Krista Reznik

August 2023 Case Study

by Nidhi Shah, MD

A 67-year-old male with past medical history of hypertension, type 2 diabetes, cirrhosis, and psoriasis presented for a pruritic rash involving his scalp, trunk, and extremities for a year. On examination, patient had small erythematous macules and telangiectasias scattered on the trunk, extremities, and scalp (Figure 1). A punch biopsy of the left lower back was obtained (Figure 2)¹. Laboratory findings demonstrated an elevated tryptase level.

Based on the clinical presentation and biopsy and laboratory findings, what is the next best test?

A.) CK
B.) Hepatitis panel
C.) c-KIT
D.) TSH
E.) HIV

 

 

 

Correct Answer: C.) c-KIT

 

Explanation of Correct Answer:

Patient’s telangiectatic and macular rash with biopsy findings of mononuclear infiltrate of mast cells around the capillaries in the upper dermis raises concerns for telangiectasia macularis eruptive perstans (TMEP), a rare form of cutaneous mastocytosis. TMEP most commonly manifests in adulthood, although rare reports of pediatric cases have been reported.^1,2 Although previously considered to be a solely cutaneous disease, recent evidence suggests the presence of systemic involvement including bone marrow, gastrointestinal tract, liver, spleen and lymph node.^2,3

TMEP classically presents as small, irregular red-brown blanchable telangiectatic macules ranging from 2-4mm in diameter overlying a tan background.² These lesions generally are non-pruritic and involve the trunk and proximal extremities in a symmetric pattern, sparing the palms, soles, and face in most cases. Commonly positive in urticaria pigmentosum or maculopapular cutaneous mastocytosis (UP/MPCP), Darier’s sign is usually negative or slight in TMEP given the low number of mast cells involved.²

If characteristic skin lesions are accompanied by symptoms like flushing, diarrhea, dyspnea, tachycardia, pruritis, syncope, or indications of anaphylaxis, it’s important to consider the possibility of systemic involvement.² Serum tryptase and 24-hour urine histamine levels are used as preliminary test to investigate for systemic involvement with tryptase levels >20 µg/L concerning for systemic mastocytosis.² In adults, a c-KIT proto-oncogene mutation is most commonly observed which leads to mast cell hyperplasia.⁴ The type III transmembrane tyrosine kinase receptor c-kit has an extracellular domain that binds to mast cell growth factor and activation leads to mast cell growth and production.² Although the mutation is not present in all patients, proto-oncogene alternations may be correlated with more aggressive systemic involvement, making it important to check for the mutation.⁴

There is no gold standard treatment for TMEP and treatment is based upon the type of systemic involvement and clinical symptoms. Lifestyle modifications to avoid stimulation of mast cell degranulation such as exposure to sunlight and extreme temperatures, alcohol, and drugs should be practiced. Additional treatment modalities include antihistamines, PUVA, and narrow-band UVB.^2,4 Beyond management of symptoms, staging studies are required to evaluate for aggressive disease. The only FDA approved treatment for cytoreduction in mastocytosis is avapritinib, an oral small molecule inhibitor of D816V-mutant KIT.⁵

 

References

1. Martín-Fuentes A, Pastor-Nieto MA, De Eusebio-Murillo E. Telangiectatic Macules in a 90-Year-Old Woman. Actas Dermo-Sifiliográficas (English Edition). 2012;103(1):65-66. doi:10.1016/j.adengl.2011.07.006
2. Watkins CE, Bokor WB, Leicht S, Youngberg G, Krishnaswamy G. Telangiectasia Macularis Eruptiva Perstans: more than skin deep. Dermatol Reports. 2011;3(1):e12. doi:10.4081/dr.2011.e12
3. Severino M, Chandesris MO, Barete S, et al. Telangiectasia macularis eruptiva perstans (TMEP): A form of cutaneous mastocytosis with potential systemic involvement. J Am Acad Dermatol. 2016;74(5):885-891.e1. doi:10.1016/j.jaad.2015.10.050

June 2023 Case Study

by Sapana Desai, MD & Kamaria Nelson, MD

A 93-year-old Caucasian female patient with significant past medical history of atrial fibrillation, chronic obstructive pulmonary disease, and rheumatoid arthritis presents with a single, painless, cherry red colored, glistening dome-shaped nodule on her right mid temporal scalp that appeared two months ago. Although asymptomatic, the palpable nodule rapidly evolved to measuring 3.5 x 4.5 x 4cm. Physical examination findings are shown in Figure 1.

Which of the following immunohistochemical marker is strongly associated with the patient’s diagnosis?

A) HHV8 LNA-1
B) CK20
C) Factor XIIIa
D) PHLDA1
E) CD31

 

 

Correct Answer: B.) CK20

 

Explanation of Correct Answer:

This elderly patient’s clinical presentation, which entails spontaneous emergence of a rapidly growing, asymptomatic reddish to violaceous spherical tumor with a smooth, shiny surface and a soft to turgid elastic consistency localized to the face- a region with greatly increased ultraviolet (UV) exposure, is highly suspicious for Merkel Cell Carcinoma (MCC).

MCC is a rare and aggressive cutaneous malignancy of neuroendocrine origin that most frequently presents with head and neck distribution and is characterized by high rates of local recurrence and nodal metastasis; five-year survival rates of all stages are 50-to-60%.¹ MCC arises in individuals of advanced age with peak incidence of 75 years of age, and predominantly affects Caucasian males when compared to women and other ethnic groups. While etiology of MCC remains elusive, clonal integration of the Merkel cell DNA double-stranded polyomavirus (MCPyV) into the host genome, or UV-mediated genetic aberrations affecting the tumor suppressor p53 and RB1 pathways as well as epigenetic factors that activate oncogenes, are accepted theories in carcinogenesis.^1,2,3 Other culprit risk factors encompass chronic UV exposure, lymphoproliferative diseases, and iatrogenic or pathological immunosuppression.³

Histopathologic assessment of MCC will reveal infiltration of the dermis and subcutaneous tissue- often sharing a connection with overlying epidermis and adnexal tissue, and exhibit sheets and nests of crowded basaloid cells with a finely granular “salt and pepper” chromatic pattern, indistinct nucleoli, and scant cytoplasm.¹ Mitoses and extensive necroses are common and reflect the detrimental nature of these tumor. Because histomorphology of MCC is rarely specific, immunohistochemistry is imperative for definitive diagnosis and can be confirmed via detection of CK20 (B), typically identified in perinuclear granules; metastasis of Small Cell Lung Carcinoma (SCLC) can be excluded if thyroid transcription factor 1 (TTF-1) is negative. In unusual circumstances if staining patterns for MCC are atypical or CK20 fails to be expressed, additional immunohistochemical markers including Pancytokeratin (AE1/3), chromogranin A, neuron specific enolase (NSE), synaptophysin, INSM1, or N-CAM (CD56) may be used.^1,4

Surgical modalities are most often utilized for primary MCC neoplasms, whether it be via wide local excisions (WLE) with 1-to-2cm margins, Mohs micrographic surgery (MMS), or excision with complete circumferential peripheral and deep margin assessment. In non-excisable circumstances and one-third of MCC cases with distant nodal and intra-abdominal metastases, immunotherapy with checkpoint inhibitors targeting programmed death receptor-1 (PD-1)/ programmed dead ligand-1(PD-L1) pathways have proved to be beneficial, preventing inhibition of T-cells and leading to increased immune system activity and antitumor responses. Current marketed immunotherapies for advanced stages of MCC include: Avelumab– a humanized anti-PD-L1 antibody (dose: 800mg IV q2weeks), Pembrolizumab– a humanized IgG4 antibody directed against PD-1 (dose: 2mg/kg q3weeks x 3 years), and Nivolumab- a fully human IgG4 antibody directed against PD-1 (dose: 240mg IV q2weeks).¹⁵

 

Explanation of Incorrect Answers:

Human Herpes Virus-8 Latency Associated Nuclear Antigen 1 (HHV8 LNA-1) (A) immunohistochemistry positivity is both sensitive and highly specific for diagnosis of Kaposi Sarcoma (KS), an angioproliferative mesenchymal malignant neoplasm caused by infection with Kaposi Sarcoma-Related Herpesvirus.^5,6 Expression of HHV8 LNA-1 causes binding of p53 and suppression of apoptosis. Subsequent activation of NF-kB elicits up-regulation of VEGF and bFGF and consequent neoangiogenesis, prompting characteristic KS histomorphological features of dermal masses of spindle cells with extravasated red blood cells and cellular atypia.⁵ KS is classified into four epidemiological subtypes: 1) classic form- presenting increased predilection amidst elderly men of Mediterranean and Eastern European descent with lower extremity involvement, 2) endemic African form– occurring amongst pediatric populations with generalized lymph node involvement, 3) AIDS-related form- afflicting HIV positive male homosexuals with diffused dermal and systemic involvement, and 4) iatrogenic form- affecting immunosuppressed individuals with analogous dissemination and effects as the latter.^5,6 While cutaneous findings in KS range from scattered pink to violaceous patches and papules to rapidly progressive, multicentric, ulcerated plaques and nodules with dissemination to visceral organs [eg. lungs and gastrointestinal system], lesions are often painful with associated lymphedema and secondary infection.⁶

Factor XIIIa (C) immunohistochemistry is a strongly positive staining marker for Dermatofibromas.⁷ Regarded as benign fibrohistocytic neoplasms, Dermatofibromas clinically present as asymptomatic, solitary, firm to hard, often hyperpigmented, slow-growing, plaque or cutaneous nodules with or without overlying dermal changes.^7,8  The “dimple sign” is a characteristic finding where lateral inward digital pressure of the skin produces central dimpling over the lesion. Dermatofibromas occur in people of all ages with increased predilection for the extremities, and most commonly ensue spontaneously with no inciting event but in a fifth of all reported cases are attributed to a primary reactive process from history of local trauma, such as vaccination or an insect bite.⁸ Classical histopathological features consist of ill-defined intersecting bundles of spindle cells with collagen trapping.^7,8 Several dermoscopic patterns of Dermatofibromas are described, of which the most common is central white scar-like patch with delicate pigmentary network at the periphery; other typical patterns include total homogenous pigmentation and irregular crypts associated with pseudofollicular openings.^7,8 It is especially vital to differentiate Dermatofibromas from its similar-appearing, more advanced and aggressive counterpart, Dermatofibrosarcoma protuberans [DFSP], with the latter staining positive for CD-34 and negative for FactorXIIIa.⁸

PHLDA1 (D) along with stromal CD34 and CD10 immunohistochemistry positivity is often used to delineate Trichoblastomas from Basal Cell Carcinoma as the two diagnoses commonly share histopathological features, including the presence of fissures between the epithelium and spindled-fibroblast follicular stroma, epithelial nests, and cells in a palisading arrangement on the tumor periphery.^9,11 Trichoblastomas are rare, benign dermal tumors arising from aberrant proliferation of primitive follicular germinate cells. They clinically present as asymptomatic, solitary, skin-colored, slow-growing nodules that measure less than 2 cm in diameter on the face or scalp. Overlying epidermis is alopecic, thin, and hyperpigmented, and occasionally exhibit superficial telangiectasias and ulcerations.¹⁰ Trichoblastomas may emerge sporadically, in association with hereditary disease including Brooke-Spiegler disease and Brooke-Fordyce syndrome, or within a nevus sebaceous, and typically affect adults of both genders within their fifth and sixth decades of life. More often than not, Trichoblastomas have favorable prognosis, with low incidence of progression, recurrence, or association with malignancy.^9,10,11

Immunohistochemistry positivity for CD31 (E) as well as for other vascular markers including CD34 and factor VIII antigen are suggestive for diagnosis of pyogenic granuloma, a benign vascular tumor that arises within cutaneous and mucosal tissues affecting patients of all ages.¹² Although staining is often unnecessary given the characteristic clinical history and histological architecture, atypical lesions may necessitate its use. Histopathology shows highly vascularized proliferation of granulation tissue, lobular arrangements of capillary vessels and proliferating endothelial cells delineated by fibrous septae, scattered fibroblasts, and a variegated inflammatory infiltrate.^12,13 Pyogenic granuloma appears as a solitary, red, pedunculated papule that is greatly friable, and exhibits rapid exophytic growth. Lesions often undergo ulceration and can bleed profusely with even minor trauma.¹⁴ While the pathophysiology is not fully elucidated, imbalance of pro-angiogenic and anti-angiogenic factors, hormonal influences with increased estrogen and progesterone levels during pregnancy, reactive granulation tissue from negligible injuries, and iatrogenic use of specific medications are all plausible contributors.^12,13,14

 

References

1. Becker, JC., Beer, A., DeTemple, V., Eigentler, T., Flaig, M., Gambichler, T., Grabbe, S., Holler, U., Klumpp, B., Lang, S., Pfohler, C., Posch, C., Prasad, V., Schlattmann, P., Ter-Nedden, J., Terheyden, P., Thoms, K., Vordermark, D., Ugurel, S. S2K Guideline- Merkel Cell Carcinoma [MCC, Neuroendrocrine Carcinoma of the Skin]- Update 2022. Journal of the German Society of Dermatology. 2023; 21(3): 305-320.
2. Hernandez, L., Mohsin, N., Yaghi, M., French, F., Dreyfuss, I., Nouri, K. Merkel Cell Carcinoma: An Updated Review of Pathogenesis, Diagnosis, and Treatment Options. Dermatologic Therapy. March 2022; 35(3).
3. MD, Y., THakuria, M. MD. Merkel Cell Carcinoma Review. Hematology/Oncology Clinics of North America. February 2019; 33(1): 39-52.
4. Brady, M., Spiker, A. Merkel Cell Carcinoma of the Skin. 2022.
5. Biship, B., Lynch, D. Kaposi Sarcoma. 2022
6. Etemad, S., Dewan, A. Kaposi Sarcoma Updates. Dermatologic Clinics. October 2019; 37(4): 505-517.
7. Singh, S., Patra, S., Bhari, N. Dermatofibroma Over the Face. Indian Dermatology Online Journal. Jan-Feb 2019; 10(1): 94-95.
8. Myers, D., Fillman, E. Dermatofibroma. 2022.
9. Schukow, C., Ahmed, A. Trichoblastoma and Trichoepithelioma. StatPearls. 2022.
10. Patel, P., Nawrocki, S., Hinther, K., Khachemoune, A. Trichoblastomas Mimicking Basal Cell Carcinoma: The Importance of Identification and Differentiation. Cureus. May 2020; 12(5).
11. Cazzato, G., Cimmino, A., Colagrande, A., Arezzo, F., Lospalluti, L., Sablone, S., Lettini, T., Resta, L., Ingravallo, G. The Multiple Faces of Nodular Trichoblastoma: Review of the Literature with Case Presentation. Dermatopathology. 2021; 8(3): 265-270.
12. Wollina, U., Langner, D., Franca, K., Gianfaldoni, S., Lotti, T., Tchernev, G. Pyogenic Granuloma- A Common Benign Vascular Tumor with Variable Clinical Presentation: New Findings and Treatment Options. Open Access Macedonian Journal of Medical Sciences. July 2017; 5(4): 423-426.
13. Komakech, D., Ssenkumba, B. Pyogenic Granuloma. New England Journal of Medicine. November 2022; 387(21): 1979.
14. Sarwal, P., Lapumnuaypol, K. Pyogenic Granuloma. 2022.
15. Gauci, M., Aristei, C., Becker, J. Garbe, J., Lebbe, C. Diagnosis and Treatment of Merkel Cell Carcinoma: European Consensus-Based Interdisciplinary Guideline- Update 2022. European Journal of Cancer. August 2022; 17(1): 203-231.

May 2023 Case Study

by Emily Murphy, MD¹, Karl Saardi, MD¹

1. Department of Dermatology, George Washington University School of Medicine and Health Sciences

A 65-year-old male with a past medical history of HIV (CD4 count 250, undetectable viral load) and chronic congestion presented with a chief complaint of recurrent cellulitis of the left lower leg. The redness and swelling persisted for 3 months despite antibiotics. On presentation, he had circumferential edema and induration of the left lower leg with erythematous, tender nodules and early bullae (figure 1). A week later, his disease progressed with ulceration and necrosis of these tender nodules (figure 2). A punch biopsy was done, which showed an atypical lymphoid infiltrate in the dermis and subcutaneous tissue with an angiocentric pattern, composed of large, pleomorphic cells. Extensive necrosis was present with karyorrhetic debris. Immunostains were positive for T cells (CD2), natural killer cells (CD56), and cytotoxicity (granzyme B). A biopsy of the nasal septum showed similar findings. The patient was diagnosed with extranodal NK/T cell lymphoma, nasal type.

Which virus is part of the diagnostic criteria for this lymphoma?

A.) Human herpesvirus-8
B.) Polyomavirus
C.) Human immunodeficiency virus
D.) Ebstein Bar Virus
E.) Cytomegalovirus

Correct Answer: D) Ebstein Bar Virus

Extranodal NK/T cell lymphoma, nasal type is an aggressive, non-Hodgkin lymphoma that has four criteria according to the World Health Organization: vascular damage, prominent necrosis, a cytotoxic phenotype, and association with the Ebstein bar virus (EBV, answer D).^1,2 EBV positivity is seen in the both the skin and serum. Pathologically, the atypical lymphocytes are positive for cytotoxic markers (granzyme B, peforin), natural killer cell markers (CD2), T cell markers (cytoplasmic CD3), and EBV.¹ Extranodal NK/T cell lymphoma is rare in the United States, but its incidence is increasing. It is more common in East Asia and Latin America.¹

This lymphoma typically affects the upper aerodigestive tract, causing congestion, epistaxis, or necrotizing lesions of the nose or hard palate.¹ Other sites can be involved, including the extranasal skin, gastrointestinal tract, testes, or lungs.^1,3,4 On the skin, either a generalized morbilliform eruption or purpuric nodules with or without ulceration can be seen.³ Hemophagocytic lymphohistiocytosis can occur, but is rare, occurring in only 3% of patients.¹

NK/T cell lymphoma has an increased incidence in patients with HIV; a study of 93 patients with this lymphoma found that it occurred at a 15 times higher incidence in patients with HIV compared to the general population.⁵ However, HIV (choice C) is not part of the diagnostic criteria like EBV. Human herpesvirus-8 (Kaposi sarcoma), Polyomavirus (Merkel Cell Carcinoma), and cytomegalovirus are not associated with Extranodal NK/T cell lymphoma (choices A, B, E).

Treatment is determined by the Ann Arbor Staging and various prognostic tools, like the PINK-E system (age > 60 years, Stage III/IV, nonnasal primary localization, distant lymph node involvement, and detectable plasma EBV DNA).⁶ Depending on the stage and prognosis, treatment is typically with an asparaginase-based regimen called SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide).^1,6,7 NK/T cell lymphoma cells are unable to synthesize the amino acid, asparagine, and as this amino acid is depleted with asparaginase, protein synthesis is disrupted and the cells ultimately undergo apoptosis.⁶ Chemotherapy is typically followed by involved field radiation therapy.¹  Various immunotherapies are currently being studied for patients with recalcitrant or relapsed disease as well, including programmed death 1 inhibitors, JAK 3 inhibitors, or anti-CD30 therapies.⁸ Response to therapy can be monitored with EBV DNA titers, which should decrease with treatment.¹

References

1. Haverkos BM, Pan Z, Gru AA, et al. Extranodal NK/T Cell Lymphoma, Nasal Type (ENKTL-NT): An Update on Epidemiology, Clinical Presentation, and Natural History in North American and European Cases. Curr Hematol Malig Rep. 2016;11(6):514-527. doi:10.1007/s11899-016-0355-9
2. Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019;133(16):1703-1714. doi:10.1182/blood-2018-11-881268
3. Orlowski GM, Tan AJ, Evan-Browning E, Scharf MJ. Primary cutaneous nasal-type NK/T-cell lymphoma presenting as purpuric nodules on the lower leg. JAAD Case Rep. 2020;6(10):1075-1078. doi:10.1016/j.jdcr.2020.08.007
4. Rahal A, Reddy PS, Alvares C. Extranodal NK/T-Cell Lymphoma, Nasal Type, Presenting as a Breast Mass. Cureus. 7(12):e408. doi:10.7759/cureus.408
5. Castillo J, Pantanowitz L. HIV-Associated NK/T-Cell Lymphomas: A Review of 93 Cases. Blood. 2007;110(11):3457-3457. doi:10.1182/blood.V110.11.3457.3457
6. van Doesum JA, Niezink AGH, Huls GA, Beijert M, Diepstra A, van Meerten T. Extranodal Natural Killer/T-cell Lymphoma, Nasal Type: Diagnosis and Treatment. Hemasphere. 2021;5(2):e523. doi:10.1097/HS9.0000000000000523
7. Yamaguchi M, Kwong YL, Kim WS, et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. J Clin Oncol. 2011;29(33):4410-4416. doi:10.1200/JCO.2011.35.6287
8. Lv K, Li X, Yu H, Chen X, Zhang M, Wu X. Selection of new immunotherapy targets for NK/T cell lymphoma. Am J Transl Res. 2020;12(11):7034-7047.

April 2023 Case Study

by Sapana Desai, MD & Azam Qureshi, MD

A 37-year-old male presents with a two-year history of multiple “bumps” on the face. Asymptomatic, small, pea-sized, skin-colored papules were first noted over his left lateral face and mandibular jawline. Gradually, the papules evolved into plaques, with some appearing as large as 3 centimeters. During this time, several new erythematous papules arose along the left parotid region, right elbow, and right shin, and were noted to be painful to palpation and when exposed to cold temperature. Physical examination findings are shown in Figure 1a-d.

Which of the following is commonly associated with the patient’s diagnosis?

A) Iron Deficiency Anemia
B) Renal Cell Carcinoma
C) Angiomyolipoma
D) Pheochromocytoma
E) Eccrine Spiradenoma

 

Correct Answer: B) Renal Cell Carcinoma

 

Explanation of Correct Answer:

This patient’s clinical presentation, which includes multiple erythematous, tender, dermal nodules of varying sizes in both a clustered and scattered distribution along the face and extensor surfaces of the extremities is highly suspicious for piloleiomyomas.^1,2

A piloleiomyoma, regarded as the most common variant of cutaneous leiomyomas [CL] followed by angioleiomyoma, and dartoic [genital] leiomyoma, is a benign dermal neoplasm arising from smooth muscles of the erector pilorum muscle and can be solitary or multiple.^1,3 Piloleiomyomas emerge with peak incidence between 20 and 40 years of age, and equally affect both genders. 90 percent of afflicted patients experience spontaneous and/or paroxysmal sharp pain often precipitated by light touch, pressure, or cold temperatures, that is believed to be attributed to cutaneous nerve compression, injury, or by contraction of tumor muscle fibers.^1,2,3 While pathophysiology of piloleiomyoma remains elusive, underlying autosomal dominant [AD] inheritance of fumerate hydratase [FH] mutations are potentially associated with the development of multiple cutaneous piloleiomyoma in Hereditary Leiomyomatosis and Renal Cell Carcinoma [HLRCC] (B), also known as Reed Syndrome.⁴

HLRCC is a rare AD familial cancer syndrome caused by a germline amorphic allele of the FH gene, in which susceptible individuals are at increased risk for the development of cutaneous leiomyomas, early onset of multiple uterine leiomyomas, and type 2 papillary renal cell cancer.^4,5 Recent meta-analyses suggest approximately 20% to 35% of individuals with germline FH mutations develop RCC and die within 5 years of diagnosis.⁶ Given the aggressive and metastatic nature of these tumors, annual surveillance in patients with known HLRCC should begin at 10 years of age, and surgical removal of even small sized renal tumors is recommended.^4,5,

 

Explanation of Incorrect Answers:

Iron Deficiency Anemia (A) may be associated with Blue Rubber Bleb Nevus Syndrome [BRBNS/ Bean’s Syndrome]. Patients have characteristic cutaneous findings of multiple blue to violaceous soft and compressible nodules on the skin or mucous membranes that present at birth or in early childhood and develop numerous venous malformations involving the skin and gastrointestinal tract over their’ lifetime.^7,8 Typical lesions range in size from a few millimeters to up to 4 centimeters in diameter, are rubbery in consistency, and gradually evolve with time eliciting pain most prevalent at night.⁸ Uniquely, lesions swell in gravity-dependent positions, and patients exhibit focal areas of hyperhidrosis overlying these lesions. Although most cases of BRBNS are sporadic, autosomal dominant inheritance has been suggested, as well as studies reporting stem cell factor/c-kit signaling systems contributing to vascular overgrowth. Lower gastrointestinal bleeding is the most common symptom ranging from obscure to massive bleeding leading to severe iron deficiency anemia. Other rare complications may include perforation, intussusception, intestinal torsion, disseminated intravascular coagulation, and thrombocytopenia.^7,8

Renal Angiomyolipoma (C) is strongly associated with tuberous sclerosis complex [TSC], an AD, neurocutaneous disorder characterized by an increased predisposition to hamartoma formation, caused by genetic mutations for the proteins hamartin and tuberin, TSC1 and TSC2, respectively.⁹  Clinical presentation of TSC is highly variable given its multisystemic involvement, with epilepsy leading the list of neurological manifestations and accounting for 94% of affected patients, followed by cortical tubors, subependymal nodules, and subependymal giant cell astrocytomas. Frequent cutaneous manifestations encompass ash-leaf shaped hypomelanotic macules, facial angiofibroma’s, and shagreen patches.^9,10 Renal angiomyolipomas may emerge in 55% to 75% of TSC patients with various longitudinal studies reporting a 75% prevalence of renal angiomyolipomas by 10.5 years of age.^10,11 Although benign, TCS-associated renal angiomyolipomas are bilateral and multifocal, and when larger than 4 centimeters pose greater risks for potentially catastrophic hemorrhage when compared with isolated renal angiomyolipoma.¹¹

Pheochromocytoma (D) may be associated with neurofibromatosis type 1- an autosomal dominantly inherited neurocutaneous disorder due to mutations in NF1 gene on 17q11.2. Pheochromocytoma is a rare neuroendocrine catecholamine-producing tumor of the adrenal medulla that synthesizes and stores excessive amounts of norepinephrine and epinephrine, which when released can evoke life-threatening cardiovascular complications.¹² It may be classified as sporadic or familial, with the latter accounting for 10% of all pheochromocytoma cases, and exhibits strong association with hereditary inheritance of multiple endocrine neoplasia IIA and IIB, neurofibromatosis type 1, tuberous sclerosis, von Hippel-Lindau syndrome, Sturge-Weber syndrome, and simple familial pheochromocytoma.^12,13 Up to 40% of pheochromocytomas are associated with known genetic mutations, with the most common encompassing NF-1 gene, RET proto-oncogene, VHL gene, and genes encoding succinate dehydrogenase subunits.^12,13

Eccrine Spiradenomas (E) are benign dermal neoplasms closely linked with Brooke-Spiegler Syndrome [BSS], a rare AD hereditary disease which arises from heterozygous mutations in the tumor suppressor gene CYLD located on chromosome 16q12. BSS is characterized by a triad of cutaneous adnexal tumors: 1) spiradenomas- painful papules on the head, neck, and trunk, 2) cylindromas- solitary or multiple tumors of the scalp, and 3) trichoepitheliomas- skin colored papules over the central face.^14,15  Eccrine spiradenomas typically emerge during late childhood or early adolescence preferentially in the head and neck region. New lesions may continue to develop throughout a patient’s lifetime. Most nodules measure 0.5 -to- 3 centimeters in diameter. Usually associated with rapid enlargement, ulceration, and bleeding, malignant transformation of either of the three tumors seen with BSS occurs in 5% to 10% of affected patients.¹⁵

  

References

1. Kudur, MH. A Generalized Multiple Cutaneous Piloleiomyomatosis in a Young Male: Rare Care Report. Indian Journal of Dermatology. 2013; 58(3): 245.
2. Albuquerque, M., Rocha, C., Costa, I., Maia, F., Sa’ Goncalves, H. Piloleiomyoma with segmental distribution- Case Report. Anais Brasileiros de Dermatologia. 2015; 90(3): 178-80.
3. Bernett, C;, Mammino, J. Cutaneous Leiomyomas. 2022.
4. Skala, SL., Dhanasekaran, S., Mehra, R. Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome [HLRCC]: A Contemporary Review and Practical Discussion of the Differential Diagnosis for HLRCC-Associated Renal Cell Carcinoma. Archives of Pathology & Laboratory Medicine. 2018; 142 (10): 1202-1215.
5. Ooi, A. Advances in hereditary leiomyomatosis and renal cell carcinoma [HLRCC] research. Seminars in Cancer Biology. 2020; 61(2): 158-166.
6. Yu, Y., Zheng, M., Zhu, W., Zhao, F., Guan, B., Shen, Q., Yang, F., He, Q., Li, X. Hereditary leiomyomatosis and renal cell carcinoma [HLRCC]: Case series and review of the literature. Urologic Oncology. 2021; 39(11).
7. Moghadam, A., Bagheri, M., Eslami, P., Farokhi, E., Asl, A., Khavaran, K., Iravani, S., Saeedi, S., Mehrvar, A., Dooghaie-Moghadam, M. Blue Rubber Bleb Nevus Syndrome because of 12 Years of Iron Deficiency Anemia in a Patient by Double Balloon Enteroscopy; A Case Report and Review of Literature. Middle East Journal of Digestive Diseases. 2021; 13(2): 153-159.
8. Hu, Z, Lin, X., Zhong, J., He, Qingfang., Peng, Q., Xiao, J., Chen, B., Zheng, J. Blue Rubber Bleb Nevus Syndrome with the Complication of Intussusception: A Case Report and Literature Review. Medicine (Baltimore). 2020; 99(28).
9. Zamora, E., Aeddula, Narothama. Tuberous Sclerosis. 2022.
10. Portocarrero, L., Quental, K., Samorano, L., de Oliveira, Z, da Matta Rivitti-Machado, M. Tuberous Sclerosis Complex: Review Based on New Diagnostic Criteria. Anais Brasileioros de Dermatologia. October 2017; 7(4): 706-708.
11. Lin, C., Jin, L., Yang, Y., Ding, Y., Wu, X., Ni, L., Yang, S., Lai, Y. Tuberous Sclerosis- Associated Renal Angiomyolipoma: A Report of Two Cases and Review of the Literature. Molecular and Clinical Oncology. August 2017; 7(4): 706-708.
12. Zografos, G., Vasiliadis, G., Zagouri, F., Aggeli, C., Korkolis, D., Vogiaki, S., Pagoni, M., Kaltsas, G., Piaditis, G. Pheochromocytoma Associated with Neurofibromatosis Type 1: Concepts and Current Trends. World Journal of Surgical Oncology. 2010; 8(14).
13. Naranjo, J., Dodd, S. MD, Martin, Y. MD. Perioperative Management of Pheochromocytoma. Journal of Cardiothoracic and Vascular Anesthesia. 2017; 31(4): 1427-1439.
14. Mohiuddin, W., Laun, J., Cruse, W. Brooke-Spiegler Syndrome. 2018.
15. Miceli, A., Ferrer-Bruker, S. Spiradenoma. 2022.

March 2023 Case Study

by Emily Murphy, MD¹

1. Department of Dermatology, George Washington University School of Medicine and Health Sciences

A 70-year-old healthy male presented with a chronic wound on his scalp that started 4 months ago. On examination, a 2.5-centimeter circular, ulcerated violaceous plaque with hemorrhagic crusting was present on the scalp (figure 1). A punch biopsy of the raised border was done (figure 2a, hematoxylin-eosin staining). The atypical cells stained positively for erythroblast transformation specific related gene (ERG) and CD31.

Based on the clinical presentation and biopsy findings, which two patients would be least likely to develop the same malignancy as the above patient?

A.) 80-year-old male with a plaque on the cheek
B.) 35-year-old male with a tumor that also stained positively for HHV-8
C.) 65-year-old male exposed to vinyl chloride for many years in his occupation
D.) 50-year-old woman with a lower limb plaque after treatment of a uterine carcinoma 10 years prior
E.) 55-year-old woman with a plaque on the scalp who reports chronic sun exposure and many blistering sunburns
F.) 40-year-old woman who had radiation for breast cancer 5 years ago

 

Correct Answer: B, E

Given the biopsy revealed proliferation of atypical and inter-anastomosing vascular channels along with increased mitotic figures, and that these atypical cells were positive for ERG and CD31, the patient was diagnosed with angiosarcoma, a rare soft tissue sarcoma, with only about 200 reported cases in the United States per year.¹ These tumors present on the skin as a purpura-like or violaceous papules to plaques, that are often multifocal.² As the tumors grow, ulceration and hemorrhage often occur, as was seen in this case.²

The cutaneous form of angiosarcoma most often occurs spontaneously, typically in elderly men on the head and neck (choice A).² The scalp is a particularly common site, as in our patient, and is also associated with a poor prognosis.^3,4 Angiosarcomas can also occur secondary to radiation (choice F) or chronic lymphedema (choice D), which is called Stewart-Treves syndrome.^1,2 Stewart-Treves can be seen after lymph node dissection in setting of breast cancer (upper limb) or uterine cancer (lower limb, choice D).¹ In cases of radiation or lymphedema, the tumor often develops at least 5 years later.^1,2 Angiosarcoma can also be seen with chronic exposure to various toxins including vinyl chloride, arsenic, thorium dioxide, and anabolic steroids (choice C).² Unlike Kaposi sarcoma, HHV-8 is not associated with angiosarcoma (choice B).⁶ Further, in contrast to many other cutaneous cancers, sun exposure is not associated with angiosarcomas (choice E).⁷

Prior to treatment, an MRI of the primary lesion should be done to evaluate the extent of disease, as well as a CT chest to rule of pulmonary disease, which is the most common site of metastasis.^1,2 A PET scan may also be done to exclude other sites of metastasis.² Given the rarity of these tumors, standard treatment algorithms do not exist. For local disease, wide local excision is done, typically followed by surgical site radiation of at least 50 gray.¹ For unresectable or metastatic disease, chemotherapy, often paclitaxel, is used in combination with radiation.¹ Clinical trials are currently examining the impact of immunotherapy on angiosarcoma as well. Despite treatment, these tumors often recur, leading to a 5-year survival less than 40%.¹

 

References

1. Fujisawa Y, Yoshino K, Fujimura T, et al. Cutaneous Angiosarcoma: The Possibility of New Treatment Options Especially for Patients with Large Primary Tumor. Front Oncol. 2018;8:46. doi:10.3389/fonc.2018.00046
2. Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ. Angiosarcoma. Lancet Oncol. 2010;11(10):983-991. doi:10.1016/S1470-2045(10)70023-1
3. Ramakrishnan N, Mokhtari R, Charville GW, Bui N, Ganjoo K. Cutaneous Angiosarcoma of the Head and Neck-A Retrospective Analysis of 47 Patients. Cancers (Basel). 2022;14(15):3841. doi:10.3390/cancers14153841
4. Shin JY, Roh SG, Lee NH, Yang KM. Predisposing factors for poor prognosis of angiosarcoma of the scalp and face: Systematic review and meta-analysis. Head Neck. 2017;39(2):380-386. doi:10.1002/hed.24554
5. Jennings TA, Peterson L, Axiotis CA, Friedlaender GE, Cooke RA, Rosai J. Angiosarcoma associated with foreign body material. A report of three cases. Cancer. 1988;62(11):2436-2444. doi:10.1002/1097-0142(19881201)62:11<2436::aid-cncr2820621132>3.0.co;2-j
6. Schmid H, Zietz C. Human herpesvirus 8 and angiosarcoma: analysis of 40 cases and review of the literature. Pathology. 2005;37(4):284-287. doi:10.1080/00313020500169495
7. North P. Vascular Neoplasms and Neoplastic-Like Proliferations. In: Dermatology. Fourth Edition. Elsevier; :2020-2049. Accessed February 18, 2023. https://www-clinicalkey-com.proxygw.wrlc.org/#!/content/book/3-s2.0-B9780702062759001148?scrollTo=%23top

February 2023 Case Study

by Alexis E. Carrington, MD

A 52 year old female with a past medical history of vulvar lichen sclerosus presents to the clinic for a rash on the back and legs for 8 months. She reports the rash is itchy and the areas on the back are worse during the summer months and with sweating. She is using Aquaphor ointment and a topical antibiotic cream with no improvement. She denies any family history of similar findings or exposure to new personal or household items. Punch biopsy of a lesion on the back is consistent with lichen sclerosus.

Which of the following is true about lichen sclerosus?

A.) It is associated with HLA-DQ2
B.) It is associated with anti-extracellular matrix protein 1 antibodies
C.) Genital lesions can be associated with development of BCC
D.) Treatment of extragenital disease involves the use of a low-potency topical steroid

 

Extragenital lichen sclerosus typically favors the neck, shoulders, trunk, proximal extremities, flexor wrists and sites of trauma. It is associated with xerosis and mild pruritus, but is usually asymptomatic. The lesions start as white, shiny, polygonal papules that coalesce into plaques and evolve into atrophic patches and plaques. Lesions may also affect the skin around the eye and other areas of the face.

Lichen sclerosus is usually a clinical diagnosis but a biopsy is reasonable to confirm diagnosis. Topical steroids are the gold standard for this condition. Patients should be referred to a dermatologist and gynecologist or urologist for management of genitourinary complications.

Correct answer: B.) It is associated with anti-extracellular matrix protein 1 antibodies

Answer A is associated with Dermatitis Herpetiformis, whereas lichen sclerosus is associated with HLA-DQ7. There is an increased risk of genital squamous cell carcinoma in both men and women with lichen sclerosus, not basal cell carcinoma (Answer C). Treatment of extragenital disease involves the use of high potency topical steroids, rather than low-potency (Answer D).

 

References

1. Bolognia, Jean Dermatology volume 2. Mosby, 2018.
2. Fistarol SK, Itin Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol. 2013 Feb;14(1):27-47. PubMed ID: 23329078
3. Lewis FM, Tatnall FM, Velangi SS, et al. British Association of Dermatologists guidelines for the management of lichen sclerosus, Br J Dermatol. 2018 Apr;178(4):839-853. PubMed ID: 29313888

January 2023 Case Study

by Adam Rosenfeld, MD

61-year-old male with history of HTN, DM, HLD who presented for a new growth on his mid abdomen. He noted a history of a trauma to the area with a metal blade 20 years prior while in active duty, with the area initially healing with a raised scar. He endorsed significant increase in size of the area over the last year, but it had been slowly growing for several years. The patient had been told this was a keloid. He denies any significant pain or associated symptoms. On examination, there was a large approximate 4x5cm protuberant skin colored to pink mass on the left mid abdomen (figure 1). A punch biopsy was obtained of this tumor demonstrating a dense dermal infiltrate of spindle cells (figure 2).

A diagnosis of a malignant dermal proliferation was made, often mimicking the diagnosis the patient had been told before. What stain was confirmatory in making this diagnosis?

A.) CD207+
B.) Factor XIIIA+
C.) S100+
D.) CD34+
E.) SMA+

Correct answer: D.) CD34+

This multi-loculated tumor is suspicious for dermatofibrosarcoma protuberans, or DFSP which classically stains diffusely positive for CD34. CD34 is a marker for vascular endothelium and hematopoietic progenitor cells⁴. It is positive in DFSP and negative in dermatofibromas. Dermatofibrosarcoma protuberans is a fibroblast derived intermediate-grade soft tissue sarcoma that can be mistaken for a keloid³. It is often slow growing and asymptomatic. It can present as a bulky multi-loculated tumor as in our patient but can also have much more innocent appearances. Its pathophysiology is unclear, but some have proposed prior injury to the skin as a triggering event¹. Evidence does support these tumors arising from fibroblastic, histiocytic or neuroectoderm tissue although a fibroblastic origin seems most likely. The growth of the tumor is driven in most cases by a translocation of chromosome 17 and 22 forming the t(17,22) COLA1A-PDGFG fusion protein¹. On histopathology, a dense dermal infiltrate of spindle cells is seen infiltrating into the deeper fat causing the “honey combing” appearance of the adipose tissue⁴. These cells stain diffusely positive for CD34+, while staining weakly or not at all for Factor XIIIA+ (answer choice B), the stain pathognomonic for dermatofibromas⁴. Importantly, it is crucial to rule out other spindle cell neoplasms including a spindle cell melanoma which would stain positive for S100 (answer choice C)⁴. While DFSPs are malignant, they typically do not demonstrate significant atypia histologically. Fibrosarcomatous change represents a subset of DFSPs that demonstrate much more atypical features, indicating tumor progression³. The differential diagnosis of DFSP includes but is not limited to a keloid, dermatofibroma, spindle cell melanoma, squamous cell carcinoma, Kaposi sarcoma.

The standard of care for treatment is surgical excision with every effort to achieve clear surgical margins both peripherally and deep². Although wide local excision can be performed, Mohs Micrographic Surgery (MMS) is now recommended for these tumors. Given that it demonstrates unpredictable microscopic, tentacle like extensions, the directionality afforded by MMS makes it uniquely fit for DFSPs³. No set margins exist but wide local excision typically includes 2-4cm. MMS initial margins vary but the literature suggest 0.5-1.3cm³. Unresectable or metastatic tumors can be treated with radiation or Imatinib, a tyrosine kinase inhibitor^5,7. NCCN guidelines do not recommended extensive systemic work up of these patients unless there are red flags for metastasis on exam or through history. Imaging with CT or MRI can be performed to assess for tumor depth but is based on a case-by-case basis⁸. These tumors have a low risk of metastasis (1-4%) but a high chance of local recurrence. Surveillance includes observation of primary site every 6 months for the first 5 years with yearly exams following³. The overall prognosis of DFSPS is good, with a 10-year survival rate of 99.1%³.

Incorrect stains in answer choices⁴

CD 207 (choice A) – surrogate marker for presence of Birbeck granules in Langerhans cells

Factor XIIIA (choice B) – stains dermal dendritic cells, positive in dermatofibroma and negative in DFSP

S100 (choice C) – stains melanocytes, Langerhans cells, sweat glands, nerves, Schwann cells, myoepithelial cells, fat, muscle and chondrocytes

SMA (choice E) – positive in smooth muscle, including vascular smooth muscle; negative in skeletal muscle; expressed in myofibroblasts and myoepithelial cells

 

References

1. Bolognia, J., Schaffer, J., & Cerroni, L. (2018). Dermatology (Fourth edition.). Philadelphia,Pa: Elsevier.
2. Dermatofibrosarcoma protuberans – statpearls – NCBI bookshelf. Dermatofibrosarcoma Protuberans. (n.d.). Retrieved August 11, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK513305/
3. Hao X;Billings SD;Wu F;Stultz TW;Procop GW;Mirkin G;Vidimos AT; (n.d.). Dermatofibrosarcoma protuberans: Update on the diagnosis and treatment. Journal of clinical medicine. Retrieved August 11, 2022, from https://pubmed.ncbi.nlm.nih.gov/32516921/
4. Elston, D. M. (2019). Dermatopathology. Elsevier.
5. Cristian Navarrete-Dechent, M. D. (2019, March 1). Imatinib treatment for locally advanced or metastatic dermatofibrosarcoma protuberans. JAMA Dermatology. Retrieved August 11, 2022, from https://jamanetwork.com/journals/jamadermatology/article-abstract/2719525
6. Raman K Madan, M. D. (2021, July 15). Dermatofibrosarcoma protuberans. Background, Pathophysiology, Etiology. Retrieved August 11, 2022, from https://emedicine.medscape.com/article/1100203-overview
7. Ugurel, S., Mentzel, T., Utikal, J., Helmbold, P., Mohr, P., Pföhler, C., Schiller, M., Hauschild, A., Hein, R., Kämpgen, E., Kellner, I., Leverkus, M., Becker, J. C., Ströbel, P., & Schadendorf, D. (2014, January 16). Neoadjuvant imatinib in advanced primary or locally recurrent dermatofibrosarcoma protuberans: A multicenter phase II decog trial with long-term follow-up. American Association for Cancer Research. Retrieved August 15, 2022, from https://aacrjournals.org/clincancerres/article/20/2/499/78307/Neoadjuvant-Imatinib-in-Advanced-Primary-or
8. Bichakjian, C. K., Olencki, T., Alam, M., Andersen, J. S., Berg, D., Bowen, G. M., Cheney, R. T., Daniels, G. A., Glass, L. F., Grekin, R. C., Grossman, K., Ho, A. L., Lewis, K. D., Lydiatt, D. D., Morrison, W. H., Nehal, K. S., Nelson, K. C., Nghiem, P., Perlis, C. S., … Ho, M. (2014, June 1).Dermatofibrosarcoma protuberans, version 1.2014. JNCCN. Retrieved January 9, 2023, from https://jnccn.org/view/journals/jnccn/12/6/article-p863.xml

December 2022 Case Study

by Adam Rosenfeld, MD

A 43-year-old gentleman with known history of Langerhans cell sarcoma (s/p numerous rounds of chemotherapy and targeted therapy) presented to the ED with a 1-month history of worsening back pain and malaise. He was admitted due to concern for sepsis and started on broad spectrum antibiotics. Dermatology was consulted for painful lesions on his legs that the patient had noticed several months prior to presentation. On examination, the patient had multifocal ulcerations on his bilateral thighs, with overlying fibrinous material (figure 1). A punch biopsy was done on one of these ulcerations (figure 2).  Although these ulcerations could represent several differential diagnoses, the primary concern was whether his known malignancy had metastasized to the skin.

Given his known malignancy history, which stain would be most useful to highlight the underlying pathology?

A.) Factor XIIIA+
B.) CD21+
C.) CD207+
D.) CD31+
E.) S100+

Correct answer: C.) CD207+

Given the multifocal ulcerations found on exam and pathologic findings of an infiltrate predominantly throughout the dermis and diving deep into the subcutaneous tissue, a malignant process was suspected. The infiltrative cells stained positive for CD207, as well as CD1a and S100. The infiltrate had frequent atypical cells and mitotic figures. As such, the patient was diagnosed with Langerhans cell sarcoma, now with cutaneous metastasis. Langerhans cell sarcoma is a rare neoplastic disorder of Langerhans cells¹. According to the Histiocyte Society, there are 5 groups in classifying histiocytoses and neoplasms of the dendritic cell lineages. Langerhans cell sarcoma falls under the malignant, or “M group,” and is a distinct entity from Langerhans cell histiocytosis². However, Langerhans cell sarcoma will stain positive for typical Langerhans cell markers. These are CD207 (Langerin), CD1a and S100. However, CD207 and CD1a are the most specific stains for Langerhans cells, either of which would have been correct for this question³. Although S100 stain positive for these cells, it also can stain positive for melanocytic proliferations amongst others, so would not be most useful in this case⁷.

Langerhans cell sarcoma has been diagnosed less than 100 times in the literature¹. It can present with both cutaneous and systemic findings, often with multiorgan involvement. There does not appear to be a certain age predilection, as a systematic review in 2015 documented an age range of diagnosis as 11 months to 81 years.¹ In this same review, 75% of patients had lymph node involvement, approximately 50% had cutaneous involvement and numerous patients had lung, liver or spleen involvement¹. The cutaneous manifestations for this disease process vary from ulcerations to fungating masses, to more indolent appearing nodules. Given its rarity, no consistent presenting cutaneous morphology or lesion is identifiable. The pathogenesis is not well elucidated but is thought to be driven by mutations in the RAS/MAPK/BRAF pathway⁴. Diagnostic criteria include malignant cytological features such as atypia, hyperchromia and atypia as well as expression of typical Langerhans cell markers as discussed above¹. Clear treatment guidelines do not exist, but include surgical excision, radiation, chemotherapy or bone marrow transplantation¹. Additionally, targeted therapies against PD-1 and BRAF have shown promise in case reports however no large studies have been published looking at the efficacy of these^5,6. The prognosis is poor, particularly in metastatic disease but can be favorable if presenting with one site disease¹.

Incorrect stains in answer choices⁷

Factor XIIIA (choice A) – stains dermal dendritic cells, positive in dermatofibroma and negative in DFSP

CD21 (choice B) – follicular dendritic cell marker, highlights residual follicle in lymphoma

CD31 (choice D) – helpful in confirming vascular origin of tumors, more specific than CD34 for vascular processes

S100 (choice E) – stains melanocytes, Langerhans cells, sweat glands, nerves, Schwann cells, myoepithelial cells, fat, muscle and chondrocytes

References

1. Langerhans Cell Sarcoma: A Systematic Review.” Cancer Treatment Reviews, U.S. National Library of Medicine
2. Revised Classification of Histiocytoses and Neoplasms of the Macrophage-Dendritic Cell Lineages.” Blood, U.S. National Library of Medicine
3. Mizumoto N, Takashima A. CD1a and langerin: acting as more than Langerhans cell markers. J Clin Invest. 2004 Mar;113(5):658-60. doi: 10.1172/JCI21140. PMID: 14991060; PMCID: PMC351325.
4. Gounder, Mrinal M, et al. “Trametinib in Histiocytic Sarcoma with an Activating MAP2K1 (MEK1) Mutation.” The New England Journal of Medicine, U.S. National Library of Medicine, 17 May 2018,
5. Zanwar, Saurabh, et al. “Prolonged Remission with Pembrolizumab and Radiation Therapy in a Patient with Multisystem Langerhans Cell Sarcoma.” Haematologica, U.S. National Library of Medicine, 1 Sept. 2022, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9425309/.
6. C;Tazi A; “Dramatic Transient Improvement of Metastatic BRAF(V600E)-Mutated Langerhans Cell Sarcoma under Treatment with Dabrafenib.” Blood, U.S. National Library of Medicine, https://pubmed.ncbi.nlm.nih.gov/26468227/.
7. Elston, D. M., Ferringer, T., & Ko, C. J. (2019).Dermatopathology. Elsevier.

November 2022 Case Study

by Erika McCormick, BS, Emily Murphy, MD, Adam Friedman, MD

A 42-year-old female presented with a rash of two years duration affecting the hands, upper arms, upper back, and chest (Figure 1). A punch biopsy from the back was performed (Figure 2). Laboratory analysis was significant for transcriptional intermediary factor (TIF)-1γ antibody positivity.

Which of the following has been associated with TIF-1γ antibody positivity in this condition?

A.) Mild or absent muscle disease
B.) Increased risk of malignancy
C.) Decreased risk of malignancy
D.) Increased risk of interstitial lung disease
E.) Immune-mediated necrotizing myopathy

Correct answer: B.) Increased risk of malignancy

This patient presented with skin changes consistent with dermatomyositis (DM), including erythematous papules overlying the knuckles (Gottron papules), photodistributed poikiloderma involving the chest (‘V-neck’ sign) and upper back (‘shawl’ sign), and erythema surrounding the periocular region (heliotrope rash; not pictured).² Punch biopsy from the back showed vacuolar interface dermatitis with necrotic keratinocytes and increased superficial dermal mucin by colloidal iron staining, consistent with DM. A myositis specific antibody panel was performed. Myositis-specific autoantibodies (MSAs) are found in approximately 60 to 70% of children and adults with idiopathic inflammatory myopathy (encompasses DM, inclusion body myositis, polymyositis, immune-mediated necrotizing myopathy, and anti-synthetase syndrome).³ MSAs tend to be mutually exclusive, therefore their detection on laboratory analysis can help identify distinct subsets of disease, predict clinical phenotype, and stratify risk for malignancy and interstitial lung disease.³

In adults greater than 40 years old with DM, anti-TIF1γ autoantibody positivity has a strong association with increased risk of malignancy.³ (Choice B) Anti-nuclear matrix protein 2 (NXP2) is the second most common MSA seen in DM patients with malignancy.^3,4 Conversely, antibodies to Mi2 are associated with decreased risk of malignancy.³ (Choice C) Prevalence of malignancy in DM is estimated at 15% to 25%² with greatest risk within the first 3 years of diagnosis.⁵ Studies suggest that over 50% of anti-TIF1γ antibody positive DM patients may develop malignancy,^6,7and that risk increases to nearly 75% if anti-TIF1α antibodies are also present.⁶ Conventional recommendations upon diagnosis of DM with elevated malignancy risk include CT scan of the chest, abdomen, and pelvis in addition to obtaining thorough medical history, physical exam, laboratory tests, and age-appropriate cancer screenings.^2,8–10 Positron emission tomography with fluorodeoxyglucose and CT (FDG-PET/CT) was found to be comparable to CT alone but may be associated with an increased biopsies without improved diagnostic yield.^9,11

DM patients with anti-TIF1 autoantibodies typically have extensive skin involvement but have decreased risk of interstitial lung disease (ILD). ¹² (Choice D) Antibodies associated with increased prevalence and severity of ILD include those to aminoacyl-tRNA synthetases (especially PL7, PL12, KS, Jo1, and OJ), PM/Scl, and melanoma differentiation associated protein 5 (MDA-5).³ In anti-MDA-5 antibody positive DM, ILD prevalence ranges from 50% to 100% and can be rapidly progressive with high mortality.¹³ MDA-5 antibodies are also associated with a characteristic phenotype of mucocutaneous ulcerations, arthritis, and mild or absent muscle disease.³ (Choice A) Immune-mediated necrotizing myopathy, characterized by severe muscle disease refractory to conventional immunosuppressive therapies,³ is associated with antibodies to signal recognition particle (SRP) and to 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR).³ (Choice E)

The treatment approach for DM varies based on severity and extent of myositis; however, it generally includes systemic corticosteroids and immunosuppressive drugs. This patient received a prednisone taper, topical clobetasol 0.05% ointment for rash on the body, and topical hydrocortisone 2.5% ointment for the face. After failing methotrexate, hydroxychloroquine, and mycophenolate mofetil, this patient was successfully transitioned to high dose IVIG. A CT scan of the chest, abdomen, and pelvis was negative for any signs of malignancy and the patient continued age-appropriate cancer screenings with her primary care physician.

 

References

1. Wolstencroft PW, Rieger KE, Leatham HW, Fiorentino DF. Clinical factors associated with cutaneous histopathologic findings in dermatomyositis. J Cutan Pathol. 2019;46(6):401-410.
2. Bolognia J, Schaffer JV, Cerroni L. Dermatology. Fourth edition. (Bolognia J, Schaffer JV, Cerroni L, eds.). Elsevier; 2018.
3. McHugh NJ, Tansley SL. Autoantibodies in myositis. Nat Rev Rheumatol. 2018;14(5):290-302.
4. Fiorentino DF, Chung LS, Christopher-Stine L, et al. Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ. Arthritis Rheum. 2013;65(11):2954-2962.
5. Kardes S, Gupta L, Aggarwal R. Cancer and myositis: Who, when, and how to screen. Best Pract Res Clin Rheumatol. 2022;36(2).
6. Fujimoto M, Hamaguchi Y, Kaji K, et al. Myositis-specific anti-155/140 autoantibodies target transcription intermediary factor 1 family proteins. Arthritis Rheum. 2012;64(2):513-522.
7. Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti-TIF1-gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology (Oxford). 2010;49(9):1726-1733.
8. Oldroyd AGS, Allard AB, Callen JP, et al. A systematic review and meta-analysis to inform cancer screening guidelines in idiopathic inflammatory myopathies. Rheumatology (Oxford). 2021;60(6):2615-2628.
9. Maliha PG, Hudson M, Abikhzer G, Singerman J, Probst S. 18F-FDG PET/CT versus conventional investigations for cancer screening in autoimmune inflammatory myopathy in the era of novel myopathy classifications. Nucl Med Commun. 2019;40(4):377-382.
10. Vaughan H, Rugo HS, Haemel A. Risk-Based Screening for Cancer in Patients With Dermatomyositis: Toward a More Individualized Approach. JAMA Dermatol. 2022;158(3):244-247.
11. Selva-O’Callaghan A, Grau JM, Gámez-Cenzano C, et al. Conventional cancer screening versus PET/CT in dermatomyositis/polymyositis. Am J Med. 2010;123(6):558-562.
12. Fiorentino DF, Kuo K, Chung L, Zaba L, Li S, Casciola-Rosen L. Distinctive cutaneous and systemic features associated with antitranscriptional intermediary factor-1γ antibodies in adults with dermatomyositis. J Am Acad Dermatol. 2015;72(3):449-455.
13. Wu W, Guo L, Fu Y, et al. Interstitial Lung Disease in Anti-MDA5 Positive Dermatomyositis. Clin Rev Allergy Immunol. 2021;60(2):293-304.

October 2022 Case Study

by Emily Murphy, MD

A 36-year-old male with a past medical history of HIV/AIDS (CD4 count of 3) presented with a diffuse pruritic rash of several weeks duration. The rash started on his arms and then spread to his legs, back, and chest. On examination, the patient had innumerable papules of varying morphologies, including many lichenified papules with keratotic cores (figure 1). A punch biopsy was done of a papule on the leg (figure 2).

Based on the clinical presentation and biopsy findings, which stain would be most useful to highlight the underlying pathology?

A.) Toluidine blue
B.) Verhoeff–Van Gieson stain
C.) Colloidal iron
D.) Congo red
E.) Von Kossa

Correct answer: B.) Verhoeff–Van Gieson stain

Given the papules with central keratotic cores present on exam and pathologic finding of a crateriform erosion with collagen extrusion, the patient was diagnosed with acquired perforating dermatosis in the setting of HIV. The clinical findings are due to the transepidermal elimination of collagen through the epidermis; the extruded collagen can be stained red with the Verhoeff–Van Gieson stain (choice B). This entity is classically seen in the setting of chronic kidney disease, often requiring dialysis, and diabetes mellitus, most often with associated nephropathy.¹ Acquired perforating dermatosis can also be seen due to numerous medications (TNFα inhibitors, epidermal growth factor inhibitors, sirolimus, or antivirals like indinavir)^1,2 and has been reported in the setting of HIV.^2–4

Acquired perforating dermatosis most commonly occurs on the legs but can be generalized, as in our patient. The head is typically minimally involved and it spares the palms/soles, intertriginous areas, and mucous membranes.⁴  Papules and nodules are seen, with the biggest clue to the diagnosis being the central keratotic cores.¹ The eruption is very pruritic; scratching can trigger further disease via the Koebner phenomenon, and the microtrauma induced by scratching may also trigger focal degeneration of collagen, contributing to the pathogenesis.² In addition to skin trauma, increased growth factors, such as TGF-β, and fibroblast activity may also play a role in the disease.² On histopathology, a well-circumscribed, cup-shaped depression bordered by epidermal hyperplasia is seen with vertically-oriented, degenerated, basophilic collagen fibers extruding through the epidermis.^2,5

Management includes treatment of the underlying disease trigger and symptomatic treatment of pruritus, using topical steroids, antipruritic emollients, keratolytics (salicylic acid, urea), or oral antihistamines.⁵ Phototherapy (typically NB-UVB) can also treat pruritus and reduce skin disease.⁵ The lesions often heal with post-inflammatory pigmentary changes or atrophic scars.^2,5

Incorrect stains in answer choices:⁶

Toluidine blue (choice A) – mast cells and mucin

Colloidal iron (choice C) – acid mucopolysaccharides (mucin)

Congo red (choice D) – amyloid

Von Kossa (choice E) – calcium salts

 

References

1. Rapini RP. Chapter 96 – Perforating Diseases. In: Dermatology. Fourth. Elsevier.
2. Wagner G, Sachse MM. Acquired reactive perforating dermatosis. J Dtsch Dermatol Ges. 2013;11(8):723-729, 723-730. doi:10.1111/ddg.12131
3. Rubio FA, Herranz P, Robayna G, Peña JM, Contreras F, Casado M. Perforating folliculitis: report of a case in an HIV-infected man. J Am Acad Dermatol. 1999;40(2 Pt 2):300-302. doi:10.1016/s0190-9622(99)70470-6
4. Bank DE, Cohen PR, Kohn SR. Reactive perforating collagenosis in a setting of double disaster: acquired immunodeficiency syndrome and end-stage renal disease. J Am Acad Dermatol. 1989;21(2 Pt 2):371-374. doi:10.1016/s0190-9622(89)80037-4
5. Lukács J, Schliemann S, Elsner P. Treatment of acquired reactive perforating dermatosis – a systematic review. J Dtsch Dermatol Ges. 2018;16(7):825-842. doi:10.1111/ddg.13561
6. Ferringer T, Ko CJ. Chapter 1 – The basics. In: Dermatopathology. Third. Elsevier.