hypergranulosis, focal dyskeratosis, and colloid bodies typically are found on H&E staining, along with a dense bandlike lymphohistiocytic infiltrate at the dermoepidermal junction (DEJ)(Figure 3). Direct immunofluorescence typically shows a shaggy band of fibrinogen along the DEJ in addition to colloid bodies that stain with various autoantibodies including IgM, IgG, IgA, and C3.¹⁶

Bullous LP is a rare variant of LP that commonly develops on the oral mucosa and the legs, with blisters confined on pre-existing LP lesions.⁹ The pathogenesis is related to an epidermal inflammatory infiltrate that leads to basal layer destruction followed by dermal-epidermal separations that cause blistering.¹⁷ Bullous LP does not have positive DIF, IIF, or ELISA because the pathophysiology does not involve autoantibody production. Histopathology typically displays an extensive inflammatory infiltrate and degeneration of the basal keratinocytes, resulting in large dermal-epidermal separations called Max-Joseph spaces (Figure 4).¹⁷ Colloid bodies are prominent in bullous LP but rarely are seen in LPP; eosinophils also are much more prominent in LPP compared to bullous LP.¹⁸ Unlike in LPP, DIF usually is negative in bullous LP, though lichenoid lesions may exhibit globular deposition of IgM, IgG, and IgA in the colloid bodies of the lower epidermis and/or papillary dermis. Similar to LP, DIF of the biopsy specimen shows linear or shaggy deposits of fibrinogen at the DEJ.¹⁷

The Diagnosis: Lichen Planus Pemphigoides

Lichen planus pemphigoides (LPP) is a rare acquired autoimmune blistering disorder with an estimated worldwide prevalence of approximately 1 in 1,000,000 individuals.¹ It often manifests with overlapping features of both LP and bullous pemphigoid (BP). The condition usually presents in the fifth decade of life and has a slight female predominance.² Although primarily idiopathic, it has been associated with certain medications and treatments, such as angiotensin-converting enzyme inhibitors, programmed cell death protein 1 inhibitors, programmed cell death ligand 1 inhibitors, labetalol, narrowband UVB, and psoralen plus UVA.^3,4

Patients initially present with lesions of classic lichen planus (LP) with pink-purple, flat-topped, pruritic, polygonal papules and plaques.⁵ After weeks to months, tense vesicles and bullae usually develop on the sites of LP as well as on uninvolved skin. One study found a mean lag time of about 8.3 months for blistering to present after LP,⁵ but concurrent presentations of both have been reported.¹ In addition, oral mucosal involvement has been seen in 36% of cases. The most commonly affected sites are the extremities; however, involvement can be widespread.²

The pathogenesis of LPP currently is unknown. It has been proposed that in LP, injury of basal keratinocytes exposes hidden basement membrane and hemidesmosome antigens including BP180, a 180 kDa transmembrane protein of the basement membrane zone (BMZ),⁶ which triggers an immune response where T cells recognize the extracellular portion of BP180 and antibodies are formed against the likely autoantigen.1 One study has suggested that the autoantigen in LPP is the MCW-4 epitope within the C-terminal end of the NC16A domain of BP180.⁷

Histopathology of LPP reveals characteristics of both LP as well as BP. Typical features of LP on hematoxylin and eosin (H&E) staining include lichenoid lymphocytic interface dermatitis, sawtooth rete ridges, wedge-shaped hypergranulosis, and colloid bodies, as demonstrated from the biopsy of our patient’s gluteal cleft lesion (quiz image 1), while the predominant feature of BP on H&E staining includes a subepidermal bulla with eosinophils.² Typically, direct immunofluorescence (DIF) shows linear deposits of IgG and/or C3 along the BMZ. Indirect immunofluorescence (IIF) often reveals IgG against the roof of the BMZ in a human split-skin substrate.¹ Antibodies against BP180 or uncommonly BP230 often are detected on enzyme-linked immunosorbent assay (ELISA). For our patient, IIF and ELISA tests were positive. Given the clinical presentation with recurrent oral and gluteal cleft erosions, histologic findings, and the results of our patient’s immunological testing, the diagnosis of LPP was made.

Topical steroids often are used to treat localized disease of LPP.8 Oral prednisone also may be given for widespread or unresponsive disease.⁹ Other treatments include azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, tetracycline in combination with nicotinamide, acitretin, ustekinumab, baricitinib, and rituximab with intravenous immunoglobulin.^3,8,10-12 Any potential medication culprits should be discontinued.⁹ Patients with oral involvement may require a soft diet to avoid further mucosal insult.¹⁰ Additionally, providers should consider dentistry, ophthalmology, and/or otolaryngology referrals depending on disease severity.

Bullous pemphigoid, the most common autoimmune blistering disease, has an estimated incidence of 10 to 43 per million individuals per year.² Classically, it presents with tense bullae on the skin of the lower abdomen, thighs, groin, forearms, and axillae. Circulating antibodies against 2 BMZ proteins—BP180 and BP230—are important factors in BP pathogenesis.² Diagnosis of BP is based on clinical features, histologic findings, and immunological studies including DIF, IIF, and ELISA. An eosinophil-rich subepidermal split typically is seen on H&E staining (Figure 1).

Direct immunofluorescence displays linear IgG and/ or C3 staining at the BMZ. Indirect immunofluorescence on a human salt-split skin substrate commonly shows linear BMZ deposition on the roof of the blister.² Indirect immunofluorescence for IgG deposition on monkey esophagus substrate shows linear BMZ deposition. Antibodies against the NC16A domain of BP180 (NC16A-BP180) are dominant, but BP230 antibodies against BP230 also are detected with ELISA.² Further studies have indicated that the NC16A epitopes of BP180 that are targeted in BP are MCW-0-3,² different from the autoantigen MCW-4 that is targeted in LPP.⁷

Paraneoplastic pemphigus (PNP) is another diagnosis to consider. Patients with PNP initially present with oral findings—most commonly chronic, erosive, and painful mucositis—followed by cutaneous involvement, which varies from the development of bullae to the formation of plaques similar to those of LP.¹³ The latter, in combination with oral erosions, may appear clinically similar to LPP. The results of DIF in conjugation with IIF and ELISA may help to further differentiate these disorders. Direct immunofluorescence in PNP typically reveals positive intercellular and/or BMZ IgG and C3, while DIF in LPP reveals depositions along the BMZ alone. Indirect immunofluorescence performed on rat bladder epithelium is particularly useful, as binding of IgG to rat bladder epithelium is characteristic of PNP and not seen in other disorders.¹⁴ Lastly, patients with PNP may develop IgG antibodies to various antigens such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, desmoglein 1, and desmoglein 3, which would not be expected in LPP patients.¹⁵ Hematoxylin and eosin staining differs from LPP, primarily with the location of the blister being intraepidermal. Acantholysis with hemorrhagic bullae can be seen (Figure 2).

Classic LP is an inflammatory disorder that mainly affects adults, with an estimated incidence of less than 1%.¹⁶ The classic form presents with purple, flat-topped, pruritic, polygonal papules and plaques of varying size that often are characterized by Wickham striae. Lichen planus possesses a broad spectrum of subtypes involving different locations, though skin lesions usually are localized to the extremities. Despite an unknown etiology, activated T cells and T helper type 1 cytokines are considered key in keratinocyte injury. Compact orthokeratosis, wedge-shaped hypergranulosis, focal dyskeratosis, and colloid bodies typically are found on H&E staining, along with a dense bandlike lymphohistiocytic infiltrate at the dermoepidermal junction (DEJ)(Figure 3). Direct immunofluorescence typically shows a shaggy band of fibrinogen along the DEJ in addition to colloid bodies that stain with various autoantibodies including IgM, IgG, IgA, and C3.¹⁶

Bullous LP is a rare variant of LP that commonly develops on the oral mucosa and the legs, with blisters confined on pre-existing LP lesions.⁹ The pathogenesis is related to an epidermal inflammatory infiltrate that leads to basal layer destruction followed by dermal-epidermal separations that cause blistering.¹⁷ Bullous LP does not have positive DIF, IIF, or ELISA because the pathophysiology does not involve autoantibody production. Histopathology typically displays an extensive inflammatory infiltrate and degeneration of the basal keratinocytes, resulting in large dermal-epidermal separations called Max-Joseph spaces (Figure 4).¹⁷ Colloid bodies are prominent in bullous LP but rarely are seen in LPP; eosinophils also are much more prominent in LPP compared to bullous LP.¹⁸ Unlike in LPP, DIF usually is negative in bullous LP, though lichenoid lesions may exhibit globular deposition of IgM, IgG, and IgA in the colloid bodies of the lower epidermis and/or papillary dermis. Similar to LP, DIF of the biopsy specimen shows linear or shaggy deposits of fibrinogen at the DEJ.¹⁷

The Diagnosis: Metastatic Carcinoid Tumor

Carcinoid tumors are derived from neuroendocrine cell compartments and generally arise in the gastrointestinal tract, with a quarter of carcinoids arising in the small bowel.¹ Carcinoid tumors have an incidence of approximately 2 to 5 per 100,000 patients.² Metastasis of carcinoids is approximately 31.2% to 46.7%.¹ Metastasis to the skin is uncommon; we present a rare case of a carcinoid tumor of the terminal ileum with metastasis to the scalp.

Unlike our patient, most patients with carcinoid tumors have an indolent clinical course. The most common cutaneous symptom is flushing, which occurs in 75% of patients.³ Secreted vasoactive peptides such as serotonin may cause other symptoms such as tachycardia, diarrhea, and bronchospasm; together, these symptoms comprise carcinoid syndrome. Carcinoid syndrome requires metastasis of the tumor to the liver or a site outside of the gastrointestinal tract because the liver will metabolize the secreted serotonin. However, even in patients with liver metastasis, carcinoid syndrome only occurs in approximately 10% of patients.⁴ Common skin findings of carcinoid syndrome include pellagralike dermatitis, flushing, and sclerodermalike changes.⁵ Our patient experienced several episodes of presyncope with symptoms of dyspnea, lightheadedness, and flushing but did not have bronchospasm or recurrent diarrhea. Intramuscular octreotide improved some symptoms.

The scalp accounts for approximately 15% of cutaneous metastases, the most common being from the lung, renal, and breast cancers.⁶ Cutaneous metastases of carcinoid tumors are rare. A PubMed search of articles indexed for MEDLINE using the terms metastatic AND [carcinoid OR neuroendocrine] tumors AND [skin OR cutaneous] revealed 47 cases.^7-11 Similar to other skin metastases, cutaneous metastases of carcinoid tumors commonly present as firm erythematous nodules of varying sizes that may be asymptomatic, tender, or pruritic (Figure 1). Cases of carcinoid tumors with cutaneous metastasis as the initial and only presenting sign are exceedingly rare.¹²

Histology of carcinoid tumors reveals a dermal neoplasm composed of loosely cohesive, mildly atypical, polygonal cells with salt-and-pepper chromatin and eosinophilic cytoplasm, which are similar findings to the primary tumor. The cells may grow in the typical trabecular or organoid neuroendocrine pattern or exhibit a pseudoglandular growth pattern with prominent vessels (quiz image, top).¹² Positive chromogranin and synaptophysin immunostaining are the most common and reliable markers used for the diagnosis of carcinoid tumors.

An important histopathologic differential diagnosis is the aggressive Merkel cell carcinoma, which also demonstrates homogenous salt-and-pepper chromatin but exhibits a higher mitotic rate and positive cytokeratin 20 staining (Figure 2).¹³ Basal cell carcinoma (BCC) also may display similar features, including a blue tumor at scanning magnification and nodular or infiltrative growth patterns. The cell morphology of BCC is characterized by islands of basaloid cells with minimal cytoplasm and frequent apoptosis, connecting to the epidermis with peripheral palisading, retraction artifact, and a myxoid stroma; BCC lacks the salt-and-pepper chromatin commonly seen in carcinoid tumors (Figure 3). Basal cell carcinoma is characterized by positive BerEP4 (epithelial cell adhesion molecule immunostain), cytokeratin 5/6, and cytokeratin 14 uptake. Cytokeratin 20, often used to diagnose Merkel cell carcinoma, is negative in BCC. Chromogranin and synaptophysin occasionally may be positive in BCC.¹⁴

The superficial Ewing sarcoma family of tumors also may be included in the differential diagnosis of small round cell tumors of the skin, but they are very rare. These tumors possess strong positive membranous staining of cytokeratin 99 and also can stain positively for synaptophysin and chromogranin.¹⁵ Epithelial membrane antigen, which is negative in Ewing sarcomas, is positive in carcinoid tumors.¹⁶ Neuroendocrine tumors of all sites share similar basic morphologic patterns, and multiple primary tumors should be considered, including small cell lung carcinoma (Figure 4).^17,18 Red granulations and true glandular lumina typically are not seen in the lungs but are common in gastrointestinal carcinoids.¹⁸ Regarding immunohistochemistry, TTF-1 is negative and CDX2 is positive in gastroenteropancreatic carcinoids, suggesting that these 2 markers can help distinguish carcinoids of unknown primary origin.¹⁹

Metastases in carcinoid tumors are common, with one study noting that the highest frequency of small intestinal metastases was from the ileal subset.²⁰ At the time of diagnosis, 58% to 64% of patients with small intestine carcinoid tumors already had nonlocalized disease, with frequent sites being the lymph nodes (89.8%), liver (44.1%), lungs (13.6%), and peritoneum (13.6%). Regional and distant metastases are associated with substantially worse prognoses, with survival rates of 71.7% and 38.5%, respectively.¹ Treatment of symptomatic unresectable disease focuses on symptomatic management with somatostatin analogs that also control tumor growth.²¹

We present a rare case of scalp metastasis of a carcinoid tumor of the terminal ileum. Distant metastasis is associated with poorer prognosis and should be considered in patients with a known history of a carcinoid tumor.

Acknowledgment—We would like to acknowledge the Research Histology and Tissue Imaging Core at University of Illinois Chicago Research Resources Center for the immunohistochemistry studies.

The Diagnosis: Metastatic Carcinoid Tumor

Carcinoid tumors are derived from neuroendocrine cell compartments and generally arise in the gastrointestinal tract, with a quarter of carcinoids arising in the small bowel.¹ Carcinoid tumors have an incidence of approximately 2 to 5 per 100,000 patients.² Metastasis of carcinoids is approximately 31.2% to 46.7%.¹ Metastasis to the skin is uncommon; we present a rare case of a carcinoid tumor of the terminal ileum with metastasis to the scalp.

Unlike our patient, most patients with carcinoid tumors have an indolent clinical course. The most common cutaneous symptom is flushing, which occurs in 75% of patients.³ Secreted vasoactive peptides such as serotonin may cause other symptoms such as tachycardia, diarrhea, and bronchospasm; together, these symptoms comprise carcinoid syndrome. Carcinoid syndrome requires metastasis of the tumor to the liver or a site outside of the gastrointestinal tract because the liver will metabolize the secreted serotonin. However, even in patients with liver metastasis, carcinoid syndrome only occurs in approximately 10% of patients.⁴ Common skin findings of carcinoid syndrome include pellagralike dermatitis, flushing, and sclerodermalike changes.⁵ Our patient experienced several episodes of presyncope with symptoms of dyspnea, lightheadedness, and flushing but did not have bronchospasm or recurrent diarrhea. Intramuscular octreotide improved some symptoms.

The scalp accounts for approximately 15% of cutaneous metastases, the most common being from the lung, renal, and breast cancers.⁶ Cutaneous metastases of carcinoid tumors are rare. A PubMed search of articles indexed for MEDLINE using the terms metastatic AND [carcinoid OR neuroendocrine] tumors AND [skin OR cutaneous] revealed 47 cases.^7-11 Similar to other skin metastases, cutaneous metastases of carcinoid tumors commonly present as firm erythematous nodules of varying sizes that may be asymptomatic, tender, or pruritic (Figure 1). Cases of carcinoid tumors with cutaneous metastasis as the initial and only presenting sign are exceedingly rare.¹²

Histology of carcinoid tumors reveals a dermal neoplasm composed of loosely cohesive, mildly atypical, polygonal cells with salt-and-pepper chromatin and eosinophilic cytoplasm, which are similar findings to the primary tumor. The cells may grow in the typical trabecular or organoid neuroendocrine pattern or exhibit a pseudoglandular growth pattern with prominent vessels (quiz image, top).¹² Positive chromogranin and synaptophysin immunostaining are the most common and reliable markers used for the diagnosis of carcinoid tumors.

An important histopathologic differential diagnosis is the aggressive Merkel cell carcinoma, which also demonstrates homogenous salt-and-pepper chromatin but exhibits a higher mitotic rate and positive cytokeratin 20 staining (Figure 2).¹³ Basal cell carcinoma (BCC) also may display similar features, including a blue tumor at scanning magnification and nodular or infiltrative growth patterns. The cell morphology of BCC is characterized by islands of basaloid cells with minimal cytoplasm and frequent apoptosis, connecting to the epidermis with peripheral palisading, retraction artifact, and a myxoid stroma; BCC lacks the salt-and-pepper chromatin commonly seen in carcinoid tumors (Figure 3). Basal cell carcinoma is characterized by positive BerEP4 (epithelial cell adhesion molecule immunostain), cytokeratin 5/6, and cytokeratin 14 uptake. Cytokeratin 20, often used to diagnose Merkel cell carcinoma, is negative in BCC. Chromogranin and synaptophysin occasionally may be positive in BCC.¹⁴

The superficial Ewing sarcoma family of tumors also may be included in the differential diagnosis of small round cell tumors of the skin, but they are very rare. These tumors possess strong positive membranous staining of cytokeratin 99 and also can stain positively for synaptophysin and chromogranin.¹⁵ Epithelial membrane antigen, which is negative in Ewing sarcomas, is positive in carcinoid tumors.¹⁶ Neuroendocrine tumors of all sites share similar basic morphologic patterns, and multiple primary tumors should be considered, including small cell lung carcinoma (Figure 4).^17,18 Red granulations and true glandular lumina typically are not seen in the lungs but are common in gastrointestinal carcinoids.¹⁸ Regarding immunohistochemistry, TTF-1 is negative and CDX2 is positive in gastroenteropancreatic carcinoids, suggesting that these 2 markers can help distinguish carcinoids of unknown primary origin.¹⁹

Metastases in carcinoid tumors are common, with one study noting that the highest frequency of small intestinal metastases was from the ileal subset.²⁰ At the time of diagnosis, 58% to 64% of patients with small intestine carcinoid tumors already had nonlocalized disease, with frequent sites being the lymph nodes (89.8%), liver (44.1%), lungs (13.6%), and peritoneum (13.6%). Regional and distant metastases are associated with substantially worse prognoses, with survival rates of 71.7% and 38.5%, respectively.¹ Treatment of symptomatic unresectable disease focuses on symptomatic management with somatostatin analogs that also control tumor growth.²¹

We present a rare case of scalp metastasis of a carcinoid tumor of the terminal ileum. Distant metastasis is associated with poorer prognosis and should be considered in patients with a known history of a carcinoid tumor.

Acknowledgment—We would like to acknowledge the Research Histology and Tissue Imaging Core at University of Illinois Chicago Research Resources Center for the immunohistochemistry studies.

The Diagnosis: Metastatic Carcinoid Tumor

Carcinoid tumors are derived from neuroendocrine cell compartments and generally arise in the gastrointestinal tract, with a quarter of carcinoids arising in the small bowel.¹ Carcinoid tumors have an incidence of approximately 2 to 5 per 100,000 patients.² Metastasis of carcinoids is approximately 31.2% to 46.7%.¹ Metastasis to the skin is uncommon; we present a rare case of a carcinoid tumor of the terminal ileum with metastasis to the scalp.

Unlike our patient, most patients with carcinoid tumors have an indolent clinical course. The most common cutaneous symptom is flushing, which occurs in 75% of patients.³ Secreted vasoactive peptides such as serotonin may cause other symptoms such as tachycardia, diarrhea, and bronchospasm; together, these symptoms comprise carcinoid syndrome. Carcinoid syndrome requires metastasis of the tumor to the liver or a site outside of the gastrointestinal tract because the liver will metabolize the secreted serotonin. However, even in patients with liver metastasis, carcinoid syndrome only occurs in approximately 10% of patients.⁴ Common skin findings of carcinoid syndrome include pellagralike dermatitis, flushing, and sclerodermalike changes.⁵ Our patient experienced several episodes of presyncope with symptoms of dyspnea, lightheadedness, and flushing but did not have bronchospasm or recurrent diarrhea. Intramuscular octreotide improved some symptoms.

The scalp accounts for approximately 15% of cutaneous metastases, the most common being from the lung, renal, and breast cancers.⁶ Cutaneous metastases of carcinoid tumors are rare. A PubMed search of articles indexed for MEDLINE using the terms metastatic AND [carcinoid OR neuroendocrine] tumors AND [skin OR cutaneous] revealed 47 cases.^7-11 Similar to other skin metastases, cutaneous metastases of carcinoid tumors commonly present as firm erythematous nodules of varying sizes that may be asymptomatic, tender, or pruritic (Figure 1). Cases of carcinoid tumors with cutaneous metastasis as the initial and only presenting sign are exceedingly rare.¹²

Histology of carcinoid tumors reveals a dermal neoplasm composed of loosely cohesive, mildly atypical, polygonal cells with salt-and-pepper chromatin and eosinophilic cytoplasm, which are similar findings to the primary tumor. The cells may grow in the typical trabecular or organoid neuroendocrine pattern or exhibit a pseudoglandular growth pattern with prominent vessels (quiz image, top).¹² Positive chromogranin and synaptophysin immunostaining are the most common and reliable markers used for the diagnosis of carcinoid tumors.

An important histopathologic differential diagnosis is the aggressive Merkel cell carcinoma, which also demonstrates homogenous salt-and-pepper chromatin but exhibits a higher mitotic rate and positive cytokeratin 20 staining (Figure 2).¹³ Basal cell carcinoma (BCC) also may display similar features, including a blue tumor at scanning magnification and nodular or infiltrative growth patterns. The cell morphology of BCC is characterized by islands of basaloid cells with minimal cytoplasm and frequent apoptosis, connecting to the epidermis with peripheral palisading, retraction artifact, and a myxoid stroma; BCC lacks the salt-and-pepper chromatin commonly seen in carcinoid tumors (Figure 3). Basal cell carcinoma is characterized by positive BerEP4 (epithelial cell adhesion molecule immunostain), cytokeratin 5/6, and cytokeratin 14 uptake. Cytokeratin 20, often used to diagnose Merkel cell carcinoma, is negative in BCC. Chromogranin and synaptophysin occasionally may be positive in BCC.¹⁴

The superficial Ewing sarcoma family of tumors also may be included in the differential diagnosis of small round cell tumors of the skin, but they are very rare. These tumors possess strong positive membranous staining of cytokeratin 99 and also can stain positively for synaptophysin and chromogranin.¹⁵ Epithelial membrane antigen, which is negative in Ewing sarcomas, is positive in carcinoid tumors.¹⁶ Neuroendocrine tumors of all sites share similar basic morphologic patterns, and multiple primary tumors should be considered, including small cell lung carcinoma (Figure 4).^17,18 Red granulations and true glandular lumina typically are not seen in the lungs but are common in gastrointestinal carcinoids.¹⁸ Regarding immunohistochemistry, TTF-1 is negative and CDX2 is positive in gastroenteropancreatic carcinoids, suggesting that these 2 markers can help distinguish carcinoids of unknown primary origin.¹⁹

Metastases in carcinoid tumors are common, with one study noting that the highest frequency of small intestinal metastases was from the ileal subset.²⁰ At the time of diagnosis, 58% to 64% of patients with small intestine carcinoid tumors already had nonlocalized disease, with frequent sites being the lymph nodes (89.8%), liver (44.1%), lungs (13.6%), and peritoneum (13.6%). Regional and distant metastases are associated with substantially worse prognoses, with survival rates of 71.7% and 38.5%, respectively.¹ Treatment of symptomatic unresectable disease focuses on symptomatic management with somatostatin analogs that also control tumor growth.²¹

We present a rare case of scalp metastasis of a carcinoid tumor of the terminal ileum. Distant metastasis is associated with poorer prognosis and should be considered in patients with a known history of a carcinoid tumor.

Acknowledgment—We would like to acknowledge the Research Histology and Tissue Imaging Core at University of Illinois Chicago Research Resources Center for the immunohistochemistry studies.