Dermatopathology

When dermatologists are uncertain about a diagnosis, they might seek help from a book or book chapter written by Dirk M. Elston, MD, a past president of the American Academy of Dermatology and the American Society of Dermatopathology who has authored more than 600 peer-reviewed publications and 92 textbook chapters.

After earning his undergraduate degree from Pennsylvania State University and his medical degree from Jefferson Medical College in Philadelphia, Dr. Elston completed an internship and a dermatology residency at Walter Reed Army Medical Center in Washington, as well as a dermatopathology fellowship at the Cleveland Clinic. He currently is professor and chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina in Charleston.

Dr. Elston is one of five authors of “Andrews’ Diseases of the Skin),” coauthor with Tammie Ferringer, MD, of the “Dermatopathology” textbook, and editor in chief of the Requisites in Dermatology series of textbooks. In 2018, he succeeded Bruce H. Thiers, MD, as editor of the Journal of the American Academy of Dermatology and in 2021, received the AAD’s Gold Medal Award, which is the academy’s highest honor.

In an interview, Dr. Elston reflected on his mentors, shared how he manages his many responsibilities as a clinician, teacher, and editor, and talked about the promising future of dermatology.

Who inspired you most to pursue a career in medicine? My grandmother, Annie Elston, was a physician and dedicated her life to helping others. She was a front-line medic during World War I, helped to run a neonatal syphilis ward after the war, and practiced pediatrics in New York City until her death. She was a great role model.

Did you enter medical school knowing that you wanted to become a dermatologist? If not, what was the turning point for you? I didn’t really know much about dermatology when I entered medical school. I fell in love with the specialty during a rotation.

What was the most memorable experience from your dermatology residency at Walter Reed Army Medical Center? There were so many interesting patients, including many tropical diseases.

Why did you choose to pursue a fellowship in dermatopathology? What was it about this subspeciality that piqued your interest? Great teachers, including Tim Berger, MD, George Lupton, MD, and Dean Pearson, MD. They inspired me to seek a dermpath fellowship and I was lucky enough to train with Wilma Bergfeld, MD.

In your opinion, what’s been the most important advance in dermatopathology to date?

Immunohistochemistry changed the specialty. Now molecular diagnostics is a second wave of major advancement.

How do you stay passionate about both dermatology and dermatopathology? The patients, residents, and fellows keep it interesting. It’s a two-way street. I learn as much as I teach.

You’ve had a remarkable run at the Journal of the American Academy of Dermatology, starting as deputy editor in 2008 before becoming editor in 2018. What’s been most rewarding about this role for you? It is a labor of love and such a privilege to see everyone’s best work.

During the peak of the COVID-19 pandemic, what were your most significant challenges from both a clinical and a personal standpoint? Fear of the unknown is always a challenge with a new epidemic and worse with a pandemic. The patients still needed to be seen but it was a challenge with some buildings closed and some personnel afraid to come to work.

Is there anything you would tell your younger self in terms of career advice? Enjoy every step of the journey.

Considering your various work responsibilities as a clinician, teacher, and editor, what’s your strategy for achieving a work-life balance? A good friend of mine is fond of saying that balance is an illusion. There is only resilience. I believe the truth lies somewhere in between. Make time for family, and decide what has to get done today and what can wait until tomorrow.

What development in dermatology are you most excited about in the next 5 years? We are in a golden age of therapeutic innovations that are life changing and lifesaving for our patients. I never would have believed I would see complete cures of patients with widely metastatic melanoma. From psoriasis to eczema to malignancy, our therapeutic armamentarium is dramatically better each year. It makes the practice of medicine exciting.

When dermatologists are uncertain about a diagnosis, they might seek help from a book or book chapter written by Dirk M. Elston, MD, a past president of the American Academy of Dermatology and the American Society of Dermatopathology who has authored more than 600 peer-reviewed publications and 92 textbook chapters.

After earning his undergraduate degree from Pennsylvania State University and his medical degree from Jefferson Medical College in Philadelphia, Dr. Elston completed an internship and a dermatology residency at Walter Reed Army Medical Center in Washington, as well as a dermatopathology fellowship at the Cleveland Clinic. He currently is professor and chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina in Charleston.

Dr. Elston is one of five authors of “Andrews’ Diseases of the Skin),” coauthor with Tammie Ferringer, MD, of the “Dermatopathology” textbook, and editor in chief of the Requisites in Dermatology series of textbooks. In 2018, he succeeded Bruce H. Thiers, MD, as editor of the Journal of the American Academy of Dermatology and in 2021, received the AAD’s Gold Medal Award, which is the academy’s highest honor.

In an interview, Dr. Elston reflected on his mentors, shared how he manages his many responsibilities as a clinician, teacher, and editor, and talked about the promising future of dermatology.

Who inspired you most to pursue a career in medicine? My grandmother, Annie Elston, was a physician and dedicated her life to helping others. She was a front-line medic during World War I, helped to run a neonatal syphilis ward after the war, and practiced pediatrics in New York City until her death. She was a great role model.

Did you enter medical school knowing that you wanted to become a dermatologist? If not, what was the turning point for you? I didn’t really know much about dermatology when I entered medical school. I fell in love with the specialty during a rotation.

What was the most memorable experience from your dermatology residency at Walter Reed Army Medical Center? There were so many interesting patients, including many tropical diseases.

Why did you choose to pursue a fellowship in dermatopathology? What was it about this subspeciality that piqued your interest? Great teachers, including Tim Berger, MD, George Lupton, MD, and Dean Pearson, MD. They inspired me to seek a dermpath fellowship and I was lucky enough to train with Wilma Bergfeld, MD.

In your opinion, what’s been the most important advance in dermatopathology to date?

Immunohistochemistry changed the specialty. Now molecular diagnostics is a second wave of major advancement.

How do you stay passionate about both dermatology and dermatopathology? The patients, residents, and fellows keep it interesting. It’s a two-way street. I learn as much as I teach.

You’ve had a remarkable run at the Journal of the American Academy of Dermatology, starting as deputy editor in 2008 before becoming editor in 2018. What’s been most rewarding about this role for you? It is a labor of love and such a privilege to see everyone’s best work.

During the peak of the COVID-19 pandemic, what were your most significant challenges from both a clinical and a personal standpoint? Fear of the unknown is always a challenge with a new epidemic and worse with a pandemic. The patients still needed to be seen but it was a challenge with some buildings closed and some personnel afraid to come to work.

Is there anything you would tell your younger self in terms of career advice? Enjoy every step of the journey.

Considering your various work responsibilities as a clinician, teacher, and editor, what’s your strategy for achieving a work-life balance? A good friend of mine is fond of saying that balance is an illusion. There is only resilience. I believe the truth lies somewhere in between. Make time for family, and decide what has to get done today and what can wait until tomorrow.

What development in dermatology are you most excited about in the next 5 years? We are in a golden age of therapeutic innovations that are life changing and lifesaving for our patients. I never would have believed I would see complete cures of patients with widely metastatic melanoma. From psoriasis to eczema to malignancy, our therapeutic armamentarium is dramatically better each year. It makes the practice of medicine exciting.

When dermatologists are uncertain about a diagnosis, they might seek help from a book or book chapter written by Dirk M. Elston, MD, a past president of the American Academy of Dermatology and the American Society of Dermatopathology who has authored more than 600 peer-reviewed publications and 92 textbook chapters.

After earning his undergraduate degree from Pennsylvania State University and his medical degree from Jefferson Medical College in Philadelphia, Dr. Elston completed an internship and a dermatology residency at Walter Reed Army Medical Center in Washington, as well as a dermatopathology fellowship at the Cleveland Clinic. He currently is professor and chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina in Charleston.

Dr. Elston is one of five authors of “Andrews’ Diseases of the Skin),” coauthor with Tammie Ferringer, MD, of the “Dermatopathology” textbook, and editor in chief of the Requisites in Dermatology series of textbooks. In 2018, he succeeded Bruce H. Thiers, MD, as editor of the Journal of the American Academy of Dermatology and in 2021, received the AAD’s Gold Medal Award, which is the academy’s highest honor.

In an interview, Dr. Elston reflected on his mentors, shared how he manages his many responsibilities as a clinician, teacher, and editor, and talked about the promising future of dermatology.

Who inspired you most to pursue a career in medicine? My grandmother, Annie Elston, was a physician and dedicated her life to helping others. She was a front-line medic during World War I, helped to run a neonatal syphilis ward after the war, and practiced pediatrics in New York City until her death. She was a great role model.

Did you enter medical school knowing that you wanted to become a dermatologist? If not, what was the turning point for you? I didn’t really know much about dermatology when I entered medical school. I fell in love with the specialty during a rotation.

What was the most memorable experience from your dermatology residency at Walter Reed Army Medical Center? There were so many interesting patients, including many tropical diseases.

Why did you choose to pursue a fellowship in dermatopathology? What was it about this subspeciality that piqued your interest? Great teachers, including Tim Berger, MD, George Lupton, MD, and Dean Pearson, MD. They inspired me to seek a dermpath fellowship and I was lucky enough to train with Wilma Bergfeld, MD.

In your opinion, what’s been the most important advance in dermatopathology to date?

Immunohistochemistry changed the specialty. Now molecular diagnostics is a second wave of major advancement.

How do you stay passionate about both dermatology and dermatopathology? The patients, residents, and fellows keep it interesting. It’s a two-way street. I learn as much as I teach.

You’ve had a remarkable run at the Journal of the American Academy of Dermatology, starting as deputy editor in 2008 before becoming editor in 2018. What’s been most rewarding about this role for you? It is a labor of love and such a privilege to see everyone’s best work.

During the peak of the COVID-19 pandemic, what were your most significant challenges from both a clinical and a personal standpoint? Fear of the unknown is always a challenge with a new epidemic and worse with a pandemic. The patients still needed to be seen but it was a challenge with some buildings closed and some personnel afraid to come to work.

Is there anything you would tell your younger self in terms of career advice? Enjoy every step of the journey.

Considering your various work responsibilities as a clinician, teacher, and editor, what’s your strategy for achieving a work-life balance? A good friend of mine is fond of saying that balance is an illusion. There is only resilience. I believe the truth lies somewhere in between. Make time for family, and decide what has to get done today and what can wait until tomorrow.

What development in dermatology are you most excited about in the next 5 years? We are in a golden age of therapeutic innovations that are life changing and lifesaving for our patients. I never would have believed I would see complete cures of patients with widely metastatic melanoma. From psoriasis to eczema to malignancy, our therapeutic armamentarium is dramatically better each year. It makes the practice of medicine exciting.

The Diagnosis: Cystic Neutrophilic Granulomatous Mastitis

The histopathologic findings in our patient were characteristic of cystic neutrophilic granulomatous mastitis (CNGM), a rare granulomatous mastitis associated with Corynebacterium and suppurative lipogranulomas. Although not seen in our patient, the lipid vacuoles may contain gram-positive bacilli.¹ The surrounding mixed inflammatory infiltrate contains Langerhans giant cells, lymphocytes, and neutrophils. Cystic neutrophilic granulomatous mastitis is seen in parous women of reproductive age. Physical examination demonstrates a palpable painful mass on the breast. Wound cultures frequently are negative, likely due to difficulty culturing Corynebacterium and prophylactic antibiotic treatment. Given the association with Corynebacterium species, early diagnosis of CNGM is essential in offering patients the most appropriate treatment. Prolonged antibiotic therapy specifically directed to corynebacteria is required, sometimes even beyond resolution of clinical symptoms. The diagnosis of CNGM often is missed or delayed due to its rarity and many potential mimickers. Clinically, CNGM may be virtually impossible to discern from invasive carcinoma.¹

Our patient was treated with vancomycin and cefepime with incision and drainage as an inpatient. Upon discharge, she was started on prednisone 1 mg/kg daily tapered by 10 mg every 5 days over 1 month and doxycycline 100 mg twice daily. She was then transitioned to topical hydrocortisone and bacitracin; she reported decreased swelling and pain. No new lesions formed after the initiation of therapy; however, most lesions remained open. Cystic neutrophilic granulomatous mastitis remains a challenging entity to treat, with a variable response rate reported in the literature for antibiotics such as doxycycline and systemic and topical steroids as well as immunosuppressants including methotrexate.^2,3

Cystic neutrophilic granulomatous mastitis can be distinguished from hidradenitis suppurativa clinically because ulcerating lesions can involve the superior portions of the breast in CNGM, whereas hidradenitis suppurativa typically is restricted to the lower intertriginous parts of the breast. Other mimics of CNGM can be distinguished with biopsy. Histology of pyoderma gangrenosum lacks prominent granuloma formation. Although sarcoidosis and mycobacterial infection show prominent granulomas, neither show the characteristic lipogranulomas seen in CNGM. Additionally, the granulomas of sarcoidosis are much larger and deeper than CNGM. Mycobacterial granulomas also typically reveal bacilli with acid-fast bacilli staining or via wound culture.

The Diagnosis: Cystic Neutrophilic Granulomatous Mastitis

The histopathologic findings in our patient were characteristic of cystic neutrophilic granulomatous mastitis (CNGM), a rare granulomatous mastitis associated with Corynebacterium and suppurative lipogranulomas. Although not seen in our patient, the lipid vacuoles may contain gram-positive bacilli.¹ The surrounding mixed inflammatory infiltrate contains Langerhans giant cells, lymphocytes, and neutrophils. Cystic neutrophilic granulomatous mastitis is seen in parous women of reproductive age. Physical examination demonstrates a palpable painful mass on the breast. Wound cultures frequently are negative, likely due to difficulty culturing Corynebacterium and prophylactic antibiotic treatment. Given the association with Corynebacterium species, early diagnosis of CNGM is essential in offering patients the most appropriate treatment. Prolonged antibiotic therapy specifically directed to corynebacteria is required, sometimes even beyond resolution of clinical symptoms. The diagnosis of CNGM often is missed or delayed due to its rarity and many potential mimickers. Clinically, CNGM may be virtually impossible to discern from invasive carcinoma.¹

Our patient was treated with vancomycin and cefepime with incision and drainage as an inpatient. Upon discharge, she was started on prednisone 1 mg/kg daily tapered by 10 mg every 5 days over 1 month and doxycycline 100 mg twice daily. She was then transitioned to topical hydrocortisone and bacitracin; she reported decreased swelling and pain. No new lesions formed after the initiation of therapy; however, most lesions remained open. Cystic neutrophilic granulomatous mastitis remains a challenging entity to treat, with a variable response rate reported in the literature for antibiotics such as doxycycline and systemic and topical steroids as well as immunosuppressants including methotrexate.^2,3

Cystic neutrophilic granulomatous mastitis can be distinguished from hidradenitis suppurativa clinically because ulcerating lesions can involve the superior portions of the breast in CNGM, whereas hidradenitis suppurativa typically is restricted to the lower intertriginous parts of the breast. Other mimics of CNGM can be distinguished with biopsy. Histology of pyoderma gangrenosum lacks prominent granuloma formation. Although sarcoidosis and mycobacterial infection show prominent granulomas, neither show the characteristic lipogranulomas seen in CNGM. Additionally, the granulomas of sarcoidosis are much larger and deeper than CNGM. Mycobacterial granulomas also typically reveal bacilli with acid-fast bacilli staining or via wound culture.

The Diagnosis: Cystic Neutrophilic Granulomatous Mastitis

The histopathologic findings in our patient were characteristic of cystic neutrophilic granulomatous mastitis (CNGM), a rare granulomatous mastitis associated with Corynebacterium and suppurative lipogranulomas. Although not seen in our patient, the lipid vacuoles may contain gram-positive bacilli.¹ The surrounding mixed inflammatory infiltrate contains Langerhans giant cells, lymphocytes, and neutrophils. Cystic neutrophilic granulomatous mastitis is seen in parous women of reproductive age. Physical examination demonstrates a palpable painful mass on the breast. Wound cultures frequently are negative, likely due to difficulty culturing Corynebacterium and prophylactic antibiotic treatment. Given the association with Corynebacterium species, early diagnosis of CNGM is essential in offering patients the most appropriate treatment. Prolonged antibiotic therapy specifically directed to corynebacteria is required, sometimes even beyond resolution of clinical symptoms. The diagnosis of CNGM often is missed or delayed due to its rarity and many potential mimickers. Clinically, CNGM may be virtually impossible to discern from invasive carcinoma.¹

Our patient was treated with vancomycin and cefepime with incision and drainage as an inpatient. Upon discharge, she was started on prednisone 1 mg/kg daily tapered by 10 mg every 5 days over 1 month and doxycycline 100 mg twice daily. She was then transitioned to topical hydrocortisone and bacitracin; she reported decreased swelling and pain. No new lesions formed after the initiation of therapy; however, most lesions remained open. Cystic neutrophilic granulomatous mastitis remains a challenging entity to treat, with a variable response rate reported in the literature for antibiotics such as doxycycline and systemic and topical steroids as well as immunosuppressants including methotrexate.^2,3

Cystic neutrophilic granulomatous mastitis can be distinguished from hidradenitis suppurativa clinically because ulcerating lesions can involve the superior portions of the breast in CNGM, whereas hidradenitis suppurativa typically is restricted to the lower intertriginous parts of the breast. Other mimics of CNGM can be distinguished with biopsy. Histology of pyoderma gangrenosum lacks prominent granuloma formation. Although sarcoidosis and mycobacterial infection show prominent granulomas, neither show the characteristic lipogranulomas seen in CNGM. Additionally, the granulomas of sarcoidosis are much larger and deeper than CNGM. Mycobacterial granulomas also typically reveal bacilli with acid-fast bacilli staining or via wound culture.

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

A diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was rendered. Subsequent needle core biopsy of a left axillary lymph node as well as bone marrow aspiration and biopsy revealed a similar diffuse blastoid infiltrate with an identical immunophenotype to that in the skin biopsy from the pretibial mass and peripheral blood.

Previously known as blastic natural killer cell leukemia/lymphoma or agranular CD4+/CD56+ hematodermic neoplasm/tumor, BPDCN is a rare, clinically aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. It often is diagnostically challenging, particularly when presenting at noncutaneous sites and in unusual (young) patient populations.¹ It was included with other myeloid neoplasms in the 2008 World Health Organization classification; however, in the 2017 classification it was categorized as a separate entity. Blastic plasmacytoid dendritic cell neoplasm typically presents in the skin of elderly patients (age range at diagnosis, 61–67 years) with or without bone marrow involvement and systemic dissemination.^1,2 The skin is the most common clinical site of disease in typical cases of BPDCN and often precedes bone marrow involvement. Thus, skin biopsy often is the key to making the diagnosis. Diagnosis of BPDCN may be delayed because of diagnostic pitfalls. Patients usually present with asymptomatic solitary or multiple lesions.^3-5 Blastic plasmacytoid dendritic cell neoplasm can present as an isolated purplish nodule or bruiselike papule or more commonly as disseminated purplish nodules, papules, and macules. Isolated nodules are found on the head and lower limbs and can be more than 10 cm in diameter. Peripheral blood and bone marrow may be minimally involved at presentation but invariably become involved with the progression of disease. Cytopenia can occur at diagnosis and in a minority of severe cases indicates bone marrow failure.^2-6

Skin involvement of BPDCN is thought to be secondary to the expression of skin migration molecules, such as cutaneous lymphocyte-associated antigen, one of the E-selectin ligands, which binds to E-selectin on high endothelial venules. In addition, the local dermal microenvironment of chemokines binding CXCR3, CXCR4, CCR6, or CCR7 present on neoplastic cells possibly leads to skin involvement. The full mechanism underlying the cutaneous tropism is still to be elucidated.^4-7 Infiltration of the oral mucosa is seen in some patients, but it may be underreported. Mucosal disease typically appears similarly to cutaneous disease.

The cutaneous differential diagnosis for BPDCN depends on the clinical presentation, extent of disease spread, and thickness of infiltration. It includes common nonneoplastic diseases such as traumatic ecchymoses; purpuric disorders; extramedullary hematopoiesis; and soft-tissue neoplasms such as angiosarcoma, Kaposi sarcoma, neuroblastoma, and vascular metastases, as well as skin involvement by other hematologic neoplasms. An adequate incisional biopsy rather than a punch or shave biopsy is recommended for diagnosis. Dermatologists should alert the pathologist that BPDCN is in the clinical differential diagnosis when possible so that judicious use of appropriate immunophenotypic markers such as CD123, CD4, CD56, and T-cell leukemia/lymphoma protein 1 will avoid misdiagnosis of this aggressive condition, in addition to excluding acute myeloid leukemia, which also may express 3 of the above markers. However, most cases of acute myeloid leukemia lack terminal deoxynucleotidyl transferase (TdT) and express monocytic and other myeloid markers. Terminal deoxynucleotidyl transferase is positive in approximately one-third of cases of BPDCN, with expression in 10% to 80% of cells.¹

It is important to include BPDCN in the differential diagnosis of immunophenotypically aberrant hematologic tumors. Diffuse large B-cell lymphoma, leg type, accounts for 4% of all primary cutaneous B-cell lymphomas.¹ Compared with BPDCN, diffuse large B-cell lymphoma usually occurs in an older age group and is of B-cell lineage. Morphologically, these neoplasms are composed of a monotonous, diffuse, nonepidermotropic infiltrate of confluent sheets of centroblasts and immunoblasts (Figure 1). They may share immunohistochemical markers of CD79a, multiple myeloma 1, Bcl-2, and Bcl-6; however, they lack plasmacytoid dendritic cell (PDC)– associated antigens such as CD4, CD56, CD123, and T-cell leukemia/lymphoma protein 1.¹

Adult T-cell leukemia/lymphoma is a neoplasm histologically composed of highly pleomorphic medium- to large-sized T cells with an irregular multilobated nuclear contour, so-called flower cells, in the peripheral blood. The nuclear chromatin is coarse and clumped with prominent nucleoli. Blastlike cells with dispersed chromatin are present in variable proportions. Most patients present with widespread lymph node and peripheral blood involvement. Skin is involved in more than half of patients with an epidermal as well as dermal pattern of infiltration (mainly perivascular)(Figure 2). Adult T-cell leukemia/lymphoma is endemic in several regions of the world, and the distribution is closely linked to the prevalence of human T-cell lymphotropic virus type 1 in the population. This neoplasm is of T-cell lineage and may share CD4 but not PDC-associated antigens with BPDCN.¹

Cutaneous involvement by T-cell lymphoblastic leukemia/lymphoma (T-LBL) is a rare occurrence with a frequency of approximately 4.3%.8 T-cell lymphoblastic leukemia/lymphoma usually presents as multiple skin lesions throughout the body. Almost all cutaneous T-LBL cases are seen in association with bone marrow and/or mediastinal, lymph node, or extranodal involvement. Cutaneous T-LBLs present as a diffuse monomorphous infiltrate located in the entire dermis and subcutis without epidermotropism, composed of medium to large blasts with finely dispersed chromatin and relatively prominent nucleoli (Figure 3). Immunophenotyping studies show an immature T-cell immunophenotype, with expression of TdT (usually uniform), CD7, and cytoplasmic CD3 and an absence of PDC-associated antigens.⁸

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a neoplasm primarily involving the skin. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection. Histologically, they show variable epidermotropism as well as dermal and subcutaneous involvement by medium to large cells with coarse clumped chromatin (Figure 4). Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. In contrast to BPCDN, the neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are positive for T-cell intracellular antigen-1 and granzyme B with loss of CD4.⁹

At the time of presentation, 27% to 87% of BPDCN patients will have bone marrow involvement, 22% to 28% will have blood involvement, and 6% to 41% will have lymph node involvement.^{1-4,6,7,10,11} The clinical course is aggressive, with a median survival of 10.0 to 19.8 months, irrespective of the initial pattern of disease.¹ Most cases have shown initial response to multiagent chemotherapy, but relapses with subsequent resistance to drugs regularly have been observed. Age has an adverse impact of prognosis. Low TdT expression has been associated with shorter survival.¹ Approximately 10% to 20% of cases of BPDCN are associated with or develop into chronic myelogenous leukemia, myelodysplastic syndrome, or acute myeloid leukemia.^1,4 Pediatric patients have a greater 5-year overall survival rate than older patients, and overall survival worsens with increasing age. The extent of cutaneous involvement and presence of systemic involvement at initial presentation do not seem to be strong predictors of survival.^{1,2,5-7,10-12} In a retrospective analysis of 90 patients, Julia et al¹² found that the type of skin disease did not predict survival. Specifically, the presence of nodular lesions and disseminated skin involvement were not adverse prognostic factors compared with macular lesions limited to 1 or 2 body areas.¹²

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

A diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was rendered. Subsequent needle core biopsy of a left axillary lymph node as well as bone marrow aspiration and biopsy revealed a similar diffuse blastoid infiltrate with an identical immunophenotype to that in the skin biopsy from the pretibial mass and peripheral blood.

Previously known as blastic natural killer cell leukemia/lymphoma or agranular CD4+/CD56+ hematodermic neoplasm/tumor, BPDCN is a rare, clinically aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. It often is diagnostically challenging, particularly when presenting at noncutaneous sites and in unusual (young) patient populations.¹ It was included with other myeloid neoplasms in the 2008 World Health Organization classification; however, in the 2017 classification it was categorized as a separate entity. Blastic plasmacytoid dendritic cell neoplasm typically presents in the skin of elderly patients (age range at diagnosis, 61–67 years) with or without bone marrow involvement and systemic dissemination.^1,2 The skin is the most common clinical site of disease in typical cases of BPDCN and often precedes bone marrow involvement. Thus, skin biopsy often is the key to making the diagnosis. Diagnosis of BPDCN may be delayed because of diagnostic pitfalls. Patients usually present with asymptomatic solitary or multiple lesions.^3-5 Blastic plasmacytoid dendritic cell neoplasm can present as an isolated purplish nodule or bruiselike papule or more commonly as disseminated purplish nodules, papules, and macules. Isolated nodules are found on the head and lower limbs and can be more than 10 cm in diameter. Peripheral blood and bone marrow may be minimally involved at presentation but invariably become involved with the progression of disease. Cytopenia can occur at diagnosis and in a minority of severe cases indicates bone marrow failure.^2-6

Skin involvement of BPDCN is thought to be secondary to the expression of skin migration molecules, such as cutaneous lymphocyte-associated antigen, one of the E-selectin ligands, which binds to E-selectin on high endothelial venules. In addition, the local dermal microenvironment of chemokines binding CXCR3, CXCR4, CCR6, or CCR7 present on neoplastic cells possibly leads to skin involvement. The full mechanism underlying the cutaneous tropism is still to be elucidated.^4-7 Infiltration of the oral mucosa is seen in some patients, but it may be underreported. Mucosal disease typically appears similarly to cutaneous disease.

The cutaneous differential diagnosis for BPDCN depends on the clinical presentation, extent of disease spread, and thickness of infiltration. It includes common nonneoplastic diseases such as traumatic ecchymoses; purpuric disorders; extramedullary hematopoiesis; and soft-tissue neoplasms such as angiosarcoma, Kaposi sarcoma, neuroblastoma, and vascular metastases, as well as skin involvement by other hematologic neoplasms. An adequate incisional biopsy rather than a punch or shave biopsy is recommended for diagnosis. Dermatologists should alert the pathologist that BPDCN is in the clinical differential diagnosis when possible so that judicious use of appropriate immunophenotypic markers such as CD123, CD4, CD56, and T-cell leukemia/lymphoma protein 1 will avoid misdiagnosis of this aggressive condition, in addition to excluding acute myeloid leukemia, which also may express 3 of the above markers. However, most cases of acute myeloid leukemia lack terminal deoxynucleotidyl transferase (TdT) and express monocytic and other myeloid markers. Terminal deoxynucleotidyl transferase is positive in approximately one-third of cases of BPDCN, with expression in 10% to 80% of cells.¹

It is important to include BPDCN in the differential diagnosis of immunophenotypically aberrant hematologic tumors. Diffuse large B-cell lymphoma, leg type, accounts for 4% of all primary cutaneous B-cell lymphomas.¹ Compared with BPDCN, diffuse large B-cell lymphoma usually occurs in an older age group and is of B-cell lineage. Morphologically, these neoplasms are composed of a monotonous, diffuse, nonepidermotropic infiltrate of confluent sheets of centroblasts and immunoblasts (Figure 1). They may share immunohistochemical markers of CD79a, multiple myeloma 1, Bcl-2, and Bcl-6; however, they lack plasmacytoid dendritic cell (PDC)– associated antigens such as CD4, CD56, CD123, and T-cell leukemia/lymphoma protein 1.¹

Adult T-cell leukemia/lymphoma is a neoplasm histologically composed of highly pleomorphic medium- to large-sized T cells with an irregular multilobated nuclear contour, so-called flower cells, in the peripheral blood. The nuclear chromatin is coarse and clumped with prominent nucleoli. Blastlike cells with dispersed chromatin are present in variable proportions. Most patients present with widespread lymph node and peripheral blood involvement. Skin is involved in more than half of patients with an epidermal as well as dermal pattern of infiltration (mainly perivascular)(Figure 2). Adult T-cell leukemia/lymphoma is endemic in several regions of the world, and the distribution is closely linked to the prevalence of human T-cell lymphotropic virus type 1 in the population. This neoplasm is of T-cell lineage and may share CD4 but not PDC-associated antigens with BPDCN.¹

Cutaneous involvement by T-cell lymphoblastic leukemia/lymphoma (T-LBL) is a rare occurrence with a frequency of approximately 4.3%.8 T-cell lymphoblastic leukemia/lymphoma usually presents as multiple skin lesions throughout the body. Almost all cutaneous T-LBL cases are seen in association with bone marrow and/or mediastinal, lymph node, or extranodal involvement. Cutaneous T-LBLs present as a diffuse monomorphous infiltrate located in the entire dermis and subcutis without epidermotropism, composed of medium to large blasts with finely dispersed chromatin and relatively prominent nucleoli (Figure 3). Immunophenotyping studies show an immature T-cell immunophenotype, with expression of TdT (usually uniform), CD7, and cytoplasmic CD3 and an absence of PDC-associated antigens.⁸

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a neoplasm primarily involving the skin. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection. Histologically, they show variable epidermotropism as well as dermal and subcutaneous involvement by medium to large cells with coarse clumped chromatin (Figure 4). Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. In contrast to BPCDN, the neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are positive for T-cell intracellular antigen-1 and granzyme B with loss of CD4.⁹

At the time of presentation, 27% to 87% of BPDCN patients will have bone marrow involvement, 22% to 28% will have blood involvement, and 6% to 41% will have lymph node involvement.^{1-4,6,7,10,11} The clinical course is aggressive, with a median survival of 10.0 to 19.8 months, irrespective of the initial pattern of disease.¹ Most cases have shown initial response to multiagent chemotherapy, but relapses with subsequent resistance to drugs regularly have been observed. Age has an adverse impact of prognosis. Low TdT expression has been associated with shorter survival.¹ Approximately 10% to 20% of cases of BPDCN are associated with or develop into chronic myelogenous leukemia, myelodysplastic syndrome, or acute myeloid leukemia.^1,4 Pediatric patients have a greater 5-year overall survival rate than older patients, and overall survival worsens with increasing age. The extent of cutaneous involvement and presence of systemic involvement at initial presentation do not seem to be strong predictors of survival.^{1,2,5-7,10-12} In a retrospective analysis of 90 patients, Julia et al¹² found that the type of skin disease did not predict survival. Specifically, the presence of nodular lesions and disseminated skin involvement were not adverse prognostic factors compared with macular lesions limited to 1 or 2 body areas.¹²

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

A diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was rendered. Subsequent needle core biopsy of a left axillary lymph node as well as bone marrow aspiration and biopsy revealed a similar diffuse blastoid infiltrate with an identical immunophenotype to that in the skin biopsy from the pretibial mass and peripheral blood.

Previously known as blastic natural killer cell leukemia/lymphoma or agranular CD4+/CD56+ hematodermic neoplasm/tumor, BPDCN is a rare, clinically aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. It often is diagnostically challenging, particularly when presenting at noncutaneous sites and in unusual (young) patient populations.¹ It was included with other myeloid neoplasms in the 2008 World Health Organization classification; however, in the 2017 classification it was categorized as a separate entity. Blastic plasmacytoid dendritic cell neoplasm typically presents in the skin of elderly patients (age range at diagnosis, 61–67 years) with or without bone marrow involvement and systemic dissemination.^1,2 The skin is the most common clinical site of disease in typical cases of BPDCN and often precedes bone marrow involvement. Thus, skin biopsy often is the key to making the diagnosis. Diagnosis of BPDCN may be delayed because of diagnostic pitfalls. Patients usually present with asymptomatic solitary or multiple lesions.^3-5 Blastic plasmacytoid dendritic cell neoplasm can present as an isolated purplish nodule or bruiselike papule or more commonly as disseminated purplish nodules, papules, and macules. Isolated nodules are found on the head and lower limbs and can be more than 10 cm in diameter. Peripheral blood and bone marrow may be minimally involved at presentation but invariably become involved with the progression of disease. Cytopenia can occur at diagnosis and in a minority of severe cases indicates bone marrow failure.^2-6

Skin involvement of BPDCN is thought to be secondary to the expression of skin migration molecules, such as cutaneous lymphocyte-associated antigen, one of the E-selectin ligands, which binds to E-selectin on high endothelial venules. In addition, the local dermal microenvironment of chemokines binding CXCR3, CXCR4, CCR6, or CCR7 present on neoplastic cells possibly leads to skin involvement. The full mechanism underlying the cutaneous tropism is still to be elucidated.^4-7 Infiltration of the oral mucosa is seen in some patients, but it may be underreported. Mucosal disease typically appears similarly to cutaneous disease.

The cutaneous differential diagnosis for BPDCN depends on the clinical presentation, extent of disease spread, and thickness of infiltration. It includes common nonneoplastic diseases such as traumatic ecchymoses; purpuric disorders; extramedullary hematopoiesis; and soft-tissue neoplasms such as angiosarcoma, Kaposi sarcoma, neuroblastoma, and vascular metastases, as well as skin involvement by other hematologic neoplasms. An adequate incisional biopsy rather than a punch or shave biopsy is recommended for diagnosis. Dermatologists should alert the pathologist that BPDCN is in the clinical differential diagnosis when possible so that judicious use of appropriate immunophenotypic markers such as CD123, CD4, CD56, and T-cell leukemia/lymphoma protein 1 will avoid misdiagnosis of this aggressive condition, in addition to excluding acute myeloid leukemia, which also may express 3 of the above markers. However, most cases of acute myeloid leukemia lack terminal deoxynucleotidyl transferase (TdT) and express monocytic and other myeloid markers. Terminal deoxynucleotidyl transferase is positive in approximately one-third of cases of BPDCN, with expression in 10% to 80% of cells.¹

It is important to include BPDCN in the differential diagnosis of immunophenotypically aberrant hematologic tumors. Diffuse large B-cell lymphoma, leg type, accounts for 4% of all primary cutaneous B-cell lymphomas.¹ Compared with BPDCN, diffuse large B-cell lymphoma usually occurs in an older age group and is of B-cell lineage. Morphologically, these neoplasms are composed of a monotonous, diffuse, nonepidermotropic infiltrate of confluent sheets of centroblasts and immunoblasts (Figure 1). They may share immunohistochemical markers of CD79a, multiple myeloma 1, Bcl-2, and Bcl-6; however, they lack plasmacytoid dendritic cell (PDC)– associated antigens such as CD4, CD56, CD123, and T-cell leukemia/lymphoma protein 1.¹

Adult T-cell leukemia/lymphoma is a neoplasm histologically composed of highly pleomorphic medium- to large-sized T cells with an irregular multilobated nuclear contour, so-called flower cells, in the peripheral blood. The nuclear chromatin is coarse and clumped with prominent nucleoli. Blastlike cells with dispersed chromatin are present in variable proportions. Most patients present with widespread lymph node and peripheral blood involvement. Skin is involved in more than half of patients with an epidermal as well as dermal pattern of infiltration (mainly perivascular)(Figure 2). Adult T-cell leukemia/lymphoma is endemic in several regions of the world, and the distribution is closely linked to the prevalence of human T-cell lymphotropic virus type 1 in the population. This neoplasm is of T-cell lineage and may share CD4 but not PDC-associated antigens with BPDCN.¹

Cutaneous involvement by T-cell lymphoblastic leukemia/lymphoma (T-LBL) is a rare occurrence with a frequency of approximately 4.3%.8 T-cell lymphoblastic leukemia/lymphoma usually presents as multiple skin lesions throughout the body. Almost all cutaneous T-LBL cases are seen in association with bone marrow and/or mediastinal, lymph node, or extranodal involvement. Cutaneous T-LBLs present as a diffuse monomorphous infiltrate located in the entire dermis and subcutis without epidermotropism, composed of medium to large blasts with finely dispersed chromatin and relatively prominent nucleoli (Figure 3). Immunophenotyping studies show an immature T-cell immunophenotype, with expression of TdT (usually uniform), CD7, and cytoplasmic CD3 and an absence of PDC-associated antigens.⁸

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a neoplasm primarily involving the skin. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection. Histologically, they show variable epidermotropism as well as dermal and subcutaneous involvement by medium to large cells with coarse clumped chromatin (Figure 4). Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. In contrast to BPCDN, the neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are positive for T-cell intracellular antigen-1 and granzyme B with loss of CD4.⁹

At the time of presentation, 27% to 87% of BPDCN patients will have bone marrow involvement, 22% to 28% will have blood involvement, and 6% to 41% will have lymph node involvement.^{1-4,6,7,10,11} The clinical course is aggressive, with a median survival of 10.0 to 19.8 months, irrespective of the initial pattern of disease.¹ Most cases have shown initial response to multiagent chemotherapy, but relapses with subsequent resistance to drugs regularly have been observed. Age has an adverse impact of prognosis. Low TdT expression has been associated with shorter survival.¹ Approximately 10% to 20% of cases of BPDCN are associated with or develop into chronic myelogenous leukemia, myelodysplastic syndrome, or acute myeloid leukemia.^1,4 Pediatric patients have a greater 5-year overall survival rate than older patients, and overall survival worsens with increasing age. The extent of cutaneous involvement and presence of systemic involvement at initial presentation do not seem to be strong predictors of survival.^{1,2,5-7,10-12} In a retrospective analysis of 90 patients, Julia et al¹² found that the type of skin disease did not predict survival. Specifically, the presence of nodular lesions and disseminated skin involvement were not adverse prognostic factors compared with macular lesions limited to 1 or 2 body areas.¹²

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with hyperandrogenism and is caused by occlusion or rupture of follicular units and inflammation of the apocrine glands.^1-3 The disease most commonly affects women (female to male ratio of 3:1) of childbearing age.^1,2,4,5 Body areas affected include the axillae and groin, and less commonly the perineum; perianal region; and skin folds, such as gluteal, inframammary, and infraumbilical folds.^1,2 Symptoms manifest as painful subcutaneous nodules with possible accompanying purulent drainage, sinus tracts, and/or dermal contractures. Although the pathophysiology is unclear, androgens affect the course of HS during pregnancy by stimulating the affected glands and altering cytokines.^1,2,6

During pregnancy, maternal immune function switches from cell-mediated T helper cell (T_H1) to humoral T_H2 cytokine production. The activity of sebaceous and eccrine glands increases while the activity of apocrine glands decreases, thus changing the inflammatory course of HS during pregnancy.³ Approximately 20% of women with HS experience improvement of symptoms during pregnancy, while the remainder either experience no relief or deterioration of symptoms.¹ Improvement in symptoms during pregnancy was found to occur more frequently in those who had worsening symptoms during menses owing to the possible hormonal effect estrogen has on inhibiting T_H1 and T_H17 proinflammatory cytokines, which promotes an immunosuppressive environment.⁴

Lactation and breastfeeding abilities may be hindered if a woman has HS affecting the apocrine glands of breast tissue and a symptom flare in the postpartum period. If HS causes notable inflammation in the nipple-areolar complex during pregnancy, the patient may experience difficulties with lactation and milk fistula formation, leading to inability to breastfeed.² Another reason why mothers with HS may not be able to breastfeed is that the medications required to treat the disease are unsafe if passed to the infant via breast milk. In addition, the teratogenic effects of HS medications may necessitate therapy adjustments in pregnancy.¹ Here, we provide a brief overview of the medical management considerations of HS in the setting of pregnancy and the impact on breastfeeding.

MEDICAL MANAGEMENT AND DRUG SAFETY

Dermatologists prescribe a myriad of topical and systemic medications to ameliorate symptoms of HS. Therapy regimens often are multimodal and include antibiotics, biologics, and immunosuppressants.^1,3

Antibiotics

First-line antibiotics include clindamycin, metronidazole, tetracyclines, erythromycin, rifampin, dapsone, and fluoroquinolones. Topical clindamycin 1%, metronidazole 0.75%, and erythromycin 2% are used for open or active HS lesions and are all safe to use in pregnancy since there is minimal systemic absorption and minimal excretion into breast milk.¹ Topical antimicrobial washes such as benzoyl peroxide and chlorhexidine often are used in combination with systemic medications to treat HS. These washes are safe during pregnancy and lactation, as they have minimal systemic absorption.⁷

Of these first-line antibiotics, only tetracyclines are contraindicated during pregnancy and lactation, as they are deemed to be in category D by the US Food and Drug Administration (FDA).¹ Aside from tetracyclines, these antibiotics do not cause birth defects and are safe for nursing infants.^1,8 Systemic clindamycin is safe during pregnancy and breastfeeding. Systemic metronidazole also is safe for use in pregnant patients but needs to be discontinued 12 to 24 hours prior to breastfeeding, which often prohibits appropriate dosing.¹

Systemic Erythromycin—There are several forms of systemic erythromycin, including erythromycin base, erythromycin estolate, erythromycin ethylsuccinate (EES), and erythromycin stearate. Erythromycin estolate is contraindicated in pregnancy because it is associated with reversible maternal hepatoxicity and jaundice.^9-11 Erythromycin ethylsuccinate is the preferred form for pregnant patients. Providers should exercise caution when prescribing EES to lactating mothers, as small amounts are still secreted through breast milk.¹¹ Some studies have shown an increased risk for development of infantile hypertrophic pyloric stenosis with systemic erythromycin use, especially if a neonate is exposed in the first 14 days of life. Thus, we recommend withholding EES for 2 weeks after delivery if the patient is breastfeeding. A follow-up study did not find any association between erythromycin and infantile hypertrophic pyloric stenosis; however, the American Academy of Pediatrics still recommends short-term use only of erythromycin if it is to be used in the systemic form.⁸

Rifampin—Rifampin is excreted into breast milk but without adverse effects to the infant. Rifampin also is safe in pregnancy but should be used on a case-by-case basis in pregnant or nursing women because it is a cytochrome P450 inducer.

Dapsone—Dapsone has no increased risk for congenital anomalies. However, it is associated with hemolytic anemia and neonatal hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹² Newborns exposed to dapsone are at an increased risk for methemoglobinemia owing to increased sensitivity of fetal erythrocytes to oxidizing agents.¹³ If dapsone use is necessary, stopping dapsone treatment in the last month of gestation is recommended to minimize risk for kernicterus.⁹ Dapsone can be found in high concentrations in breast milk at 14.3% of the maternal dose. It is still safe to use during breastfeeding, but there is a risk of the infant developing hyperbilirubinemia/G6PD deficiency.^1,8 Thus, physicians may consider performing a G6PD screen on infants to determine if breastfeeding is safe.¹²

Fluoroquinolones—Quinolones are not contraindicated during pregnancy, but they can damage fetal cartilage and thus should be reserved for use in complicated infections when the benefits outweigh the risks.¹² Quinolones are believed to increase risk for arthropathy but are safe for use in lactation. When quinolones are digested with milk, exposure decreases below pediatric doses because of the ionized property of calcium in milk.⁸

Tumor Necrosis Factor α Inhibitors—The safety of anti–tumor necrosis factor (TNF) α biologics in pregnancy is less certain when compared with antibiotics.¹ Anti–TNF-α inhibitors such as etanercept, adalimumab, and infliximab are all labeled as FDA category B, meaning there are no well-controlled human studies of the drugs.⁹ There are limited data that support safe use of TNF-α inhibitors prior to the third trimester before maternal IgG antibodies are transferred to the fetus via the placenta.^1,13 Anti–TNF-α inhibitors may be safe when breastfeeding because the drugs have large molecular weights that prevent them from entering breast milk in large amounts. Absorption also is limited due to the infant’s digestive acids and enzymes breaking down the protein structure of the medication.⁸ Overall, TNF-α inhibitor use is still controversial and only used if the benefits outweigh the risks during pregnancy or if there is no alternative treatment.^1,3,9

Ustekinumab and Anakinra—Ustekinumab (an IL-12/IL-23 inhibitor) and anakinra (an IL-1α and IL-1β inhibitor) also are FDA category B drugs and have limited data supporting their use as HS treatment in pregnancy. Anakinra may have evidence of compatibility with breastfeeding, as endogenous IL-1α inhibitor is found in colostrum and mature breast milk.¹

Immunosuppressants

Immunosuppressants that are used to treat HS include corticosteroids and cyclosporine.

Corticosteroids—Topical corticosteroids can be used safely in lactation if they are not applied directly to the nipple or any area that makes direct contact with the infant’s mouth. Intralesional corticosteroid injections are safe for use during both pregnancy and breastfeeding to decrease inflammation of acutely flaring lesions and can be considered first-line treatment.¹ Oral glucocorticoids also can be safely used for acute flares during pregnancy; however, prolonged use is associated with pregnancy complications such as preeclampsia, eclampsia, premature delivery, and gestational diabetes.¹² There also is a small risk of oral cleft deformity in the infant; thus, potent corticosteroids are recommended in short durations during pregnancy, and there are no adverse effects if the maternal dose is less than 10 mg daily.^8,12 Systemic steroids are safe to use with breastfeeding, but patients should be advised to wait 4 hours after ingesting medication before breastfeeding.^1,8

Cyclosporine—Topical and oral calcineurin inhibitors such as cyclosporine have low risk for transmission into breast milk; however, potential effects of exposure through breast milk are unknown. For that reason, manufacturers state that cyclosporine use is contraindicated during lactation.⁸ If cyclosporine is to be used by a breastfeeding woman, monitoring cyclosporine concentrations in the infant is suggested to ensure that the exposure is less than 5% to 10% of the therapeutic dose.¹³ The use of cyclosporine has been extensively studied in pregnant transplant patients and is considered relatively safe for use in pregnancy.¹⁴ Cyclosporine is lipid soluble and thus is quickly metabolized and spread throughout the body; it can easily cross the placenta.^9,13 Blood concentration in the fetus is 30% to 64% that of the maternal circulation. However, cyclosporine is only toxic to the fetus at maternally toxic doses, which can result in low birth weight and increased prenatal and postnatal mortality.¹³

Isotretinoin, Oral Contraceptive Pills, and Spironolactone

Isotretinoin and hormonal treatments such as oral contraceptive pills and spironolactone (an androgen receptor blocker) commonly are used to treat HS, but all are contraindicated in pregnancy and lactation. Isotretinoin is a well-established teratogen, but adverse effects on nursing babies have not been described. However, the manufacturer of isotretinoin advises against its use in lactation. Oral contraceptive pill use in early pregnancy is associated with increased risk for Down syndrome. Oral contraceptive pill use also is contraindicated in lactation for 2 reasons: decreased milk production and risk for fetal feminization. Antiandrogenic agents such as spironolactone have been shown to be associated with hypospadias and feminization of the male fetus.⁷

COMMENT

Women with HS usually require ongoing medical treatment during pregnancy and immediately postpartum; thus, it is important that treatments are proven to be safe for use in this specific population. Current management guidelines are not entirely suitable for pregnant and breastfeeding women given that many HS drugs have teratogenic effects and/or can be excreted into breast milk.¹ Several treatments have uncertain safety profiles in pregnancy and breastfeeding, which calls for dermatologists to change or create new regimens for their patients. Close management also is necessary to prevent excess inflammation of breast tissue and milk fistula formation, which would hinder normal breastfeeding.

The eTable lists medications used to treat HS. The FDA category is listed next to each drug. However, it should be noted that these FDA letter categories were replaced with the Pregnancy and Lactation Labeling Rule in 2015. The letter ratings were deemed overly simplistic and replaced with narrative-based labeling that provides more detailed adverse effects and clinical considerations.⁹

Risk Factors of HS—Predisposing risk factors for HS flares that are controllable include obesity and smoking.² Pregnancy weight gain may cause increased skin maceration at intertriginous sites, which can contribute to worsening HS symptoms.^1,5 Adipocytes play a role in HS exacerbation by promoting secretion of TNF-α, leading to increased inflammation.⁵ Dermatologists can help prevent postpartum HS flares by monitoring weight gain during pregnancy, encouraging smoking cessation, and promoting weight and nutrition goals as set by an obstetrician.¹ In addition to medications, management of HS should include emotional support and education on wearing loose-fitting clothing to avoid irritation of the affected areas.³ An emphasis on dermatologist counseling for all patients with HS, even for those with milder disease, can reduce exacerbations during pregnancy.⁵

CONCLUSION

The selection of dermatologic drugs for the treatment of HS in the setting of pregnancy involves complex decision-making. Dermatologists need more guidelines and proven safety data in human trials, especially regarding use of biologics and immunosuppressants to better treat HS in pregnancy. With more data, they can create more evidence-based treatment regimens to help prevent postpartum exacerbations of HS. Thus, patients can breastfeed their infants comfortably and without any risks of impaired child development. In the meantime, dermatologists can continue to work together with obstetricians and psychiatrists to decrease disease flares through counseling patients on nutrition and weight gain and providing emotional support.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with hyperandrogenism and is caused by occlusion or rupture of follicular units and inflammation of the apocrine glands.^1-3 The disease most commonly affects women (female to male ratio of 3:1) of childbearing age.^1,2,4,5 Body areas affected include the axillae and groin, and less commonly the perineum; perianal region; and skin folds, such as gluteal, inframammary, and infraumbilical folds.^1,2 Symptoms manifest as painful subcutaneous nodules with possible accompanying purulent drainage, sinus tracts, and/or dermal contractures. Although the pathophysiology is unclear, androgens affect the course of HS during pregnancy by stimulating the affected glands and altering cytokines.^1,2,6

During pregnancy, maternal immune function switches from cell-mediated T helper cell (T_H1) to humoral T_H2 cytokine production. The activity of sebaceous and eccrine glands increases while the activity of apocrine glands decreases, thus changing the inflammatory course of HS during pregnancy.³ Approximately 20% of women with HS experience improvement of symptoms during pregnancy, while the remainder either experience no relief or deterioration of symptoms.¹ Improvement in symptoms during pregnancy was found to occur more frequently in those who had worsening symptoms during menses owing to the possible hormonal effect estrogen has on inhibiting T_H1 and T_H17 proinflammatory cytokines, which promotes an immunosuppressive environment.⁴

Lactation and breastfeeding abilities may be hindered if a woman has HS affecting the apocrine glands of breast tissue and a symptom flare in the postpartum period. If HS causes notable inflammation in the nipple-areolar complex during pregnancy, the patient may experience difficulties with lactation and milk fistula formation, leading to inability to breastfeed.² Another reason why mothers with HS may not be able to breastfeed is that the medications required to treat the disease are unsafe if passed to the infant via breast milk. In addition, the teratogenic effects of HS medications may necessitate therapy adjustments in pregnancy.¹ Here, we provide a brief overview of the medical management considerations of HS in the setting of pregnancy and the impact on breastfeeding.

MEDICAL MANAGEMENT AND DRUG SAFETY

Dermatologists prescribe a myriad of topical and systemic medications to ameliorate symptoms of HS. Therapy regimens often are multimodal and include antibiotics, biologics, and immunosuppressants.^1,3

Antibiotics

First-line antibiotics include clindamycin, metronidazole, tetracyclines, erythromycin, rifampin, dapsone, and fluoroquinolones. Topical clindamycin 1%, metronidazole 0.75%, and erythromycin 2% are used for open or active HS lesions and are all safe to use in pregnancy since there is minimal systemic absorption and minimal excretion into breast milk.¹ Topical antimicrobial washes such as benzoyl peroxide and chlorhexidine often are used in combination with systemic medications to treat HS. These washes are safe during pregnancy and lactation, as they have minimal systemic absorption.⁷

Of these first-line antibiotics, only tetracyclines are contraindicated during pregnancy and lactation, as they are deemed to be in category D by the US Food and Drug Administration (FDA).¹ Aside from tetracyclines, these antibiotics do not cause birth defects and are safe for nursing infants.^1,8 Systemic clindamycin is safe during pregnancy and breastfeeding. Systemic metronidazole also is safe for use in pregnant patients but needs to be discontinued 12 to 24 hours prior to breastfeeding, which often prohibits appropriate dosing.¹

Systemic Erythromycin—There are several forms of systemic erythromycin, including erythromycin base, erythromycin estolate, erythromycin ethylsuccinate (EES), and erythromycin stearate. Erythromycin estolate is contraindicated in pregnancy because it is associated with reversible maternal hepatoxicity and jaundice.^9-11 Erythromycin ethylsuccinate is the preferred form for pregnant patients. Providers should exercise caution when prescribing EES to lactating mothers, as small amounts are still secreted through breast milk.¹¹ Some studies have shown an increased risk for development of infantile hypertrophic pyloric stenosis with systemic erythromycin use, especially if a neonate is exposed in the first 14 days of life. Thus, we recommend withholding EES for 2 weeks after delivery if the patient is breastfeeding. A follow-up study did not find any association between erythromycin and infantile hypertrophic pyloric stenosis; however, the American Academy of Pediatrics still recommends short-term use only of erythromycin if it is to be used in the systemic form.⁸

Rifampin—Rifampin is excreted into breast milk but without adverse effects to the infant. Rifampin also is safe in pregnancy but should be used on a case-by-case basis in pregnant or nursing women because it is a cytochrome P450 inducer.

Dapsone—Dapsone has no increased risk for congenital anomalies. However, it is associated with hemolytic anemia and neonatal hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹² Newborns exposed to dapsone are at an increased risk for methemoglobinemia owing to increased sensitivity of fetal erythrocytes to oxidizing agents.¹³ If dapsone use is necessary, stopping dapsone treatment in the last month of gestation is recommended to minimize risk for kernicterus.⁹ Dapsone can be found in high concentrations in breast milk at 14.3% of the maternal dose. It is still safe to use during breastfeeding, but there is a risk of the infant developing hyperbilirubinemia/G6PD deficiency.^1,8 Thus, physicians may consider performing a G6PD screen on infants to determine if breastfeeding is safe.¹²

Fluoroquinolones—Quinolones are not contraindicated during pregnancy, but they can damage fetal cartilage and thus should be reserved for use in complicated infections when the benefits outweigh the risks.¹² Quinolones are believed to increase risk for arthropathy but are safe for use in lactation. When quinolones are digested with milk, exposure decreases below pediatric doses because of the ionized property of calcium in milk.⁸

Tumor Necrosis Factor α Inhibitors—The safety of anti–tumor necrosis factor (TNF) α biologics in pregnancy is less certain when compared with antibiotics.¹ Anti–TNF-α inhibitors such as etanercept, adalimumab, and infliximab are all labeled as FDA category B, meaning there are no well-controlled human studies of the drugs.⁹ There are limited data that support safe use of TNF-α inhibitors prior to the third trimester before maternal IgG antibodies are transferred to the fetus via the placenta.^1,13 Anti–TNF-α inhibitors may be safe when breastfeeding because the drugs have large molecular weights that prevent them from entering breast milk in large amounts. Absorption also is limited due to the infant’s digestive acids and enzymes breaking down the protein structure of the medication.⁸ Overall, TNF-α inhibitor use is still controversial and only used if the benefits outweigh the risks during pregnancy or if there is no alternative treatment.^1,3,9

Ustekinumab and Anakinra—Ustekinumab (an IL-12/IL-23 inhibitor) and anakinra (an IL-1α and IL-1β inhibitor) also are FDA category B drugs and have limited data supporting their use as HS treatment in pregnancy. Anakinra may have evidence of compatibility with breastfeeding, as endogenous IL-1α inhibitor is found in colostrum and mature breast milk.¹

Immunosuppressants

Immunosuppressants that are used to treat HS include corticosteroids and cyclosporine.

Corticosteroids—Topical corticosteroids can be used safely in lactation if they are not applied directly to the nipple or any area that makes direct contact with the infant’s mouth. Intralesional corticosteroid injections are safe for use during both pregnancy and breastfeeding to decrease inflammation of acutely flaring lesions and can be considered first-line treatment.¹ Oral glucocorticoids also can be safely used for acute flares during pregnancy; however, prolonged use is associated with pregnancy complications such as preeclampsia, eclampsia, premature delivery, and gestational diabetes.¹² There also is a small risk of oral cleft deformity in the infant; thus, potent corticosteroids are recommended in short durations during pregnancy, and there are no adverse effects if the maternal dose is less than 10 mg daily.^8,12 Systemic steroids are safe to use with breastfeeding, but patients should be advised to wait 4 hours after ingesting medication before breastfeeding.^1,8

Cyclosporine—Topical and oral calcineurin inhibitors such as cyclosporine have low risk for transmission into breast milk; however, potential effects of exposure through breast milk are unknown. For that reason, manufacturers state that cyclosporine use is contraindicated during lactation.⁸ If cyclosporine is to be used by a breastfeeding woman, monitoring cyclosporine concentrations in the infant is suggested to ensure that the exposure is less than 5% to 10% of the therapeutic dose.¹³ The use of cyclosporine has been extensively studied in pregnant transplant patients and is considered relatively safe for use in pregnancy.¹⁴ Cyclosporine is lipid soluble and thus is quickly metabolized and spread throughout the body; it can easily cross the placenta.^9,13 Blood concentration in the fetus is 30% to 64% that of the maternal circulation. However, cyclosporine is only toxic to the fetus at maternally toxic doses, which can result in low birth weight and increased prenatal and postnatal mortality.¹³

Isotretinoin, Oral Contraceptive Pills, and Spironolactone

Isotretinoin and hormonal treatments such as oral contraceptive pills and spironolactone (an androgen receptor blocker) commonly are used to treat HS, but all are contraindicated in pregnancy and lactation. Isotretinoin is a well-established teratogen, but adverse effects on nursing babies have not been described. However, the manufacturer of isotretinoin advises against its use in lactation. Oral contraceptive pill use in early pregnancy is associated with increased risk for Down syndrome. Oral contraceptive pill use also is contraindicated in lactation for 2 reasons: decreased milk production and risk for fetal feminization. Antiandrogenic agents such as spironolactone have been shown to be associated with hypospadias and feminization of the male fetus.⁷

COMMENT

Women with HS usually require ongoing medical treatment during pregnancy and immediately postpartum; thus, it is important that treatments are proven to be safe for use in this specific population. Current management guidelines are not entirely suitable for pregnant and breastfeeding women given that many HS drugs have teratogenic effects and/or can be excreted into breast milk.¹ Several treatments have uncertain safety profiles in pregnancy and breastfeeding, which calls for dermatologists to change or create new regimens for their patients. Close management also is necessary to prevent excess inflammation of breast tissue and milk fistula formation, which would hinder normal breastfeeding.

The eTable lists medications used to treat HS. The FDA category is listed next to each drug. However, it should be noted that these FDA letter categories were replaced with the Pregnancy and Lactation Labeling Rule in 2015. The letter ratings were deemed overly simplistic and replaced with narrative-based labeling that provides more detailed adverse effects and clinical considerations.⁹

Risk Factors of HS—Predisposing risk factors for HS flares that are controllable include obesity and smoking.² Pregnancy weight gain may cause increased skin maceration at intertriginous sites, which can contribute to worsening HS symptoms.^1,5 Adipocytes play a role in HS exacerbation by promoting secretion of TNF-α, leading to increased inflammation.⁵ Dermatologists can help prevent postpartum HS flares by monitoring weight gain during pregnancy, encouraging smoking cessation, and promoting weight and nutrition goals as set by an obstetrician.¹ In addition to medications, management of HS should include emotional support and education on wearing loose-fitting clothing to avoid irritation of the affected areas.³ An emphasis on dermatologist counseling for all patients with HS, even for those with milder disease, can reduce exacerbations during pregnancy.⁵

CONCLUSION

The selection of dermatologic drugs for the treatment of HS in the setting of pregnancy involves complex decision-making. Dermatologists need more guidelines and proven safety data in human trials, especially regarding use of biologics and immunosuppressants to better treat HS in pregnancy. With more data, they can create more evidence-based treatment regimens to help prevent postpartum exacerbations of HS. Thus, patients can breastfeed their infants comfortably and without any risks of impaired child development. In the meantime, dermatologists can continue to work together with obstetricians and psychiatrists to decrease disease flares through counseling patients on nutrition and weight gain and providing emotional support.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with hyperandrogenism and is caused by occlusion or rupture of follicular units and inflammation of the apocrine glands.^1-3 The disease most commonly affects women (female to male ratio of 3:1) of childbearing age.^1,2,4,5 Body areas affected include the axillae and groin, and less commonly the perineum; perianal region; and skin folds, such as gluteal, inframammary, and infraumbilical folds.^1,2 Symptoms manifest as painful subcutaneous nodules with possible accompanying purulent drainage, sinus tracts, and/or dermal contractures. Although the pathophysiology is unclear, androgens affect the course of HS during pregnancy by stimulating the affected glands and altering cytokines.^1,2,6

During pregnancy, maternal immune function switches from cell-mediated T helper cell (T_H1) to humoral T_H2 cytokine production. The activity of sebaceous and eccrine glands increases while the activity of apocrine glands decreases, thus changing the inflammatory course of HS during pregnancy.³ Approximately 20% of women with HS experience improvement of symptoms during pregnancy, while the remainder either experience no relief or deterioration of symptoms.¹ Improvement in symptoms during pregnancy was found to occur more frequently in those who had worsening symptoms during menses owing to the possible hormonal effect estrogen has on inhibiting T_H1 and T_H17 proinflammatory cytokines, which promotes an immunosuppressive environment.⁴

Lactation and breastfeeding abilities may be hindered if a woman has HS affecting the apocrine glands of breast tissue and a symptom flare in the postpartum period. If HS causes notable inflammation in the nipple-areolar complex during pregnancy, the patient may experience difficulties with lactation and milk fistula formation, leading to inability to breastfeed.² Another reason why mothers with HS may not be able to breastfeed is that the medications required to treat the disease are unsafe if passed to the infant via breast milk. In addition, the teratogenic effects of HS medications may necessitate therapy adjustments in pregnancy.¹ Here, we provide a brief overview of the medical management considerations of HS in the setting of pregnancy and the impact on breastfeeding.

MEDICAL MANAGEMENT AND DRUG SAFETY

Dermatologists prescribe a myriad of topical and systemic medications to ameliorate symptoms of HS. Therapy regimens often are multimodal and include antibiotics, biologics, and immunosuppressants.^1,3

Antibiotics

First-line antibiotics include clindamycin, metronidazole, tetracyclines, erythromycin, rifampin, dapsone, and fluoroquinolones. Topical clindamycin 1%, metronidazole 0.75%, and erythromycin 2% are used for open or active HS lesions and are all safe to use in pregnancy since there is minimal systemic absorption and minimal excretion into breast milk.¹ Topical antimicrobial washes such as benzoyl peroxide and chlorhexidine often are used in combination with systemic medications to treat HS. These washes are safe during pregnancy and lactation, as they have minimal systemic absorption.⁷

Of these first-line antibiotics, only tetracyclines are contraindicated during pregnancy and lactation, as they are deemed to be in category D by the US Food and Drug Administration (FDA).¹ Aside from tetracyclines, these antibiotics do not cause birth defects and are safe for nursing infants.^1,8 Systemic clindamycin is safe during pregnancy and breastfeeding. Systemic metronidazole also is safe for use in pregnant patients but needs to be discontinued 12 to 24 hours prior to breastfeeding, which often prohibits appropriate dosing.¹

Systemic Erythromycin—There are several forms of systemic erythromycin, including erythromycin base, erythromycin estolate, erythromycin ethylsuccinate (EES), and erythromycin stearate. Erythromycin estolate is contraindicated in pregnancy because it is associated with reversible maternal hepatoxicity and jaundice.^9-11 Erythromycin ethylsuccinate is the preferred form for pregnant patients. Providers should exercise caution when prescribing EES to lactating mothers, as small amounts are still secreted through breast milk.¹¹ Some studies have shown an increased risk for development of infantile hypertrophic pyloric stenosis with systemic erythromycin use, especially if a neonate is exposed in the first 14 days of life. Thus, we recommend withholding EES for 2 weeks after delivery if the patient is breastfeeding. A follow-up study did not find any association between erythromycin and infantile hypertrophic pyloric stenosis; however, the American Academy of Pediatrics still recommends short-term use only of erythromycin if it is to be used in the systemic form.⁸

Rifampin—Rifampin is excreted into breast milk but without adverse effects to the infant. Rifampin also is safe in pregnancy but should be used on a case-by-case basis in pregnant or nursing women because it is a cytochrome P450 inducer.

Dapsone—Dapsone has no increased risk for congenital anomalies. However, it is associated with hemolytic anemia and neonatal hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹² Newborns exposed to dapsone are at an increased risk for methemoglobinemia owing to increased sensitivity of fetal erythrocytes to oxidizing agents.¹³ If dapsone use is necessary, stopping dapsone treatment in the last month of gestation is recommended to minimize risk for kernicterus.⁹ Dapsone can be found in high concentrations in breast milk at 14.3% of the maternal dose. It is still safe to use during breastfeeding, but there is a risk of the infant developing hyperbilirubinemia/G6PD deficiency.^1,8 Thus, physicians may consider performing a G6PD screen on infants to determine if breastfeeding is safe.¹²

Fluoroquinolones—Quinolones are not contraindicated during pregnancy, but they can damage fetal cartilage and thus should be reserved for use in complicated infections when the benefits outweigh the risks.¹² Quinolones are believed to increase risk for arthropathy but are safe for use in lactation. When quinolones are digested with milk, exposure decreases below pediatric doses because of the ionized property of calcium in milk.⁸

Tumor Necrosis Factor α Inhibitors—The safety of anti–tumor necrosis factor (TNF) α biologics in pregnancy is less certain when compared with antibiotics.¹ Anti–TNF-α inhibitors such as etanercept, adalimumab, and infliximab are all labeled as FDA category B, meaning there are no well-controlled human studies of the drugs.⁹ There are limited data that support safe use of TNF-α inhibitors prior to the third trimester before maternal IgG antibodies are transferred to the fetus via the placenta.^1,13 Anti–TNF-α inhibitors may be safe when breastfeeding because the drugs have large molecular weights that prevent them from entering breast milk in large amounts. Absorption also is limited due to the infant’s digestive acids and enzymes breaking down the protein structure of the medication.⁸ Overall, TNF-α inhibitor use is still controversial and only used if the benefits outweigh the risks during pregnancy or if there is no alternative treatment.^1,3,9

Ustekinumab and Anakinra—Ustekinumab (an IL-12/IL-23 inhibitor) and anakinra (an IL-1α and IL-1β inhibitor) also are FDA category B drugs and have limited data supporting their use as HS treatment in pregnancy. Anakinra may have evidence of compatibility with breastfeeding, as endogenous IL-1α inhibitor is found in colostrum and mature breast milk.¹

Immunosuppressants

Immunosuppressants that are used to treat HS include corticosteroids and cyclosporine.

Corticosteroids—Topical corticosteroids can be used safely in lactation if they are not applied directly to the nipple or any area that makes direct contact with the infant’s mouth. Intralesional corticosteroid injections are safe for use during both pregnancy and breastfeeding to decrease inflammation of acutely flaring lesions and can be considered first-line treatment.¹ Oral glucocorticoids also can be safely used for acute flares during pregnancy; however, prolonged use is associated with pregnancy complications such as preeclampsia, eclampsia, premature delivery, and gestational diabetes.¹² There also is a small risk of oral cleft deformity in the infant; thus, potent corticosteroids are recommended in short durations during pregnancy, and there are no adverse effects if the maternal dose is less than 10 mg daily.^8,12 Systemic steroids are safe to use with breastfeeding, but patients should be advised to wait 4 hours after ingesting medication before breastfeeding.^1,8

Cyclosporine—Topical and oral calcineurin inhibitors such as cyclosporine have low risk for transmission into breast milk; however, potential effects of exposure through breast milk are unknown. For that reason, manufacturers state that cyclosporine use is contraindicated during lactation.⁸ If cyclosporine is to be used by a breastfeeding woman, monitoring cyclosporine concentrations in the infant is suggested to ensure that the exposure is less than 5% to 10% of the therapeutic dose.¹³ The use of cyclosporine has been extensively studied in pregnant transplant patients and is considered relatively safe for use in pregnancy.¹⁴ Cyclosporine is lipid soluble and thus is quickly metabolized and spread throughout the body; it can easily cross the placenta.^9,13 Blood concentration in the fetus is 30% to 64% that of the maternal circulation. However, cyclosporine is only toxic to the fetus at maternally toxic doses, which can result in low birth weight and increased prenatal and postnatal mortality.¹³

Isotretinoin, Oral Contraceptive Pills, and Spironolactone

Isotretinoin and hormonal treatments such as oral contraceptive pills and spironolactone (an androgen receptor blocker) commonly are used to treat HS, but all are contraindicated in pregnancy and lactation. Isotretinoin is a well-established teratogen, but adverse effects on nursing babies have not been described. However, the manufacturer of isotretinoin advises against its use in lactation. Oral contraceptive pill use in early pregnancy is associated with increased risk for Down syndrome. Oral contraceptive pill use also is contraindicated in lactation for 2 reasons: decreased milk production and risk for fetal feminization. Antiandrogenic agents such as spironolactone have been shown to be associated with hypospadias and feminization of the male fetus.⁷

COMMENT

Women with HS usually require ongoing medical treatment during pregnancy and immediately postpartum; thus, it is important that treatments are proven to be safe for use in this specific population. Current management guidelines are not entirely suitable for pregnant and breastfeeding women given that many HS drugs have teratogenic effects and/or can be excreted into breast milk.¹ Several treatments have uncertain safety profiles in pregnancy and breastfeeding, which calls for dermatologists to change or create new regimens for their patients. Close management also is necessary to prevent excess inflammation of breast tissue and milk fistula formation, which would hinder normal breastfeeding.

The eTable lists medications used to treat HS. The FDA category is listed next to each drug. However, it should be noted that these FDA letter categories were replaced with the Pregnancy and Lactation Labeling Rule in 2015. The letter ratings were deemed overly simplistic and replaced with narrative-based labeling that provides more detailed adverse effects and clinical considerations.⁹

Risk Factors of HS—Predisposing risk factors for HS flares that are controllable include obesity and smoking.² Pregnancy weight gain may cause increased skin maceration at intertriginous sites, which can contribute to worsening HS symptoms.^1,5 Adipocytes play a role in HS exacerbation by promoting secretion of TNF-α, leading to increased inflammation.⁵ Dermatologists can help prevent postpartum HS flares by monitoring weight gain during pregnancy, encouraging smoking cessation, and promoting weight and nutrition goals as set by an obstetrician.¹ In addition to medications, management of HS should include emotional support and education on wearing loose-fitting clothing to avoid irritation of the affected areas.³ An emphasis on dermatologist counseling for all patients with HS, even for those with milder disease, can reduce exacerbations during pregnancy.⁵

CONCLUSION

The selection of dermatologic drugs for the treatment of HS in the setting of pregnancy involves complex decision-making. Dermatologists need more guidelines and proven safety data in human trials, especially regarding use of biologics and immunosuppressants to better treat HS in pregnancy. With more data, they can create more evidence-based treatment regimens to help prevent postpartum exacerbations of HS. Thus, patients can breastfeed their infants comfortably and without any risks of impaired child development. In the meantime, dermatologists can continue to work together with obstetricians and psychiatrists to decrease disease flares through counseling patients on nutrition and weight gain and providing emotional support.

The Diagnosis: Bullous Pyoderma Gangrenosum

A bone marrow biopsy revealed 60% myeloblasts, leading to a diagnosis of acute myeloid leukemia (AML). A biopsy obtained from the edge of the bullous plaque demonstrated a dense dermal neutrophilic infiltrate with extravasated erythrocytes (Figure). Fite, Gram, and Grocott-Gomori methenamine-silver staining failed to reveal infectious organisms. Tissue and blood cultures were negative. Given the pathologic findings, clinical presentation including recent diagnosis of AML, and exclusion of other underlying disease processes including infection, the diagnosis of bullous pyoderma gangrenosum (PG) was made. The lesion improved with systemic steroids and treatment of the underlying AML with fludarabine and venetoclax chemotherapy.

First recognized in 1916 by French dermatologist Louis Brocq, MD, PG is a sterile neutrophilic dermatosis that predominantly affects women older than 50 years.^1,2 This disorder can develop idiopathically; secondary to trauma; or in association with systemic diseases such as inflammatory bowel disease, rheumatoid arthritis, and hematologic malignancies. The pathogenesis of PG remains unclear; however, overexpression of inflammatory cytokines may mediate its development by stimulating T cells and promoting neutrophilic chemotaxis.³

Pyoderma gangrenosum classically presents as a rapidly enlarging ulcer with cribriform scarring but manifests variably. Four variants of the disorder exist: classic ulcerative, pustular, bullous, and vegetative PG. Ulcerative PG is the most common variant. Bullous PG is associated with hematologic malignancies such as primary myelofibrosis, myelodysplastic disease, and AML. In these patients, hematologic malignancy often exists prior to the development of PG and portends a poorer prognosis. This association underscores the importance of timely diagnosis and thorough hematologic evaluation by obtaining a complete blood cell count with differential, peripheral smear, serum protein electrophoresis with immunofixation, and quantitative immunoglobulins (IgA, IgG, IgM). If any of the results are positive, prompt referral to a hematologist and bone marrow biopsy are paramount.³

The diagnosis of PG remains elusive, as no validated clinical or pathological criteria exist. Histopathologic evaluation may be nonspecific and variable depending on the subtype. Biopsy results for classic ulcerative PG may reveal a neutrophilic infiltrate with leukocytoclasia. Bullous PG may include subepidermal hemorrhagic bullae. Notably, bullous PG appears histologically similar to the superficial bullous variant of Sweet syndrome.

Sweet syndrome (also known as acute febrile neutrophilic dermatosis) is a type of neutrophilic dermatosis characterized by fever, neutrophilia, and the sudden onset of tender erythematous lesions. Variations include idiopathic, subcutaneous, and bullous Sweet syndrome, which present as plaques, nodules, or bullae, respectively.⁴ Similar to PG, Sweet syndrome can manifest in patients with hematologic malignancies. Both PG and Sweet syndrome are thought to exist along a continuum and can be considered intersecting diagnoses in the setting of leukemia or other hematologic malignancies.⁵ There have been reports of the coexistence of distinct PG and Sweet syndrome lesions on a single patient, further supporting the belief that these entities share a common pathologic mechanism.⁶ Sweet syndrome also commonly can be associated with upper respiratory infections; pregnancy; and medications, with culprits including granulocyte colony-stimulating factor, azathioprine, vemurafenib, and isotretinoin.⁷

Other differential diagnoses include brown recluse spider bite, bullous fixed drug eruption (FDE), and necrotizing fasciitis (NF). Venom from the brown recluse spider (Loxosceles reclusa) can trigger toxin-mediated hemolysis, complement-mediated erythrocyte destruction, and basement membrane zone degradation due to the synergistic effects of the toxin’s sphingomyelinase D and protease content.⁸ The inciting bite is painless. After 8 hours, the site becomes painful and pruritic and presents with peripheral erythema and central pallor. After 24 hours, the lesion blisters. The blister ruptures within 3 to 4 days, resulting in eschar formation with the subsequent development of an indurated blue ulcer with a stellate center. Ulcers can take months to heal.⁹ Based on the clinical findings in our patient, this diagnosis was less likely.

Fixed drug eruption is a localized cutaneous reaction that manifests in fixed locations minutes to days after exposure to medications such as trimethoprimsulfamethoxazole, nonsteroidal anti-inflammatory drugs, salicylates, and oral contraceptives. Commonly affected areas include the hands, legs, genitals, and trunk. Lesions initially present as well-demarcated, erythematous to violaceous, round plaques. A rarer variant manifesting as bullae also has been described. Careful consideration of the patient’s history and physical examination findings is sufficient for establishing this diagnosis; however, a punch biopsy can provide clarity. Histopathology reveals a lichenoid tissue reaction with dyskeratosis, broad epidermal necrosis, and damage to the stratum basalis. A lymphocytic perivascular infiltrate also may appear in the dermis.¹⁰ Both the clinical findings and histopathology of our case were not characteristic of FDE.

Necrotizing fasciitis is a fulminant, life-threatening, soft-tissue infection precipitated by polymicrobial flora. Early recognition of NF is difficult, as in its early stages it can mimic cellulitis. As the infection takes its course, necrosis can extend from the skin and into the subcutaneous tissue. Patients also develop fever, leukocytosis, and signs of sepsis. Histopathology demonstrates neutrophilic infiltration with bacterial invasion as well as necrosis of the superficial fascia and subepidermal edema.¹¹ Pyoderma gangrenosum previously has been reported to mimic NF; however, lack of responsiveness to antibiotic therapy would favor a diagnosis of PG over NF.¹²

Treatment of PG is driven by the extent of cutaneous involvement. In mild cases, wound care and topical therapy with corticosteroids and tacrolimus may suffice. Severe cases necessitate systemic therapy with oral corticosteroids or cyclosporine; biologic therapy also may play a role in treatment.⁴ In patients with hematologic malignancy, chemotherapy alone may partially or completely resolve the lesion; however, systemic corticosteroids commonly are included in management.³

The Diagnosis: Bullous Pyoderma Gangrenosum

A bone marrow biopsy revealed 60% myeloblasts, leading to a diagnosis of acute myeloid leukemia (AML). A biopsy obtained from the edge of the bullous plaque demonstrated a dense dermal neutrophilic infiltrate with extravasated erythrocytes (Figure). Fite, Gram, and Grocott-Gomori methenamine-silver staining failed to reveal infectious organisms. Tissue and blood cultures were negative. Given the pathologic findings, clinical presentation including recent diagnosis of AML, and exclusion of other underlying disease processes including infection, the diagnosis of bullous pyoderma gangrenosum (PG) was made. The lesion improved with systemic steroids and treatment of the underlying AML with fludarabine and venetoclax chemotherapy.

First recognized in 1916 by French dermatologist Louis Brocq, MD, PG is a sterile neutrophilic dermatosis that predominantly affects women older than 50 years.^1,2 This disorder can develop idiopathically; secondary to trauma; or in association with systemic diseases such as inflammatory bowel disease, rheumatoid arthritis, and hematologic malignancies. The pathogenesis of PG remains unclear; however, overexpression of inflammatory cytokines may mediate its development by stimulating T cells and promoting neutrophilic chemotaxis.³

Pyoderma gangrenosum classically presents as a rapidly enlarging ulcer with cribriform scarring but manifests variably. Four variants of the disorder exist: classic ulcerative, pustular, bullous, and vegetative PG. Ulcerative PG is the most common variant. Bullous PG is associated with hematologic malignancies such as primary myelofibrosis, myelodysplastic disease, and AML. In these patients, hematologic malignancy often exists prior to the development of PG and portends a poorer prognosis. This association underscores the importance of timely diagnosis and thorough hematologic evaluation by obtaining a complete blood cell count with differential, peripheral smear, serum protein electrophoresis with immunofixation, and quantitative immunoglobulins (IgA, IgG, IgM). If any of the results are positive, prompt referral to a hematologist and bone marrow biopsy are paramount.³

The diagnosis of PG remains elusive, as no validated clinical or pathological criteria exist. Histopathologic evaluation may be nonspecific and variable depending on the subtype. Biopsy results for classic ulcerative PG may reveal a neutrophilic infiltrate with leukocytoclasia. Bullous PG may include subepidermal hemorrhagic bullae. Notably, bullous PG appears histologically similar to the superficial bullous variant of Sweet syndrome.

Sweet syndrome (also known as acute febrile neutrophilic dermatosis) is a type of neutrophilic dermatosis characterized by fever, neutrophilia, and the sudden onset of tender erythematous lesions. Variations include idiopathic, subcutaneous, and bullous Sweet syndrome, which present as plaques, nodules, or bullae, respectively.⁴ Similar to PG, Sweet syndrome can manifest in patients with hematologic malignancies. Both PG and Sweet syndrome are thought to exist along a continuum and can be considered intersecting diagnoses in the setting of leukemia or other hematologic malignancies.⁵ There have been reports of the coexistence of distinct PG and Sweet syndrome lesions on a single patient, further supporting the belief that these entities share a common pathologic mechanism.⁶ Sweet syndrome also commonly can be associated with upper respiratory infections; pregnancy; and medications, with culprits including granulocyte colony-stimulating factor, azathioprine, vemurafenib, and isotretinoin.⁷

Other differential diagnoses include brown recluse spider bite, bullous fixed drug eruption (FDE), and necrotizing fasciitis (NF). Venom from the brown recluse spider (Loxosceles reclusa) can trigger toxin-mediated hemolysis, complement-mediated erythrocyte destruction, and basement membrane zone degradation due to the synergistic effects of the toxin’s sphingomyelinase D and protease content.⁸ The inciting bite is painless. After 8 hours, the site becomes painful and pruritic and presents with peripheral erythema and central pallor. After 24 hours, the lesion blisters. The blister ruptures within 3 to 4 days, resulting in eschar formation with the subsequent development of an indurated blue ulcer with a stellate center. Ulcers can take months to heal.⁹ Based on the clinical findings in our patient, this diagnosis was less likely.

Fixed drug eruption is a localized cutaneous reaction that manifests in fixed locations minutes to days after exposure to medications such as trimethoprimsulfamethoxazole, nonsteroidal anti-inflammatory drugs, salicylates, and oral contraceptives. Commonly affected areas include the hands, legs, genitals, and trunk. Lesions initially present as well-demarcated, erythematous to violaceous, round plaques. A rarer variant manifesting as bullae also has been described. Careful consideration of the patient’s history and physical examination findings is sufficient for establishing this diagnosis; however, a punch biopsy can provide clarity. Histopathology reveals a lichenoid tissue reaction with dyskeratosis, broad epidermal necrosis, and damage to the stratum basalis. A lymphocytic perivascular infiltrate also may appear in the dermis.¹⁰ Both the clinical findings and histopathology of our case were not characteristic of FDE.

Necrotizing fasciitis is a fulminant, life-threatening, soft-tissue infection precipitated by polymicrobial flora. Early recognition of NF is difficult, as in its early stages it can mimic cellulitis. As the infection takes its course, necrosis can extend from the skin and into the subcutaneous tissue. Patients also develop fever, leukocytosis, and signs of sepsis. Histopathology demonstrates neutrophilic infiltration with bacterial invasion as well as necrosis of the superficial fascia and subepidermal edema.¹¹ Pyoderma gangrenosum previously has been reported to mimic NF; however, lack of responsiveness to antibiotic therapy would favor a diagnosis of PG over NF.¹²

Treatment of PG is driven by the extent of cutaneous involvement. In mild cases, wound care and topical therapy with corticosteroids and tacrolimus may suffice. Severe cases necessitate systemic therapy with oral corticosteroids or cyclosporine; biologic therapy also may play a role in treatment.⁴ In patients with hematologic malignancy, chemotherapy alone may partially or completely resolve the lesion; however, systemic corticosteroids commonly are included in management.³

The Diagnosis: Bullous Pyoderma Gangrenosum

A bone marrow biopsy revealed 60% myeloblasts, leading to a diagnosis of acute myeloid leukemia (AML). A biopsy obtained from the edge of the bullous plaque demonstrated a dense dermal neutrophilic infiltrate with extravasated erythrocytes (Figure). Fite, Gram, and Grocott-Gomori methenamine-silver staining failed to reveal infectious organisms. Tissue and blood cultures were negative. Given the pathologic findings, clinical presentation including recent diagnosis of AML, and exclusion of other underlying disease processes including infection, the diagnosis of bullous pyoderma gangrenosum (PG) was made. The lesion improved with systemic steroids and treatment of the underlying AML with fludarabine and venetoclax chemotherapy.

First recognized in 1916 by French dermatologist Louis Brocq, MD, PG is a sterile neutrophilic dermatosis that predominantly affects women older than 50 years.^1,2 This disorder can develop idiopathically; secondary to trauma; or in association with systemic diseases such as inflammatory bowel disease, rheumatoid arthritis, and hematologic malignancies. The pathogenesis of PG remains unclear; however, overexpression of inflammatory cytokines may mediate its development by stimulating T cells and promoting neutrophilic chemotaxis.³

Pyoderma gangrenosum classically presents as a rapidly enlarging ulcer with cribriform scarring but manifests variably. Four variants of the disorder exist: classic ulcerative, pustular, bullous, and vegetative PG. Ulcerative PG is the most common variant. Bullous PG is associated with hematologic malignancies such as primary myelofibrosis, myelodysplastic disease, and AML. In these patients, hematologic malignancy often exists prior to the development of PG and portends a poorer prognosis. This association underscores the importance of timely diagnosis and thorough hematologic evaluation by obtaining a complete blood cell count with differential, peripheral smear, serum protein electrophoresis with immunofixation, and quantitative immunoglobulins (IgA, IgG, IgM). If any of the results are positive, prompt referral to a hematologist and bone marrow biopsy are paramount.³

The diagnosis of PG remains elusive, as no validated clinical or pathological criteria exist. Histopathologic evaluation may be nonspecific and variable depending on the subtype. Biopsy results for classic ulcerative PG may reveal a neutrophilic infiltrate with leukocytoclasia. Bullous PG may include subepidermal hemorrhagic bullae. Notably, bullous PG appears histologically similar to the superficial bullous variant of Sweet syndrome.

Sweet syndrome (also known as acute febrile neutrophilic dermatosis) is a type of neutrophilic dermatosis characterized by fever, neutrophilia, and the sudden onset of tender erythematous lesions. Variations include idiopathic, subcutaneous, and bullous Sweet syndrome, which present as plaques, nodules, or bullae, respectively.⁴ Similar to PG, Sweet syndrome can manifest in patients with hematologic malignancies. Both PG and Sweet syndrome are thought to exist along a continuum and can be considered intersecting diagnoses in the setting of leukemia or other hematologic malignancies.⁵ There have been reports of the coexistence of distinct PG and Sweet syndrome lesions on a single patient, further supporting the belief that these entities share a common pathologic mechanism.⁶ Sweet syndrome also commonly can be associated with upper respiratory infections; pregnancy; and medications, with culprits including granulocyte colony-stimulating factor, azathioprine, vemurafenib, and isotretinoin.⁷

Other differential diagnoses include brown recluse spider bite, bullous fixed drug eruption (FDE), and necrotizing fasciitis (NF). Venom from the brown recluse spider (Loxosceles reclusa) can trigger toxin-mediated hemolysis, complement-mediated erythrocyte destruction, and basement membrane zone degradation due to the synergistic effects of the toxin’s sphingomyelinase D and protease content.⁸ The inciting bite is painless. After 8 hours, the site becomes painful and pruritic and presents with peripheral erythema and central pallor. After 24 hours, the lesion blisters. The blister ruptures within 3 to 4 days, resulting in eschar formation with the subsequent development of an indurated blue ulcer with a stellate center. Ulcers can take months to heal.⁹ Based on the clinical findings in our patient, this diagnosis was less likely.

Fixed drug eruption is a localized cutaneous reaction that manifests in fixed locations minutes to days after exposure to medications such as trimethoprimsulfamethoxazole, nonsteroidal anti-inflammatory drugs, salicylates, and oral contraceptives. Commonly affected areas include the hands, legs, genitals, and trunk. Lesions initially present as well-demarcated, erythematous to violaceous, round plaques. A rarer variant manifesting as bullae also has been described. Careful consideration of the patient’s history and physical examination findings is sufficient for establishing this diagnosis; however, a punch biopsy can provide clarity. Histopathology reveals a lichenoid tissue reaction with dyskeratosis, broad epidermal necrosis, and damage to the stratum basalis. A lymphocytic perivascular infiltrate also may appear in the dermis.¹⁰ Both the clinical findings and histopathology of our case were not characteristic of FDE.

Necrotizing fasciitis is a fulminant, life-threatening, soft-tissue infection precipitated by polymicrobial flora. Early recognition of NF is difficult, as in its early stages it can mimic cellulitis. As the infection takes its course, necrosis can extend from the skin and into the subcutaneous tissue. Patients also develop fever, leukocytosis, and signs of sepsis. Histopathology demonstrates neutrophilic infiltration with bacterial invasion as well as necrosis of the superficial fascia and subepidermal edema.¹¹ Pyoderma gangrenosum previously has been reported to mimic NF; however, lack of responsiveness to antibiotic therapy would favor a diagnosis of PG over NF.¹²

Treatment of PG is driven by the extent of cutaneous involvement. In mild cases, wound care and topical therapy with corticosteroids and tacrolimus may suffice. Severe cases necessitate systemic therapy with oral corticosteroids or cyclosporine; biologic therapy also may play a role in treatment.⁴ In patients with hematologic malignancy, chemotherapy alone may partially or completely resolve the lesion; however, systemic corticosteroids commonly are included in management.³

To the Editor:

Iododerma is a rare dermatologic condition caused by exposure to iodinated contrast media, oral iodine suspensions, or topical povidone-iodine that can manifest as eruptive acneform lesions.^1-3

A 27-year-old woman in septic shock presented for worsening facial lesions that showed no improvement on broad-spectrum antibiotics, antifungals, and antivirals. She initially presented to an outside hospital with abdominal pain and underwent computed tomography (CT) with intravenous (IV) iodinated contrast; 24 hours after this imaging study, the family reported the appearance of “explosive acne overnight.” The lesions first appeared as vegetative and acneform ulcerations on the face. A second abdominal CT scan with IV contrast was performed 4 days after the initial scan, given the concern for spontaneous bacterial peritonitis. Hours after the second study, the lesions progressed to involve the buccal mucosae, tongue, mucosal airway, and distal arms and legs. She became progressively disoriented and developed an altered mentation over the course of the following week. Due to progressive facial edema, she required intubation 5 days after the second CT scan.

The patient had a medical history of end-stage renal disease secondary to crescenteric glomerulonephritis on peritoneal dialysis. Physical examination revealed numerous beefy-red, heaped-up, weepy, crusted nodules clustered on the face (Figure 1) and a few newer bullous-appearing lesions on the hands and feet. She had similar lesions involving the buccal mucosae and tongue with substantial facial edema. Infectious workup was notable for a positive skin culture growing methicillin-susceptible Staphylococcus aureus. All blood and tissue cultures as well as serologies for fungal and viral etiologies were negative. A tissue biopsy revealed necrosis with a neutrophilic infiltrate with mixed cell inflammation (Figure 2), and direct immunofluorescence was negative.

The patient initially was thought to be septic due to viral or bacterial infection. She was transferred from an outside hospital 7 days after the initial appearance of the acneform lesions, having already received IV contrast on 2 occasions within the first 48 hours of illness. Infectious disease was consulted and initiated broad-spectrum antiviral, antimicrobial, and antifungal therapy with acyclovir, linezolid, meropenem, and later micafungin without improvement. The diagnosis of iododerma ultimately was established based on the patient’s elevated urinary iodine levels with preceding iodine exposure in the context of renal failure. The preferential involvement of sebaceous areas and pathology findings were supportive of this diagnosis. Aggressive supportive measures including respiratory support, IV fluids, and dialysis were initiated. Topical iodine solutions, iodine-containing medications, and additional contrast subsequently were avoided. Despite these supportive measures, the patient died within 48 hours of admission from acute respiratory failure. Her autopsy attributed “septic complications of multifocal ulcerative cutaneous disease” as the anatomic cause of death.

Iododerma is an extremely rare neutrophilic dermatosis. The proposed mechanism of action involves a cell-mediated hypersensitivity reaction to iodine with induction of neutrophil degranulation.² There have been documented cases with exposure to oral potassium iodide supplements, amiodarone, topical povidone-iodine, and IV iodinated contrast material.^1-3 Iododerma typically presents 1 to 3 days after exposure to iodine. The most common source is IV radiocontrast. Diagnosis is based on the clinical presentation including acneform to vegetative nodular or bullous eruptions involving sebaceous areas in the context of recent iodine exposure. Elevated urinary iodine levels and histologic findings of neutrophilic infiltrate of the dermis support the diagnosis.^3,4

Although there have been reported cases of iododerma in patients with normal renal function, patients with renal failure are much more susceptible due to the decreased clearance of iodine.⁵ The plasma half-life of radiocontrast is 23 hours in patients with end-stage renal disease vs 2 hours in patients with normal kidney function.³ Dosage adjustments for renal impairment have not been well studied, and no specific guidelines exist for the prevention of iododerma in patients with renal failure.

The first step in treating iododerma is to remove the offending iodine-containing agent. In most cases, cutaneous lesions resolve in 4 to 6 weeks after discontinuation of the source of iodine; however, there have been reported fatalities in the literature secondary to pulmonary edema in patients with iododerma.^6,7 Despite the rarity and diagnostically challenging nature of iododerma, early recognition of this disease is crucial. Although our patient showed symptoms of iododerma after 1 dose of radiocontrast, she was not diagnosed at that time and received a second imaging study with contrast less than 48 hours later. These 2 consecutive exposures to iodine as well as the delayed diagnosis unfortunately resulted in rapid clinical deterioration.

The mainstay of therapy for iododerma includes avoidance of iodine-containing materials as soon as the diagnosis is suspected as well as supportive care. Patients have been successfully treated with systemic corticosteroids, with the addition of cyclosporine and hemodialysis in severe cases.³ Patients with a history of iododerma are advised to avoid iodine in their diet, in topical preparations, and in future imaging studies.⁸

To the Editor:

Iododerma is a rare dermatologic condition caused by exposure to iodinated contrast media, oral iodine suspensions, or topical povidone-iodine that can manifest as eruptive acneform lesions.^1-3

A 27-year-old woman in septic shock presented for worsening facial lesions that showed no improvement on broad-spectrum antibiotics, antifungals, and antivirals. She initially presented to an outside hospital with abdominal pain and underwent computed tomography (CT) with intravenous (IV) iodinated contrast; 24 hours after this imaging study, the family reported the appearance of “explosive acne overnight.” The lesions first appeared as vegetative and acneform ulcerations on the face. A second abdominal CT scan with IV contrast was performed 4 days after the initial scan, given the concern for spontaneous bacterial peritonitis. Hours after the second study, the lesions progressed to involve the buccal mucosae, tongue, mucosal airway, and distal arms and legs. She became progressively disoriented and developed an altered mentation over the course of the following week. Due to progressive facial edema, she required intubation 5 days after the second CT scan.

The patient had a medical history of end-stage renal disease secondary to crescenteric glomerulonephritis on peritoneal dialysis. Physical examination revealed numerous beefy-red, heaped-up, weepy, crusted nodules clustered on the face (Figure 1) and a few newer bullous-appearing lesions on the hands and feet. She had similar lesions involving the buccal mucosae and tongue with substantial facial edema. Infectious workup was notable for a positive skin culture growing methicillin-susceptible Staphylococcus aureus. All blood and tissue cultures as well as serologies for fungal and viral etiologies were negative. A tissue biopsy revealed necrosis with a neutrophilic infiltrate with mixed cell inflammation (Figure 2), and direct immunofluorescence was negative.

The patient initially was thought to be septic due to viral or bacterial infection. She was transferred from an outside hospital 7 days after the initial appearance of the acneform lesions, having already received IV contrast on 2 occasions within the first 48 hours of illness. Infectious disease was consulted and initiated broad-spectrum antiviral, antimicrobial, and antifungal therapy with acyclovir, linezolid, meropenem, and later micafungin without improvement. The diagnosis of iododerma ultimately was established based on the patient’s elevated urinary iodine levels with preceding iodine exposure in the context of renal failure. The preferential involvement of sebaceous areas and pathology findings were supportive of this diagnosis. Aggressive supportive measures including respiratory support, IV fluids, and dialysis were initiated. Topical iodine solutions, iodine-containing medications, and additional contrast subsequently were avoided. Despite these supportive measures, the patient died within 48 hours of admission from acute respiratory failure. Her autopsy attributed “septic complications of multifocal ulcerative cutaneous disease” as the anatomic cause of death.

Iododerma is an extremely rare neutrophilic dermatosis. The proposed mechanism of action involves a cell-mediated hypersensitivity reaction to iodine with induction of neutrophil degranulation.² There have been documented cases with exposure to oral potassium iodide supplements, amiodarone, topical povidone-iodine, and IV iodinated contrast material.^1-3 Iododerma typically presents 1 to 3 days after exposure to iodine. The most common source is IV radiocontrast. Diagnosis is based on the clinical presentation including acneform to vegetative nodular or bullous eruptions involving sebaceous areas in the context of recent iodine exposure. Elevated urinary iodine levels and histologic findings of neutrophilic infiltrate of the dermis support the diagnosis.^3,4

Although there have been reported cases of iododerma in patients with normal renal function, patients with renal failure are much more susceptible due to the decreased clearance of iodine.⁵ The plasma half-life of radiocontrast is 23 hours in patients with end-stage renal disease vs 2 hours in patients with normal kidney function.³ Dosage adjustments for renal impairment have not been well studied, and no specific guidelines exist for the prevention of iododerma in patients with renal failure.

The first step in treating iododerma is to remove the offending iodine-containing agent. In most cases, cutaneous lesions resolve in 4 to 6 weeks after discontinuation of the source of iodine; however, there have been reported fatalities in the literature secondary to pulmonary edema in patients with iododerma.^6,7 Despite the rarity and diagnostically challenging nature of iododerma, early recognition of this disease is crucial. Although our patient showed symptoms of iododerma after 1 dose of radiocontrast, she was not diagnosed at that time and received a second imaging study with contrast less than 48 hours later. These 2 consecutive exposures to iodine as well as the delayed diagnosis unfortunately resulted in rapid clinical deterioration.

The mainstay of therapy for iododerma includes avoidance of iodine-containing materials as soon as the diagnosis is suspected as well as supportive care. Patients have been successfully treated with systemic corticosteroids, with the addition of cyclosporine and hemodialysis in severe cases.³ Patients with a history of iododerma are advised to avoid iodine in their diet, in topical preparations, and in future imaging studies.⁸

To the Editor:

Iododerma is a rare dermatologic condition caused by exposure to iodinated contrast media, oral iodine suspensions, or topical povidone-iodine that can manifest as eruptive acneform lesions.^1-3

A 27-year-old woman in septic shock presented for worsening facial lesions that showed no improvement on broad-spectrum antibiotics, antifungals, and antivirals. She initially presented to an outside hospital with abdominal pain and underwent computed tomography (CT) with intravenous (IV) iodinated contrast; 24 hours after this imaging study, the family reported the appearance of “explosive acne overnight.” The lesions first appeared as vegetative and acneform ulcerations on the face. A second abdominal CT scan with IV contrast was performed 4 days after the initial scan, given the concern for spontaneous bacterial peritonitis. Hours after the second study, the lesions progressed to involve the buccal mucosae, tongue, mucosal airway, and distal arms and legs. She became progressively disoriented and developed an altered mentation over the course of the following week. Due to progressive facial edema, she required intubation 5 days after the second CT scan.

The patient had a medical history of end-stage renal disease secondary to crescenteric glomerulonephritis on peritoneal dialysis. Physical examination revealed numerous beefy-red, heaped-up, weepy, crusted nodules clustered on the face (Figure 1) and a few newer bullous-appearing lesions on the hands and feet. She had similar lesions involving the buccal mucosae and tongue with substantial facial edema. Infectious workup was notable for a positive skin culture growing methicillin-susceptible Staphylococcus aureus. All blood and tissue cultures as well as serologies for fungal and viral etiologies were negative. A tissue biopsy revealed necrosis with a neutrophilic infiltrate with mixed cell inflammation (Figure 2), and direct immunofluorescence was negative.

The patient initially was thought to be septic due to viral or bacterial infection. She was transferred from an outside hospital 7 days after the initial appearance of the acneform lesions, having already received IV contrast on 2 occasions within the first 48 hours of illness. Infectious disease was consulted and initiated broad-spectrum antiviral, antimicrobial, and antifungal therapy with acyclovir, linezolid, meropenem, and later micafungin without improvement. The diagnosis of iododerma ultimately was established based on the patient’s elevated urinary iodine levels with preceding iodine exposure in the context of renal failure. The preferential involvement of sebaceous areas and pathology findings were supportive of this diagnosis. Aggressive supportive measures including respiratory support, IV fluids, and dialysis were initiated. Topical iodine solutions, iodine-containing medications, and additional contrast subsequently were avoided. Despite these supportive measures, the patient died within 48 hours of admission from acute respiratory failure. Her autopsy attributed “septic complications of multifocal ulcerative cutaneous disease” as the anatomic cause of death.

Iododerma is an extremely rare neutrophilic dermatosis. The proposed mechanism of action involves a cell-mediated hypersensitivity reaction to iodine with induction of neutrophil degranulation.² There have been documented cases with exposure to oral potassium iodide supplements, amiodarone, topical povidone-iodine, and IV iodinated contrast material.^1-3 Iododerma typically presents 1 to 3 days after exposure to iodine. The most common source is IV radiocontrast. Diagnosis is based on the clinical presentation including acneform to vegetative nodular or bullous eruptions involving sebaceous areas in the context of recent iodine exposure. Elevated urinary iodine levels and histologic findings of neutrophilic infiltrate of the dermis support the diagnosis.^3,4

Although there have been reported cases of iododerma in patients with normal renal function, patients with renal failure are much more susceptible due to the decreased clearance of iodine.⁵ The plasma half-life of radiocontrast is 23 hours in patients with end-stage renal disease vs 2 hours in patients with normal kidney function.³ Dosage adjustments for renal impairment have not been well studied, and no specific guidelines exist for the prevention of iododerma in patients with renal failure.

The first step in treating iododerma is to remove the offending iodine-containing agent. In most cases, cutaneous lesions resolve in 4 to 6 weeks after discontinuation of the source of iodine; however, there have been reported fatalities in the literature secondary to pulmonary edema in patients with iododerma.^6,7 Despite the rarity and diagnostically challenging nature of iododerma, early recognition of this disease is crucial. Although our patient showed symptoms of iododerma after 1 dose of radiocontrast, she was not diagnosed at that time and received a second imaging study with contrast less than 48 hours later. These 2 consecutive exposures to iodine as well as the delayed diagnosis unfortunately resulted in rapid clinical deterioration.

The mainstay of therapy for iododerma includes avoidance of iodine-containing materials as soon as the diagnosis is suspected as well as supportive care. Patients have been successfully treated with systemic corticosteroids, with the addition of cyclosporine and hemodialysis in severe cases.³ Patients with a history of iododerma are advised to avoid iodine in their diet, in topical preparations, and in future imaging studies.⁸

In patients with persistent atopic dermatitis (AD) who are taking dupilumab, is there benefit of patch testing to determine if allergic contact dermatitis (ACD) also is contributing to their disease? Results of patch testing are likely be influenced by the immunomodulatory effects of dupilumab. Similar to the recommendation for patients to refrain from using topical or systemic corticosteroids for 1 week or more prior to patch testing to eliminate false negatives, we reviewed the literature to create practice guidelines for dermatologists regarding patch testing while a patient is taking dupilumab.

Pathophysiology and Pathomechanism

Dupilumab functions through the blockade of T helper 2 (T_H2) cells; ACD is propagated through the T helper 1 (T_H1) cellular pathway. However, patients with ACD that is unresponsive to allergen avoidance and traditional therapies, such as topical and oral corticosteroids, have responded to dupilumab. The more common reports of this responsiveness are with fragrances; multiple case series described patients with ACD to fragrance mix I¹ and balsam of Peru^1,2 who improved on dupilumab when other treatments failed. There also are reports of response when ACD was secondary to nickel,^2,3p-phenylenediamine,¹ Compositae,⁴ and non–formaldehyde-releasing preservatives (non-FRPs).⁵ Therefore, not all ACD is propagated through the T_H1 cellular pathway.

As noted in these cases, ACD can be a response to an allergen whose pathogenesis involves the T_H2 pathway or when patient characteristics favor a T_H2 response. It has been suggested that AD patients are more susceptible to T_H2-mediated contact sensitization to less-potent allergens, such as fragrances.⁶

Patch Test Results

Positive patch test results for allergens have been reported while patients are on dupilumab therapy, including a few studies in which results prior to starting dupilumab were compared with those while patients were on dupilumab therapy. In a retrospective chart review of 48 patients on dupilumab for AD with persistent disease, 23 patients were patch tested before and during dupilumab therapy. In these patients, the majority of contact allergies were persistent and only 10% (13/125) of patch test–positive results resolved on dupilumab therapy.⁷ Contact allergies that resolved included those to emulsifiers (propylene glycol, Amerchol L101 [lanolin-containing products found in cosmetics and other goods], dimethylaminopropylamine), fragrances (fragrance mix I, balsam of Peru), sunscreens (sulisobenzone, phenylbenzimidazole-5-sulfonic acid), and metals (vanadium chloride, phenylmercuric acetate).⁷ The following results observed in individual cases demonstrated conflicting findings: persistence of allergy to non-FRPs (methylisothiazolinone [MI]) but resolution of allergy to formaldehyde⁸; persistence of allergy to corticosteroids (budesonide and alclometasone)⁹; persistence of allergy to an antibiotic (neomycin sulfate) but resolution of allergies to a different antibiotic (bacitracin), glues (ethyl acrylate), bleach, and glutaraldehyde⁹; persistence of nickel allergy but resolution of allergies to fragrances (cinnamic aldehyde, balsam of Peru) and non-FRPs (methylchloroisothiazolinone or MI)¹⁰; and persistence of allergies to non-FRPs (MI) and FRPs (bronopol) but resolution of allergies to nickel, fragrances (hydroperoxides of linalool), and Compositae.¹¹ Additional case reports of positive patch test results while on dupilumab but with no pretreatment results for comparison include allergies to rubber additives,^12-14 nickel,¹⁴ textile dyes,¹⁴ cosmetic and hair care additives,^12,14,15 corticosteroids,¹⁵ FRPs,¹⁵ fragrances,^15,16 emulsifiers,¹⁶ and non-FRPs.¹⁷

An evident theme in the dupilumab patch-testing literature has been that results are variable and case specific: a given patient with ACD to an allergen will respond to dupilumab treatment and have subsequent negative patch testing, while another patient will not respond to dupilumab treatment and have persistent positive patch testing. This is likely because, in certain individuals, the allergen-immune system combination shifts ACD pathogenesis from a purely T_H1 response to at least a partial T_H2 response, thus allowing for benefit from dupilumab therapy. T helper 1 cell–mediated ACD should not be affected by dupilumab; therefore, reliable results can be elucidated from patch testing despite the drug.

Final Thoughts

We propose that AD patients with residual disease after taking dupilumab undergo patch testing. Positive results indicate allergens that are not inhibited by the drug. Patients will need to follow strict allergen avoidance to resolve this component of their disease; failure to improve might suggest the result was a nonrelevant positive.

If patch testing is negative, an alternative cause for residual disease must be sought. We do not recommend stopping dupilumab prior to patch testing to avoid a disease flare from AD or possible T_H2-mediated ACD.

In patients with persistent atopic dermatitis (AD) who are taking dupilumab, is there benefit of patch testing to determine if allergic contact dermatitis (ACD) also is contributing to their disease? Results of patch testing are likely be influenced by the immunomodulatory effects of dupilumab. Similar to the recommendation for patients to refrain from using topical or systemic corticosteroids for 1 week or more prior to patch testing to eliminate false negatives, we reviewed the literature to create practice guidelines for dermatologists regarding patch testing while a patient is taking dupilumab.

Pathophysiology and Pathomechanism

Dupilumab functions through the blockade of T helper 2 (T_H2) cells; ACD is propagated through the T helper 1 (T_H1) cellular pathway. However, patients with ACD that is unresponsive to allergen avoidance and traditional therapies, such as topical and oral corticosteroids, have responded to dupilumab. The more common reports of this responsiveness are with fragrances; multiple case series described patients with ACD to fragrance mix I¹ and balsam of Peru^1,2 who improved on dupilumab when other treatments failed. There also are reports of response when ACD was secondary to nickel,^2,3p-phenylenediamine,¹ Compositae,⁴ and non–formaldehyde-releasing preservatives (non-FRPs).⁵ Therefore, not all ACD is propagated through the T_H1 cellular pathway.

As noted in these cases, ACD can be a response to an allergen whose pathogenesis involves the T_H2 pathway or when patient characteristics favor a T_H2 response. It has been suggested that AD patients are more susceptible to T_H2-mediated contact sensitization to less-potent allergens, such as fragrances.⁶

Patch Test Results

Positive patch test results for allergens have been reported while patients are on dupilumab therapy, including a few studies in which results prior to starting dupilumab were compared with those while patients were on dupilumab therapy. In a retrospective chart review of 48 patients on dupilumab for AD with persistent disease, 23 patients were patch tested before and during dupilumab therapy. In these patients, the majority of contact allergies were persistent and only 10% (13/125) of patch test–positive results resolved on dupilumab therapy.⁷ Contact allergies that resolved included those to emulsifiers (propylene glycol, Amerchol L101 [lanolin-containing products found in cosmetics and other goods], dimethylaminopropylamine), fragrances (fragrance mix I, balsam of Peru), sunscreens (sulisobenzone, phenylbenzimidazole-5-sulfonic acid), and metals (vanadium chloride, phenylmercuric acetate).⁷ The following results observed in individual cases demonstrated conflicting findings: persistence of allergy to non-FRPs (methylisothiazolinone [MI]) but resolution of allergy to formaldehyde⁸; persistence of allergy to corticosteroids (budesonide and alclometasone)⁹; persistence of allergy to an antibiotic (neomycin sulfate) but resolution of allergies to a different antibiotic (bacitracin), glues (ethyl acrylate), bleach, and glutaraldehyde⁹; persistence of nickel allergy but resolution of allergies to fragrances (cinnamic aldehyde, balsam of Peru) and non-FRPs (methylchloroisothiazolinone or MI)¹⁰; and persistence of allergies to non-FRPs (MI) and FRPs (bronopol) but resolution of allergies to nickel, fragrances (hydroperoxides of linalool), and Compositae.¹¹ Additional case reports of positive patch test results while on dupilumab but with no pretreatment results for comparison include allergies to rubber additives,^12-14 nickel,¹⁴ textile dyes,¹⁴ cosmetic and hair care additives,^12,14,15 corticosteroids,¹⁵ FRPs,¹⁵ fragrances,^15,16 emulsifiers,¹⁶ and non-FRPs.¹⁷

An evident theme in the dupilumab patch-testing literature has been that results are variable and case specific: a given patient with ACD to an allergen will respond to dupilumab treatment and have subsequent negative patch testing, while another patient will not respond to dupilumab treatment and have persistent positive patch testing. This is likely because, in certain individuals, the allergen-immune system combination shifts ACD pathogenesis from a purely T_H1 response to at least a partial T_H2 response, thus allowing for benefit from dupilumab therapy. T helper 1 cell–mediated ACD should not be affected by dupilumab; therefore, reliable results can be elucidated from patch testing despite the drug.

Final Thoughts

We propose that AD patients with residual disease after taking dupilumab undergo patch testing. Positive results indicate allergens that are not inhibited by the drug. Patients will need to follow strict allergen avoidance to resolve this component of their disease; failure to improve might suggest the result was a nonrelevant positive.

If patch testing is negative, an alternative cause for residual disease must be sought. We do not recommend stopping dupilumab prior to patch testing to avoid a disease flare from AD or possible T_H2-mediated ACD.

In patients with persistent atopic dermatitis (AD) who are taking dupilumab, is there benefit of patch testing to determine if allergic contact dermatitis (ACD) also is contributing to their disease? Results of patch testing are likely be influenced by the immunomodulatory effects of dupilumab. Similar to the recommendation for patients to refrain from using topical or systemic corticosteroids for 1 week or more prior to patch testing to eliminate false negatives, we reviewed the literature to create practice guidelines for dermatologists regarding patch testing while a patient is taking dupilumab.

Pathophysiology and Pathomechanism

Dupilumab functions through the blockade of T helper 2 (T_H2) cells; ACD is propagated through the T helper 1 (T_H1) cellular pathway. However, patients with ACD that is unresponsive to allergen avoidance and traditional therapies, such as topical and oral corticosteroids, have responded to dupilumab. The more common reports of this responsiveness are with fragrances; multiple case series described patients with ACD to fragrance mix I¹ and balsam of Peru^1,2 who improved on dupilumab when other treatments failed. There also are reports of response when ACD was secondary to nickel,^2,3p-phenylenediamine,¹ Compositae,⁴ and non–formaldehyde-releasing preservatives (non-FRPs).⁵ Therefore, not all ACD is propagated through the T_H1 cellular pathway.

As noted in these cases, ACD can be a response to an allergen whose pathogenesis involves the T_H2 pathway or when patient characteristics favor a T_H2 response. It has been suggested that AD patients are more susceptible to T_H2-mediated contact sensitization to less-potent allergens, such as fragrances.⁶

Patch Test Results

Positive patch test results for allergens have been reported while patients are on dupilumab therapy, including a few studies in which results prior to starting dupilumab were compared with those while patients were on dupilumab therapy. In a retrospective chart review of 48 patients on dupilumab for AD with persistent disease, 23 patients were patch tested before and during dupilumab therapy. In these patients, the majority of contact allergies were persistent and only 10% (13/125) of patch test–positive results resolved on dupilumab therapy.⁷ Contact allergies that resolved included those to emulsifiers (propylene glycol, Amerchol L101 [lanolin-containing products found in cosmetics and other goods], dimethylaminopropylamine), fragrances (fragrance mix I, balsam of Peru), sunscreens (sulisobenzone, phenylbenzimidazole-5-sulfonic acid), and metals (vanadium chloride, phenylmercuric acetate).⁷ The following results observed in individual cases demonstrated conflicting findings: persistence of allergy to non-FRPs (methylisothiazolinone [MI]) but resolution of allergy to formaldehyde⁸; persistence of allergy to corticosteroids (budesonide and alclometasone)⁹; persistence of allergy to an antibiotic (neomycin sulfate) but resolution of allergies to a different antibiotic (bacitracin), glues (ethyl acrylate), bleach, and glutaraldehyde⁹; persistence of nickel allergy but resolution of allergies to fragrances (cinnamic aldehyde, balsam of Peru) and non-FRPs (methylchloroisothiazolinone or MI)¹⁰; and persistence of allergies to non-FRPs (MI) and FRPs (bronopol) but resolution of allergies to nickel, fragrances (hydroperoxides of linalool), and Compositae.¹¹ Additional case reports of positive patch test results while on dupilumab but with no pretreatment results for comparison include allergies to rubber additives,^12-14 nickel,¹⁴ textile dyes,¹⁴ cosmetic and hair care additives,^12,14,15 corticosteroids,¹⁵ FRPs,¹⁵ fragrances,^15,16 emulsifiers,¹⁶ and non-FRPs.¹⁷

An evident theme in the dupilumab patch-testing literature has been that results are variable and case specific: a given patient with ACD to an allergen will respond to dupilumab treatment and have subsequent negative patch testing, while another patient will not respond to dupilumab treatment and have persistent positive patch testing. This is likely because, in certain individuals, the allergen-immune system combination shifts ACD pathogenesis from a purely T_H1 response to at least a partial T_H2 response, thus allowing for benefit from dupilumab therapy. T helper 1 cell–mediated ACD should not be affected by dupilumab; therefore, reliable results can be elucidated from patch testing despite the drug.

Final Thoughts

We propose that AD patients with residual disease after taking dupilumab undergo patch testing. Positive results indicate allergens that are not inhibited by the drug. Patients will need to follow strict allergen avoidance to resolve this component of their disease; failure to improve might suggest the result was a nonrelevant positive.

If patch testing is negative, an alternative cause for residual disease must be sought. We do not recommend stopping dupilumab prior to patch testing to avoid a disease flare from AD or possible T_H2-mediated ACD.

To the Editor:

A 72-year-old man presented with symptomatic anemia and nonpalpable purpura of the legs, abdomen, and arms of 2 weeks’ duration (Figure 1). There were no associated perifollicular papules. Physical examination of the hair and gingiva were normal.

The patient’s medical history was notable for a poorly differentiated pancreatic adenocarcinoma (pT3N1M0) resected 7 months prior using a Whipple operation (pancreaticoduodenectomy). Adjuvant therapy consisted of 5 cycles of intravenous gemcitabine and paclitaxel. Treatment was discontinued 1 month prior due to progressive weight loss and the presence of new liver metastases on computed tomography. There was no recent history of corticosteroid, antiplatelet, or anticoagulant use. The patient had no known history of trauma at the affected sites.

The patient’s laboratory workup revealed the following results: hemoglobin, 5.5 g/dL (reference range, 13–18 g/dL); platelets, 128×10⁹/L (reference range, 150–400×10⁹/L); total white blood cell count (24.0×10⁹/L [reference range, 4.0–11.0×10⁹/L]), consisting of neutrophils (2.4×10⁹/L [reference range, 2.0–7.5×10⁹/L]), lymphocytes (3.1×10⁹/L [reference range, 1.5–4.0×10⁹/L]), and monocytes (18.5×10⁹/L [reference range, 0.2–0.8×10⁹/L]). Fibrinogen, activated partial thromboplastin time, and prothrombin time were within reference range. Results of a bone marrow biopsy showed 64% blasts. The lactate dehydrogenase level was 286 U/L (reference range, 135–220 U/L) and CA-19-9 antigen was 238 U/mL (reference range, 0–39 U/mL).

Results from a skin punch biopsy from the right leg showed a normal epidermis and papillary dermis. The reticular dermis was expanded by a diffuse cellular infiltrate with dermal edema and separation of collagen bundles (Figure 2), which consisted of small cells with irregular, cleaved, and notched nuclei, containing a variable amount of eosinophilic cytoplasm. Mitotic figures were present (Figure 3). There was no evidence of vasculitis, and Congo red stain for amyloid was negative. These atypical cells were positive for the leukocyte common antigen, favoring a hematopoietic infiltrate (Figure 4). Other positive markers included CD4 (associated with helper T cells, and mature and immature monocytes), CD68 (a monocyte/macrophage marker), and CD56 (associated with natural killer cells, myeloma, acute myeloid leukemia [AML], and neuroendocrine tumors). The cells were negative for CD3 (T-cell lineage–specific antigen), CD5 (marker of T cells and a subset of IgM-secreting B cells), CD34 (early hematopoietic marker), and CD20 (B-cell marker). Other negative myeloid markers included myeloperoxidase, CD117, and CD138. These findings suggested leukemic cell recruitment at the site of a reactive infiltrate. The patient completed 2 cycles of intravenous azacitidine with little response and subsequently opted for palliative measures.

Nonpalpable purpura has a broad differential diagnosis including primary and secondary thrombocytopenia; coagulopathies, including vitamin K deficiency, specific clotting factor deficiencies, and amyloid-related purpura; genetic or acquired collagen disorders, including vitamin C deficiency; and eruptions induced by drugs and herbal remedies.

Leukemia cutis is a relatively rare cause of purpura and is defined as cutaneous infiltration by neoplastic leucocytes.¹ It most commonly is associated with AML and complicates approximately 5% to 15%of all adult cases.² Cutaneous involvement occurs predominantly in monocytic variants; acute myelomonocytic leukemia and acute monocytic leukemia may arise in up to 50% of these cases.³ The clinical presentation may vary from papules, nodules, and plaques to rarer manifestations including purpura. A leukemic infiltrate often is associated with sites of inflammation, such as infection or ulceration,⁴ though there was no reported history of any known triggering events in our patient. Lesions usually involve the legs, followed by the arms, back, chest, scalp, and face.⁴ One-third of cases coincide with systemic symptoms, and approximately 10% precede bone marrow or peripheral blood involvement, referred to as aleukemic leukemia. The remainder of cases arise following an established diagnosis of systemic leukemia.⁵ Leukemia cutis is considered a marker of poor prognosis in AML,^4,6 requiring treatment for the underlying systemic disease. Our case also was complicated by a concurrent pancreatic malignancy and relatively advanced age, which limited the feasibility of further treatment.

To the Editor:

A 72-year-old man presented with symptomatic anemia and nonpalpable purpura of the legs, abdomen, and arms of 2 weeks’ duration (Figure 1). There were no associated perifollicular papules. Physical examination of the hair and gingiva were normal.

The patient’s medical history was notable for a poorly differentiated pancreatic adenocarcinoma (pT3N1M0) resected 7 months prior using a Whipple operation (pancreaticoduodenectomy). Adjuvant therapy consisted of 5 cycles of intravenous gemcitabine and paclitaxel. Treatment was discontinued 1 month prior due to progressive weight loss and the presence of new liver metastases on computed tomography. There was no recent history of corticosteroid, antiplatelet, or anticoagulant use. The patient had no known history of trauma at the affected sites.

The patient’s laboratory workup revealed the following results: hemoglobin, 5.5 g/dL (reference range, 13–18 g/dL); platelets, 128×10⁹/L (reference range, 150–400×10⁹/L); total white blood cell count (24.0×10⁹/L [reference range, 4.0–11.0×10⁹/L]), consisting of neutrophils (2.4×10⁹/L [reference range, 2.0–7.5×10⁹/L]), lymphocytes (3.1×10⁹/L [reference range, 1.5–4.0×10⁹/L]), and monocytes (18.5×10⁹/L [reference range, 0.2–0.8×10⁹/L]). Fibrinogen, activated partial thromboplastin time, and prothrombin time were within reference range. Results of a bone marrow biopsy showed 64% blasts. The lactate dehydrogenase level was 286 U/L (reference range, 135–220 U/L) and CA-19-9 antigen was 238 U/mL (reference range, 0–39 U/mL).

Results from a skin punch biopsy from the right leg showed a normal epidermis and papillary dermis. The reticular dermis was expanded by a diffuse cellular infiltrate with dermal edema and separation of collagen bundles (Figure 2), which consisted of small cells with irregular, cleaved, and notched nuclei, containing a variable amount of eosinophilic cytoplasm. Mitotic figures were present (Figure 3). There was no evidence of vasculitis, and Congo red stain for amyloid was negative. These atypical cells were positive for the leukocyte common antigen, favoring a hematopoietic infiltrate (Figure 4). Other positive markers included CD4 (associated with helper T cells, and mature and immature monocytes), CD68 (a monocyte/macrophage marker), and CD56 (associated with natural killer cells, myeloma, acute myeloid leukemia [AML], and neuroendocrine tumors). The cells were negative for CD3 (T-cell lineage–specific antigen), CD5 (marker of T cells and a subset of IgM-secreting B cells), CD34 (early hematopoietic marker), and CD20 (B-cell marker). Other negative myeloid markers included myeloperoxidase, CD117, and CD138. These findings suggested leukemic cell recruitment at the site of a reactive infiltrate. The patient completed 2 cycles of intravenous azacitidine with little response and subsequently opted for palliative measures.

Nonpalpable purpura has a broad differential diagnosis including primary and secondary thrombocytopenia; coagulopathies, including vitamin K deficiency, specific clotting factor deficiencies, and amyloid-related purpura; genetic or acquired collagen disorders, including vitamin C deficiency; and eruptions induced by drugs and herbal remedies.

Leukemia cutis is a relatively rare cause of purpura and is defined as cutaneous infiltration by neoplastic leucocytes.¹ It most commonly is associated with AML and complicates approximately 5% to 15%of all adult cases.² Cutaneous involvement occurs predominantly in monocytic variants; acute myelomonocytic leukemia and acute monocytic leukemia may arise in up to 50% of these cases.³ The clinical presentation may vary from papules, nodules, and plaques to rarer manifestations including purpura. A leukemic infiltrate often is associated with sites of inflammation, such as infection or ulceration,⁴ though there was no reported history of any known triggering events in our patient. Lesions usually involve the legs, followed by the arms, back, chest, scalp, and face.⁴ One-third of cases coincide with systemic symptoms, and approximately 10% precede bone marrow or peripheral blood involvement, referred to as aleukemic leukemia. The remainder of cases arise following an established diagnosis of systemic leukemia.⁵ Leukemia cutis is considered a marker of poor prognosis in AML,^4,6 requiring treatment for the underlying systemic disease. Our case also was complicated by a concurrent pancreatic malignancy and relatively advanced age, which limited the feasibility of further treatment.

To the Editor:

A 72-year-old man presented with symptomatic anemia and nonpalpable purpura of the legs, abdomen, and arms of 2 weeks’ duration (Figure 1). There were no associated perifollicular papules. Physical examination of the hair and gingiva were normal.

The patient’s medical history was notable for a poorly differentiated pancreatic adenocarcinoma (pT3N1M0) resected 7 months prior using a Whipple operation (pancreaticoduodenectomy). Adjuvant therapy consisted of 5 cycles of intravenous gemcitabine and paclitaxel. Treatment was discontinued 1 month prior due to progressive weight loss and the presence of new liver metastases on computed tomography. There was no recent history of corticosteroid, antiplatelet, or anticoagulant use. The patient had no known history of trauma at the affected sites.

The patient’s laboratory workup revealed the following results: hemoglobin, 5.5 g/dL (reference range, 13–18 g/dL); platelets, 128×10⁹/L (reference range, 150–400×10⁹/L); total white blood cell count (24.0×10⁹/L [reference range, 4.0–11.0×10⁹/L]), consisting of neutrophils (2.4×10⁹/L [reference range, 2.0–7.5×10⁹/L]), lymphocytes (3.1×10⁹/L [reference range, 1.5–4.0×10⁹/L]), and monocytes (18.5×10⁹/L [reference range, 0.2–0.8×10⁹/L]). Fibrinogen, activated partial thromboplastin time, and prothrombin time were within reference range. Results of a bone marrow biopsy showed 64% blasts. The lactate dehydrogenase level was 286 U/L (reference range, 135–220 U/L) and CA-19-9 antigen was 238 U/mL (reference range, 0–39 U/mL).

Results from a skin punch biopsy from the right leg showed a normal epidermis and papillary dermis. The reticular dermis was expanded by a diffuse cellular infiltrate with dermal edema and separation of collagen bundles (Figure 2), which consisted of small cells with irregular, cleaved, and notched nuclei, containing a variable amount of eosinophilic cytoplasm. Mitotic figures were present (Figure 3). There was no evidence of vasculitis, and Congo red stain for amyloid was negative. These atypical cells were positive for the leukocyte common antigen, favoring a hematopoietic infiltrate (Figure 4). Other positive markers included CD4 (associated with helper T cells, and mature and immature monocytes), CD68 (a monocyte/macrophage marker), and CD56 (associated with natural killer cells, myeloma, acute myeloid leukemia [AML], and neuroendocrine tumors). The cells were negative for CD3 (T-cell lineage–specific antigen), CD5 (marker of T cells and a subset of IgM-secreting B cells), CD34 (early hematopoietic marker), and CD20 (B-cell marker). Other negative myeloid markers included myeloperoxidase, CD117, and CD138. These findings suggested leukemic cell recruitment at the site of a reactive infiltrate. The patient completed 2 cycles of intravenous azacitidine with little response and subsequently opted for palliative measures.

Nonpalpable purpura has a broad differential diagnosis including primary and secondary thrombocytopenia; coagulopathies, including vitamin K deficiency, specific clotting factor deficiencies, and amyloid-related purpura; genetic or acquired collagen disorders, including vitamin C deficiency; and eruptions induced by drugs and herbal remedies.

Leukemia cutis is a relatively rare cause of purpura and is defined as cutaneous infiltration by neoplastic leucocytes.¹ It most commonly is associated with AML and complicates approximately 5% to 15%of all adult cases.² Cutaneous involvement occurs predominantly in monocytic variants; acute myelomonocytic leukemia and acute monocytic leukemia may arise in up to 50% of these cases.³ The clinical presentation may vary from papules, nodules, and plaques to rarer manifestations including purpura. A leukemic infiltrate often is associated with sites of inflammation, such as infection or ulceration,⁴ though there was no reported history of any known triggering events in our patient. Lesions usually involve the legs, followed by the arms, back, chest, scalp, and face.⁴ One-third of cases coincide with systemic symptoms, and approximately 10% precede bone marrow or peripheral blood involvement, referred to as aleukemic leukemia. The remainder of cases arise following an established diagnosis of systemic leukemia.⁵ Leukemia cutis is considered a marker of poor prognosis in AML,^4,6 requiring treatment for the underlying systemic disease. Our case also was complicated by a concurrent pancreatic malignancy and relatively advanced age, which limited the feasibility of further treatment.

To the Editor:

Pretibial myxedema (PTM) is bilateral, nonpitting, scaly thickening and induration of the skin that most commonly occurs on the anterior aspects of the legs and feet. Pretibial myxedema occurs in approximately 0.5% to 4.3% of patients with hyperthyroidism.¹ Thyroid dermopathy often is thought of as the classic nonpitting PTM with skin induration and color change. However, rarer forms of PTM, including plaque, nodular, and elephantiasic, also are important to note.²

Elephantiasic PTM is extremely rare, occurring in less than 1% of patients with PTM.² Elephantiasic PTM is characterized by the persistent swelling of 1 or both legs; thickening of the skin overlying the dorsum of the feet, ankles, and toes; and verrucous irregular plaques that often are fleshy and flattened. The clinical differential diagnosis of elephantiasic PTM includes elephantiasis nostra verrucosa, a late-stage complication of chronic lymphedema that can be related to a variety of infectious or noninfectious obstructive processes. Few effective therapeutic modalities exist in the treatment of elephantiasic PTM. We present a case of elephantiasic PTM.

A 59-year-old man presented to dermatology with leonine facies with pronounced glabellar creases and indentations of the earlobes. He had diffuse woody induration, hyperpigmentation, and nonpitting edema of the lower extremities as well as several flesh-colored exophytic nodules scattered throughout the anterior shins and dorsal feet (Figure 1). On the left posterior calf, there was a large, 3-cm, exophytic, firm, flesh-colored nodule. Examination of the hands revealed mild hyperpigmentation of the distal digits, clubbing of the distal phalanges, and cheiroarthropathy.

The patient was diagnosed with Graves disease after experiencing the classic symptoms of hyperthyroidism, including heat intolerance, tremor, palpitations, and anxiety. He received thyroid ablation and subsequently was supplemented with levothyroxine 75 mg daily. Twelve years later, he was diagnosed with Graves ophthalmopathy with ocular proptosis requiring multiple courses of retro-orbital irradiation and surgical procedures for decompression. Approximately 1 year later, he noted increased swelling, firmness, and darkening of the pretibial surfaces. Initially, he was referred to vascular surgery and underwent bilateral saphenous vein ablation. He also was referred to a lymphedema specialist, and workup revealed an unremarkable lymphatic system. Minimal improvement was noted following the saphenous vein ablation, and he subsequently was referred to dermatology for further workup.

At the current presentation, laboratory analysis revealed a low thyrotropin level (0.03 mIU/L [reference range, 0.4–4.2 mIU/L]), and free thyroxine was within reference range. Radiography of the chest was unremarkable; however, radiography of the hand demonstrated arthrosis of the left fifth proximal interphalangeal joint. Nuclear medicine lymphoscintigraphy and lower extremity ultrasonography were unremarkable. Punch biopsies were performed of the left lateral leg and posterior calf. Hematoxylin and eosin staining demonstrated marked mucin deposition extending to the deep dermis along with deep fibroplasia and was read as consistent with PTM. Colloidal iron highlighted prominent mucin within the dermis (Figure 2).

The patient’s medical history, physical examination, laboratory analysis, imaging, and biopsies were considered, and a diagnosis of elephantiasic PTM was made. Minimal improvement was noted with initial therapeutic interventions including compression therapy and application of super high–potency topical corticosteroids. After further evaluation in our multidisciplinary rheumatology-dermatology clinic, the decision was made to initiate rituximab infusions.

Two months after 1 course of rituximab consisting of two 1000-mg infusions separated by 2 weeks, the patient showed substantial clinical improvement. There was striking improvement of the pretibial surfaces with resolution of the exophytic nodules and improvement of the induration (Figure 3). In addition, there was decreased induration of the glabella and earlobes and decreased fullness of the digital pulp on the hands. The patient also reported subjective improvements in mobility.

Our patient demonstrated all 3 aspects of the Diamond triad: PTM, exophthalmos, and acropachy. Patients present with all 3 features in less than 1% of reported cases of Graves disease.³ Although all 3 features are seen together infrequently, thyroid dermopathy and acropachy often are markers of severe Graves ophthalmopathy. In a study of 114 patients with Graves ophthalmopathy, patients who also had dermopathy and acropachy were more likely to have optic neuropathy or require orbital decompression.⁴

After overcoming the diagnostic dilemma that the elephantiasic presentation of PTM can present, therapeutic management remains a challenge. Heyes et al⁵ documented the successful treatment of highly recalcitrant elephantiasic PTM with rituximab and plasmapheresis therapy. In this case, a 44-year-old woman with an 11-year history of Graves disease and elephantiasic PTM received 29 rituximab infusions and 241 plasmapheresis treatments over the course of 3.5 years. Her elephantiasic PTM clinically resolved, and she was able to resume daily activities and wear normal shoes after being nonambulatory for years.⁵

Rituximab is a monoclonal antibody against CD20, a protein found primarily on the surface of B-cell lymphocytes. Although rituximab initially was approved by the US Food and Drug administration for the treatment of malignant lymphoma, it has had an increasing role in the treatment of autoimmune disorders such as rheumatoid arthritis. Rituximab is postulated to target B lymphocytes and halt their progression to plasma cells. By limiting the population of long-lasting, antibody-producing plasma cells and decreasing the autoantibodies that cause many of the symptoms in Graves disease, rituximab may be an effective therapy to consider in the treatment of elephantiasic PTM.⁶

Although the exact mechanism is poorly understood, PTM likely is a sequela of hyperthyroidism because of the expression of thyroid-stimulating hormone receptor proteins found on normal dermal fibroblasts. Thyroid-stimulating hormone receptor autoantibodies are thought to stimulate these fibroblasts to produce glycosaminoglycans. Histopathologically, accumulation of glycosaminoglycans deposited in the reticular dermis with high concentrations of hyaluronic acid is observed in PTM.⁷

Treatment of elephantiasic PTM remains a therapeutic challenge. Given the rarity of the disease process and limited information on effective therapeutic modalities, rituximab should be viewed as a viable treatment option in the management of recalcitrant elephantiasic PTM.

To the Editor:

Pretibial myxedema (PTM) is bilateral, nonpitting, scaly thickening and induration of the skin that most commonly occurs on the anterior aspects of the legs and feet. Pretibial myxedema occurs in approximately 0.5% to 4.3% of patients with hyperthyroidism.¹ Thyroid dermopathy often is thought of as the classic nonpitting PTM with skin induration and color change. However, rarer forms of PTM, including plaque, nodular, and elephantiasic, also are important to note.²

Elephantiasic PTM is extremely rare, occurring in less than 1% of patients with PTM.² Elephantiasic PTM is characterized by the persistent swelling of 1 or both legs; thickening of the skin overlying the dorsum of the feet, ankles, and toes; and verrucous irregular plaques that often are fleshy and flattened. The clinical differential diagnosis of elephantiasic PTM includes elephantiasis nostra verrucosa, a late-stage complication of chronic lymphedema that can be related to a variety of infectious or noninfectious obstructive processes. Few effective therapeutic modalities exist in the treatment of elephantiasic PTM. We present a case of elephantiasic PTM.

A 59-year-old man presented to dermatology with leonine facies with pronounced glabellar creases and indentations of the earlobes. He had diffuse woody induration, hyperpigmentation, and nonpitting edema of the lower extremities as well as several flesh-colored exophytic nodules scattered throughout the anterior shins and dorsal feet (Figure 1). On the left posterior calf, there was a large, 3-cm, exophytic, firm, flesh-colored nodule. Examination of the hands revealed mild hyperpigmentation of the distal digits, clubbing of the distal phalanges, and cheiroarthropathy.

The patient was diagnosed with Graves disease after experiencing the classic symptoms of hyperthyroidism, including heat intolerance, tremor, palpitations, and anxiety. He received thyroid ablation and subsequently was supplemented with levothyroxine 75 mg daily. Twelve years later, he was diagnosed with Graves ophthalmopathy with ocular proptosis requiring multiple courses of retro-orbital irradiation and surgical procedures for decompression. Approximately 1 year later, he noted increased swelling, firmness, and darkening of the pretibial surfaces. Initially, he was referred to vascular surgery and underwent bilateral saphenous vein ablation. He also was referred to a lymphedema specialist, and workup revealed an unremarkable lymphatic system. Minimal improvement was noted following the saphenous vein ablation, and he subsequently was referred to dermatology for further workup.

At the current presentation, laboratory analysis revealed a low thyrotropin level (0.03 mIU/L [reference range, 0.4–4.2 mIU/L]), and free thyroxine was within reference range. Radiography of the chest was unremarkable; however, radiography of the hand demonstrated arthrosis of the left fifth proximal interphalangeal joint. Nuclear medicine lymphoscintigraphy and lower extremity ultrasonography were unremarkable. Punch biopsies were performed of the left lateral leg and posterior calf. Hematoxylin and eosin staining demonstrated marked mucin deposition extending to the deep dermis along with deep fibroplasia and was read as consistent with PTM. Colloidal iron highlighted prominent mucin within the dermis (Figure 2).

The patient’s medical history, physical examination, laboratory analysis, imaging, and biopsies were considered, and a diagnosis of elephantiasic PTM was made. Minimal improvement was noted with initial therapeutic interventions including compression therapy and application of super high–potency topical corticosteroids. After further evaluation in our multidisciplinary rheumatology-dermatology clinic, the decision was made to initiate rituximab infusions.

Two months after 1 course of rituximab consisting of two 1000-mg infusions separated by 2 weeks, the patient showed substantial clinical improvement. There was striking improvement of the pretibial surfaces with resolution of the exophytic nodules and improvement of the induration (Figure 3). In addition, there was decreased induration of the glabella and earlobes and decreased fullness of the digital pulp on the hands. The patient also reported subjective improvements in mobility.

Our patient demonstrated all 3 aspects of the Diamond triad: PTM, exophthalmos, and acropachy. Patients present with all 3 features in less than 1% of reported cases of Graves disease.³ Although all 3 features are seen together infrequently, thyroid dermopathy and acropachy often are markers of severe Graves ophthalmopathy. In a study of 114 patients with Graves ophthalmopathy, patients who also had dermopathy and acropachy were more likely to have optic neuropathy or require orbital decompression.⁴

After overcoming the diagnostic dilemma that the elephantiasic presentation of PTM can present, therapeutic management remains a challenge. Heyes et al⁵ documented the successful treatment of highly recalcitrant elephantiasic PTM with rituximab and plasmapheresis therapy. In this case, a 44-year-old woman with an 11-year history of Graves disease and elephantiasic PTM received 29 rituximab infusions and 241 plasmapheresis treatments over the course of 3.5 years. Her elephantiasic PTM clinically resolved, and she was able to resume daily activities and wear normal shoes after being nonambulatory for years.⁵

Rituximab is a monoclonal antibody against CD20, a protein found primarily on the surface of B-cell lymphocytes. Although rituximab initially was approved by the US Food and Drug administration for the treatment of malignant lymphoma, it has had an increasing role in the treatment of autoimmune disorders such as rheumatoid arthritis. Rituximab is postulated to target B lymphocytes and halt their progression to plasma cells. By limiting the population of long-lasting, antibody-producing plasma cells and decreasing the autoantibodies that cause many of the symptoms in Graves disease, rituximab may be an effective therapy to consider in the treatment of elephantiasic PTM.⁶

Although the exact mechanism is poorly understood, PTM likely is a sequela of hyperthyroidism because of the expression of thyroid-stimulating hormone receptor proteins found on normal dermal fibroblasts. Thyroid-stimulating hormone receptor autoantibodies are thought to stimulate these fibroblasts to produce glycosaminoglycans. Histopathologically, accumulation of glycosaminoglycans deposited in the reticular dermis with high concentrations of hyaluronic acid is observed in PTM.⁷

Treatment of elephantiasic PTM remains a therapeutic challenge. Given the rarity of the disease process and limited information on effective therapeutic modalities, rituximab should be viewed as a viable treatment option in the management of recalcitrant elephantiasic PTM.

To the Editor:

Pretibial myxedema (PTM) is bilateral, nonpitting, scaly thickening and induration of the skin that most commonly occurs on the anterior aspects of the legs and feet. Pretibial myxedema occurs in approximately 0.5% to 4.3% of patients with hyperthyroidism.¹ Thyroid dermopathy often is thought of as the classic nonpitting PTM with skin induration and color change. However, rarer forms of PTM, including plaque, nodular, and elephantiasic, also are important to note.²

Elephantiasic PTM is extremely rare, occurring in less than 1% of patients with PTM.² Elephantiasic PTM is characterized by the persistent swelling of 1 or both legs; thickening of the skin overlying the dorsum of the feet, ankles, and toes; and verrucous irregular plaques that often are fleshy and flattened. The clinical differential diagnosis of elephantiasic PTM includes elephantiasis nostra verrucosa, a late-stage complication of chronic lymphedema that can be related to a variety of infectious or noninfectious obstructive processes. Few effective therapeutic modalities exist in the treatment of elephantiasic PTM. We present a case of elephantiasic PTM.

A 59-year-old man presented to dermatology with leonine facies with pronounced glabellar creases and indentations of the earlobes. He had diffuse woody induration, hyperpigmentation, and nonpitting edema of the lower extremities as well as several flesh-colored exophytic nodules scattered throughout the anterior shins and dorsal feet (Figure 1). On the left posterior calf, there was a large, 3-cm, exophytic, firm, flesh-colored nodule. Examination of the hands revealed mild hyperpigmentation of the distal digits, clubbing of the distal phalanges, and cheiroarthropathy.

The patient was diagnosed with Graves disease after experiencing the classic symptoms of hyperthyroidism, including heat intolerance, tremor, palpitations, and anxiety. He received thyroid ablation and subsequently was supplemented with levothyroxine 75 mg daily. Twelve years later, he was diagnosed with Graves ophthalmopathy with ocular proptosis requiring multiple courses of retro-orbital irradiation and surgical procedures for decompression. Approximately 1 year later, he noted increased swelling, firmness, and darkening of the pretibial surfaces. Initially, he was referred to vascular surgery and underwent bilateral saphenous vein ablation. He also was referred to a lymphedema specialist, and workup revealed an unremarkable lymphatic system. Minimal improvement was noted following the saphenous vein ablation, and he subsequently was referred to dermatology for further workup.

At the current presentation, laboratory analysis revealed a low thyrotropin level (0.03 mIU/L [reference range, 0.4–4.2 mIU/L]), and free thyroxine was within reference range. Radiography of the chest was unremarkable; however, radiography of the hand demonstrated arthrosis of the left fifth proximal interphalangeal joint. Nuclear medicine lymphoscintigraphy and lower extremity ultrasonography were unremarkable. Punch biopsies were performed of the left lateral leg and posterior calf. Hematoxylin and eosin staining demonstrated marked mucin deposition extending to the deep dermis along with deep fibroplasia and was read as consistent with PTM. Colloidal iron highlighted prominent mucin within the dermis (Figure 2).

The patient’s medical history, physical examination, laboratory analysis, imaging, and biopsies were considered, and a diagnosis of elephantiasic PTM was made. Minimal improvement was noted with initial therapeutic interventions including compression therapy and application of super high–potency topical corticosteroids. After further evaluation in our multidisciplinary rheumatology-dermatology clinic, the decision was made to initiate rituximab infusions.

Two months after 1 course of rituximab consisting of two 1000-mg infusions separated by 2 weeks, the patient showed substantial clinical improvement. There was striking improvement of the pretibial surfaces with resolution of the exophytic nodules and improvement of the induration (Figure 3). In addition, there was decreased induration of the glabella and earlobes and decreased fullness of the digital pulp on the hands. The patient also reported subjective improvements in mobility.

Our patient demonstrated all 3 aspects of the Diamond triad: PTM, exophthalmos, and acropachy. Patients present with all 3 features in less than 1% of reported cases of Graves disease.³ Although all 3 features are seen together infrequently, thyroid dermopathy and acropachy often are markers of severe Graves ophthalmopathy. In a study of 114 patients with Graves ophthalmopathy, patients who also had dermopathy and acropachy were more likely to have optic neuropathy or require orbital decompression.⁴

After overcoming the diagnostic dilemma that the elephantiasic presentation of PTM can present, therapeutic management remains a challenge. Heyes et al⁵ documented the successful treatment of highly recalcitrant elephantiasic PTM with rituximab and plasmapheresis therapy. In this case, a 44-year-old woman with an 11-year history of Graves disease and elephantiasic PTM received 29 rituximab infusions and 241 plasmapheresis treatments over the course of 3.5 years. Her elephantiasic PTM clinically resolved, and she was able to resume daily activities and wear normal shoes after being nonambulatory for years.⁵

Rituximab is a monoclonal antibody against CD20, a protein found primarily on the surface of B-cell lymphocytes. Although rituximab initially was approved by the US Food and Drug administration for the treatment of malignant lymphoma, it has had an increasing role in the treatment of autoimmune disorders such as rheumatoid arthritis. Rituximab is postulated to target B lymphocytes and halt their progression to plasma cells. By limiting the population of long-lasting, antibody-producing plasma cells and decreasing the autoantibodies that cause many of the symptoms in Graves disease, rituximab may be an effective therapy to consider in the treatment of elephantiasic PTM.⁶

Although the exact mechanism is poorly understood, PTM likely is a sequela of hyperthyroidism because of the expression of thyroid-stimulating hormone receptor proteins found on normal dermal fibroblasts. Thyroid-stimulating hormone receptor autoantibodies are thought to stimulate these fibroblasts to produce glycosaminoglycans. Histopathologically, accumulation of glycosaminoglycans deposited in the reticular dermis with high concentrations of hyaluronic acid is observed in PTM.⁷

Treatment of elephantiasic PTM remains a therapeutic challenge. Given the rarity of the disease process and limited information on effective therapeutic modalities, rituximab should be viewed as a viable treatment option in the management of recalcitrant elephantiasic PTM.

To the Editor:

Acute graft-vs-host disease (GVHD) remains a limitation to hematopoietic stem cell transplantation (HSCT) in 20% to 50% of patients after transplant. Furthermore, failed treatment with corticosteroids is frequent and portends a poor prognosis.¹ Toxic epidermal necrolysis (TEN) is an epidermolytic skin disorder thought to represent an adverse drug reaction, though its pathogenesis remains unclear. Severe forms of acute GVHD can mimic TEN clinically and histologically. Both can present with widespread cutaneous and mucosal bullae, erosions, and desquamation. Toxic epidermal necrolysis in the context of allogeneic hematopoietic stem cell transplantation is extremely rare, with almost 100% mortality in adult patients. Features that favor acute GVHD over TEN include diarrhea, elevation in bilirubin level, and chimerism.² However, these features might be absent, posing a therapeutic dilemma, as current treatment preferences for each of these entities differ.

Growing evidence supports the use of anti–tumor necrosis factor (TNF) α drugs for the treatment of TEN. Success has been reported with both anti–TNF-α monoclonal antibodies as well as the soluble fusion protein etanercept.^3,4 The use of TNF-α inhibitors in acute GVHD remains anecdotal.

A 58-year-old man (patient 1) with a history of acute myelogenous leukemia presented with a pruritic morbilliform eruption 28 days after HSCT. There was no desquamation or mucosal involvement and the biopsy obtained was histologically suggestive of grade 2 acute GVHD. His immunosuppressive regimen included sirolimus and cyclophosphamide. He was receiving trimethoprim-sulfamethoxazole (TMP-SMX), voriconazole, and acyclovir for infectious prophylaxis. At the time of presentation, he was treated with high-dose systemic steroids (prednisone 2 mg/kg/d) for acute GVHD with partial improvement. Upon tapering of the steroids 3 weeks after initiating TMP-SMX and 1 week after initiating voriconazole, he developed painful desquamation and erosions involving 95% of the body surface area (BSA), necessitating admission to the local burn unit (Figure 1). Biopsies demonstrated full-thickness epidermal necrosis with subepidermal blistering and interface dermatitis (Figure 2). No gastrointestinal tract involvement of acute GVHD was noted. The patient was a 100% donor chimera, supporting the diagnosis of acute GVHD; however, the patient and donor carried the HLA-C*06:02 allele, which previously has been described in association with TMP-SMX–related Stevens-Johnson syndrome/TEN.⁵ In addition, causality assessment using the algorithm of drug causality for epidermal necrolysis indicated TMP-SMX as a probable cause and voriconazole as a possible cause. The diagnosis of TEN with a SCORe of Toxic Epidermal Necrosis (SCORTEN) of 4 in the setting of acute GVHD was favored, though grade 4 acute GVHD could not be excluded. Trimethoprim-sulfamethoxazole was discontinued, and voriconazole was changed to posaconazole. He received supportive care along with 1 dose of 25-mg subcutaneous etanercept and 3 days of intravenous immunoglobulin (IVIG). Skin re-epithelialization was complete by 3 weeks. At 4 weeks, the patient developed a new asymptomatic erythematous eruption. Biopsies demonstrated changes of acute and chronic GVHD (Figure 3) that resolved with up-titration of sirolimus. The patient remained hospitalized for 96 days and continued to follow up with his transplant team as well as ophthalmology and dermatology. He died 2 years after HSCT.

A 67-year-old woman (patient 2) with high-grade myelodysplastic syndrome presented with an erythematous morbilliform eruption on the torso on day 20 after a matched unrelated HSCT that histologically was consistent with grade 2 GVHD (Figure 4). She had been receiving sirolimus and tacrolimus for GVHD prophylaxis. Infectious prophylaxis included acyclovir, pentamidine, micafungin, and TMP-SMX. Despite high-dose systemic steroids, the rash progressed and ultimately involved 80% BSA. A positive Nikolsky sign was noted involving 21% BSA (Figure 5), in addition to oral and genital mucosal ulcers. She denied nausea, vomiting, fever, or diarrhea. Chimerism studies were negative. Trimethoprim-sulfamethoxazole was discontinued, and she was transferred to a burn unit. Biopsies showed full-thickness epidermal necrosis. A diagnosis of TEN with a SCORTEN of 4 in the setting of acute GVHD was favored; grade 4 acute GVHD could not be excluded. Steroids were discontinued. Because laboratory studies indicated IgA deficiency, IVIG was not considered as a systemic option for therapy. The patient received 1 dose of infliximab (5 mg/kg). Cyclophosphamide 1600 mg weekly was added for GVHD therapy. The wounds progressively healed, and 2 weeks into her admission she was noted to have only 3% BSA with denuded skin. The patient was transferred to the cancer treatment center for further management of the malignancy. Unfortunately, after 2 months she died due to ischemic colitis that was confirmed on autopsy.

Graft-vs-host disease and TEN are rare, life-threatening complications seen in patients with allogeneic HSCT.² Graft-vs-host disease and TEN share clinicopathologic characteristics and effector immune mechanisms, largely the substantial role of T-cell activation and tissue destruction, which occur through mediators such as TNF-α.^6-8

Given the sparse lymphocytic infiltrate, keratinocyte death in TEN is thought to result from soluble molecules, including TNF-α and TNF-related apoptosis-inducing ligand.⁹ Tumor necrosis factor α has been identified in blister fluid, biopsy specimens, and serum of patients with TEN. Tumor necrosis factor α increases the expression of keratinocyte-inducible nitric oxide synthase, which upregulates keratinocyte Fas ligand expression and subsequent Fas- and caspase-8–mediated keratinocyte cell death.¹⁰

Acute GVHD results from donor lymphocyte activation after infusion into damaged recipient tissues that previously have been radiated or chemoablated. Mismatches in histocompatibility complexes between donor cells and recipient tissue antigens serve as the initial trigger for immune activation. Activation of antigen-presenting cells followed by activation, proliferation, differentiation, and migration of donor T cells ultimately results in destruction of the target tissue.¹¹ Immune mediators, such as TNF-α and lymphotoxin α (another member of the TNF superfamily), play a nonredundant role in the pathogenesis of GVHD.¹²

Current treatment strategies for severe acute GVHD and TEN differ. In North America, high-dose IVIG frequently is used as first-line systemic therapy, while high-dose systemic corticosteroids rarely are used.¹³ Studies have demonstrated successful use of anti–TNF-α drugs for the treatment of TEN.^3,4 Moreover, etanercept has shown to effectively inhibit lymphotoxin α.¹⁴ Similarly, TNF inhibition in the management of steroid-refractory acute GVHD has been successful.¹ These studies coupled with the underlying immune mechanisms that both diseases share encouraged initiating a trial of anti–TNF-α therapy in our patients.

Patient 1 merits further discussion because he was both a 100% donor chimera as well as a carrier of an human leukocyte antigen susceptibility candidate allele to TMP-SMX. Historical features of his presentation are consistent with either steroid-refractory GVHD or TEN superimposed on acute GVHD. His initial presentation of the more typical macular exanthem of cutaneous acute GVHD was both biopsy proven and supported by clinical improvement with steroid therapy, which was later followed by a robust blistering mucocutaneous presentation approximately 3 weeks after the administration of TMP-SMX and 1 week after initiating voriconazole that improved with IVIG and etanercept.

It is difficult to determine if TEN represents a continuum or result of the underlying drivers of acute GVHD vs a drug reaction. Although there is insufficient evidence to establish a clear-cut diagnosis of TEN, these cases illustrate the need for better diagnostic techniques to allow differentiation between TEN and grade 4 acute GVHD, and in the context of uncertainty, TNF-α inhibition poses a viable therapeutic strategy for these 2 often lethal conditions. Our cases do unequivocally indicate the benefit of this therapeutic modality, add to the current body of literature supporting the use of TNF-α inhibitors in patients such as ours without an official TEN diagnosis, and may guide future investigative efforts.

To the Editor:

Acute graft-vs-host disease (GVHD) remains a limitation to hematopoietic stem cell transplantation (HSCT) in 20% to 50% of patients after transplant. Furthermore, failed treatment with corticosteroids is frequent and portends a poor prognosis.¹ Toxic epidermal necrolysis (TEN) is an epidermolytic skin disorder thought to represent an adverse drug reaction, though its pathogenesis remains unclear. Severe forms of acute GVHD can mimic TEN clinically and histologically. Both can present with widespread cutaneous and mucosal bullae, erosions, and desquamation. Toxic epidermal necrolysis in the context of allogeneic hematopoietic stem cell transplantation is extremely rare, with almost 100% mortality in adult patients. Features that favor acute GVHD over TEN include diarrhea, elevation in bilirubin level, and chimerism.² However, these features might be absent, posing a therapeutic dilemma, as current treatment preferences for each of these entities differ.

Growing evidence supports the use of anti–tumor necrosis factor (TNF) α drugs for the treatment of TEN. Success has been reported with both anti–TNF-α monoclonal antibodies as well as the soluble fusion protein etanercept.^3,4 The use of TNF-α inhibitors in acute GVHD remains anecdotal.

A 58-year-old man (patient 1) with a history of acute myelogenous leukemia presented with a pruritic morbilliform eruption 28 days after HSCT. There was no desquamation or mucosal involvement and the biopsy obtained was histologically suggestive of grade 2 acute GVHD. His immunosuppressive regimen included sirolimus and cyclophosphamide. He was receiving trimethoprim-sulfamethoxazole (TMP-SMX), voriconazole, and acyclovir for infectious prophylaxis. At the time of presentation, he was treated with high-dose systemic steroids (prednisone 2 mg/kg/d) for acute GVHD with partial improvement. Upon tapering of the steroids 3 weeks after initiating TMP-SMX and 1 week after initiating voriconazole, he developed painful desquamation and erosions involving 95% of the body surface area (BSA), necessitating admission to the local burn unit (Figure 1). Biopsies demonstrated full-thickness epidermal necrosis with subepidermal blistering and interface dermatitis (Figure 2). No gastrointestinal tract involvement of acute GVHD was noted. The patient was a 100% donor chimera, supporting the diagnosis of acute GVHD; however, the patient and donor carried the HLA-C*06:02 allele, which previously has been described in association with TMP-SMX–related Stevens-Johnson syndrome/TEN.⁵ In addition, causality assessment using the algorithm of drug causality for epidermal necrolysis indicated TMP-SMX as a probable cause and voriconazole as a possible cause. The diagnosis of TEN with a SCORe of Toxic Epidermal Necrosis (SCORTEN) of 4 in the setting of acute GVHD was favored, though grade 4 acute GVHD could not be excluded. Trimethoprim-sulfamethoxazole was discontinued, and voriconazole was changed to posaconazole. He received supportive care along with 1 dose of 25-mg subcutaneous etanercept and 3 days of intravenous immunoglobulin (IVIG). Skin re-epithelialization was complete by 3 weeks. At 4 weeks, the patient developed a new asymptomatic erythematous eruption. Biopsies demonstrated changes of acute and chronic GVHD (Figure 3) that resolved with up-titration of sirolimus. The patient remained hospitalized for 96 days and continued to follow up with his transplant team as well as ophthalmology and dermatology. He died 2 years after HSCT.

A 67-year-old woman (patient 2) with high-grade myelodysplastic syndrome presented with an erythematous morbilliform eruption on the torso on day 20 after a matched unrelated HSCT that histologically was consistent with grade 2 GVHD (Figure 4). She had been receiving sirolimus and tacrolimus for GVHD prophylaxis. Infectious prophylaxis included acyclovir, pentamidine, micafungin, and TMP-SMX. Despite high-dose systemic steroids, the rash progressed and ultimately involved 80% BSA. A positive Nikolsky sign was noted involving 21% BSA (Figure 5), in addition to oral and genital mucosal ulcers. She denied nausea, vomiting, fever, or diarrhea. Chimerism studies were negative. Trimethoprim-sulfamethoxazole was discontinued, and she was transferred to a burn unit. Biopsies showed full-thickness epidermal necrosis. A diagnosis of TEN with a SCORTEN of 4 in the setting of acute GVHD was favored; grade 4 acute GVHD could not be excluded. Steroids were discontinued. Because laboratory studies indicated IgA deficiency, IVIG was not considered as a systemic option for therapy. The patient received 1 dose of infliximab (5 mg/kg). Cyclophosphamide 1600 mg weekly was added for GVHD therapy. The wounds progressively healed, and 2 weeks into her admission she was noted to have only 3% BSA with denuded skin. The patient was transferred to the cancer treatment center for further management of the malignancy. Unfortunately, after 2 months she died due to ischemic colitis that was confirmed on autopsy.

Graft-vs-host disease and TEN are rare, life-threatening complications seen in patients with allogeneic HSCT.² Graft-vs-host disease and TEN share clinicopathologic characteristics and effector immune mechanisms, largely the substantial role of T-cell activation and tissue destruction, which occur through mediators such as TNF-α.^6-8

Given the sparse lymphocytic infiltrate, keratinocyte death in TEN is thought to result from soluble molecules, including TNF-α and TNF-related apoptosis-inducing ligand.⁹ Tumor necrosis factor α has been identified in blister fluid, biopsy specimens, and serum of patients with TEN. Tumor necrosis factor α increases the expression of keratinocyte-inducible nitric oxide synthase, which upregulates keratinocyte Fas ligand expression and subsequent Fas- and caspase-8–mediated keratinocyte cell death.¹⁰

Acute GVHD results from donor lymphocyte activation after infusion into damaged recipient tissues that previously have been radiated or chemoablated. Mismatches in histocompatibility complexes between donor cells and recipient tissue antigens serve as the initial trigger for immune activation. Activation of antigen-presenting cells followed by activation, proliferation, differentiation, and migration of donor T cells ultimately results in destruction of the target tissue.¹¹ Immune mediators, such as TNF-α and lymphotoxin α (another member of the TNF superfamily), play a nonredundant role in the pathogenesis of GVHD.¹²

Current treatment strategies for severe acute GVHD and TEN differ. In North America, high-dose IVIG frequently is used as first-line systemic therapy, while high-dose systemic corticosteroids rarely are used.¹³ Studies have demonstrated successful use of anti–TNF-α drugs for the treatment of TEN.^3,4 Moreover, etanercept has shown to effectively inhibit lymphotoxin α.¹⁴ Similarly, TNF inhibition in the management of steroid-refractory acute GVHD has been successful.¹ These studies coupled with the underlying immune mechanisms that both diseases share encouraged initiating a trial of anti–TNF-α therapy in our patients.

Patient 1 merits further discussion because he was both a 100% donor chimera as well as a carrier of an human leukocyte antigen susceptibility candidate allele to TMP-SMX. Historical features of his presentation are consistent with either steroid-refractory GVHD or TEN superimposed on acute GVHD. His initial presentation of the more typical macular exanthem of cutaneous acute GVHD was both biopsy proven and supported by clinical improvement with steroid therapy, which was later followed by a robust blistering mucocutaneous presentation approximately 3 weeks after the administration of TMP-SMX and 1 week after initiating voriconazole that improved with IVIG and etanercept.

It is difficult to determine if TEN represents a continuum or result of the underlying drivers of acute GVHD vs a drug reaction. Although there is insufficient evidence to establish a clear-cut diagnosis of TEN, these cases illustrate the need for better diagnostic techniques to allow differentiation between TEN and grade 4 acute GVHD, and in the context of uncertainty, TNF-α inhibition poses a viable therapeutic strategy for these 2 often lethal conditions. Our cases do unequivocally indicate the benefit of this therapeutic modality, add to the current body of literature supporting the use of TNF-α inhibitors in patients such as ours without an official TEN diagnosis, and may guide future investigative efforts.

To the Editor:

Acute graft-vs-host disease (GVHD) remains a limitation to hematopoietic stem cell transplantation (HSCT) in 20% to 50% of patients after transplant. Furthermore, failed treatment with corticosteroids is frequent and portends a poor prognosis.¹ Toxic epidermal necrolysis (TEN) is an epidermolytic skin disorder thought to represent an adverse drug reaction, though its pathogenesis remains unclear. Severe forms of acute GVHD can mimic TEN clinically and histologically. Both can present with widespread cutaneous and mucosal bullae, erosions, and desquamation. Toxic epidermal necrolysis in the context of allogeneic hematopoietic stem cell transplantation is extremely rare, with almost 100% mortality in adult patients. Features that favor acute GVHD over TEN include diarrhea, elevation in bilirubin level, and chimerism.² However, these features might be absent, posing a therapeutic dilemma, as current treatment preferences for each of these entities differ.

Growing evidence supports the use of anti–tumor necrosis factor (TNF) α drugs for the treatment of TEN. Success has been reported with both anti–TNF-α monoclonal antibodies as well as the soluble fusion protein etanercept.^3,4 The use of TNF-α inhibitors in acute GVHD remains anecdotal.

A 58-year-old man (patient 1) with a history of acute myelogenous leukemia presented with a pruritic morbilliform eruption 28 days after HSCT. There was no desquamation or mucosal involvement and the biopsy obtained was histologically suggestive of grade 2 acute GVHD. His immunosuppressive regimen included sirolimus and cyclophosphamide. He was receiving trimethoprim-sulfamethoxazole (TMP-SMX), voriconazole, and acyclovir for infectious prophylaxis. At the time of presentation, he was treated with high-dose systemic steroids (prednisone 2 mg/kg/d) for acute GVHD with partial improvement. Upon tapering of the steroids 3 weeks after initiating TMP-SMX and 1 week after initiating voriconazole, he developed painful desquamation and erosions involving 95% of the body surface area (BSA), necessitating admission to the local burn unit (Figure 1). Biopsies demonstrated full-thickness epidermal necrosis with subepidermal blistering and interface dermatitis (Figure 2). No gastrointestinal tract involvement of acute GVHD was noted. The patient was a 100% donor chimera, supporting the diagnosis of acute GVHD; however, the patient and donor carried the HLA-C*06:02 allele, which previously has been described in association with TMP-SMX–related Stevens-Johnson syndrome/TEN.⁵ In addition, causality assessment using the algorithm of drug causality for epidermal necrolysis indicated TMP-SMX as a probable cause and voriconazole as a possible cause. The diagnosis of TEN with a SCORe of Toxic Epidermal Necrosis (SCORTEN) of 4 in the setting of acute GVHD was favored, though grade 4 acute GVHD could not be excluded. Trimethoprim-sulfamethoxazole was discontinued, and voriconazole was changed to posaconazole. He received supportive care along with 1 dose of 25-mg subcutaneous etanercept and 3 days of intravenous immunoglobulin (IVIG). Skin re-epithelialization was complete by 3 weeks. At 4 weeks, the patient developed a new asymptomatic erythematous eruption. Biopsies demonstrated changes of acute and chronic GVHD (Figure 3) that resolved with up-titration of sirolimus. The patient remained hospitalized for 96 days and continued to follow up with his transplant team as well as ophthalmology and dermatology. He died 2 years after HSCT.

A 67-year-old woman (patient 2) with high-grade myelodysplastic syndrome presented with an erythematous morbilliform eruption on the torso on day 20 after a matched unrelated HSCT that histologically was consistent with grade 2 GVHD (Figure 4). She had been receiving sirolimus and tacrolimus for GVHD prophylaxis. Infectious prophylaxis included acyclovir, pentamidine, micafungin, and TMP-SMX. Despite high-dose systemic steroids, the rash progressed and ultimately involved 80% BSA. A positive Nikolsky sign was noted involving 21% BSA (Figure 5), in addition to oral and genital mucosal ulcers. She denied nausea, vomiting, fever, or diarrhea. Chimerism studies were negative. Trimethoprim-sulfamethoxazole was discontinued, and she was transferred to a burn unit. Biopsies showed full-thickness epidermal necrosis. A diagnosis of TEN with a SCORTEN of 4 in the setting of acute GVHD was favored; grade 4 acute GVHD could not be excluded. Steroids were discontinued. Because laboratory studies indicated IgA deficiency, IVIG was not considered as a systemic option for therapy. The patient received 1 dose of infliximab (5 mg/kg). Cyclophosphamide 1600 mg weekly was added for GVHD therapy. The wounds progressively healed, and 2 weeks into her admission she was noted to have only 3% BSA with denuded skin. The patient was transferred to the cancer treatment center for further management of the malignancy. Unfortunately, after 2 months she died due to ischemic colitis that was confirmed on autopsy.

Graft-vs-host disease and TEN are rare, life-threatening complications seen in patients with allogeneic HSCT.² Graft-vs-host disease and TEN share clinicopathologic characteristics and effector immune mechanisms, largely the substantial role of T-cell activation and tissue destruction, which occur through mediators such as TNF-α.^6-8

Given the sparse lymphocytic infiltrate, keratinocyte death in TEN is thought to result from soluble molecules, including TNF-α and TNF-related apoptosis-inducing ligand.⁹ Tumor necrosis factor α has been identified in blister fluid, biopsy specimens, and serum of patients with TEN. Tumor necrosis factor α increases the expression of keratinocyte-inducible nitric oxide synthase, which upregulates keratinocyte Fas ligand expression and subsequent Fas- and caspase-8–mediated keratinocyte cell death.¹⁰

Acute GVHD results from donor lymphocyte activation after infusion into damaged recipient tissues that previously have been radiated or chemoablated. Mismatches in histocompatibility complexes between donor cells and recipient tissue antigens serve as the initial trigger for immune activation. Activation of antigen-presenting cells followed by activation, proliferation, differentiation, and migration of donor T cells ultimately results in destruction of the target tissue.¹¹ Immune mediators, such as TNF-α and lymphotoxin α (another member of the TNF superfamily), play a nonredundant role in the pathogenesis of GVHD.¹²

Current treatment strategies for severe acute GVHD and TEN differ. In North America, high-dose IVIG frequently is used as first-line systemic therapy, while high-dose systemic corticosteroids rarely are used.¹³ Studies have demonstrated successful use of anti–TNF-α drugs for the treatment of TEN.^3,4 Moreover, etanercept has shown to effectively inhibit lymphotoxin α.¹⁴ Similarly, TNF inhibition in the management of steroid-refractory acute GVHD has been successful.¹ These studies coupled with the underlying immune mechanisms that both diseases share encouraged initiating a trial of anti–TNF-α therapy in our patients.

Patient 1 merits further discussion because he was both a 100% donor chimera as well as a carrier of an human leukocyte antigen susceptibility candidate allele to TMP-SMX. Historical features of his presentation are consistent with either steroid-refractory GVHD or TEN superimposed on acute GVHD. His initial presentation of the more typical macular exanthem of cutaneous acute GVHD was both biopsy proven and supported by clinical improvement with steroid therapy, which was later followed by a robust blistering mucocutaneous presentation approximately 3 weeks after the administration of TMP-SMX and 1 week after initiating voriconazole that improved with IVIG and etanercept.

It is difficult to determine if TEN represents a continuum or result of the underlying drivers of acute GVHD vs a drug reaction. Although there is insufficient evidence to establish a clear-cut diagnosis of TEN, these cases illustrate the need for better diagnostic techniques to allow differentiation between TEN and grade 4 acute GVHD, and in the context of uncertainty, TNF-α inhibition poses a viable therapeutic strategy for these 2 often lethal conditions. Our cases do unequivocally indicate the benefit of this therapeutic modality, add to the current body of literature supporting the use of TNF-α inhibitors in patients such as ours without an official TEN diagnosis, and may guide future investigative efforts.