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Rapidly Enlarging Nodular Plaque on the Leg

Rapidly Enlarging Nodular Plaque on the Leg Case A white man in his 60s was referred to our dermatology clinic for rapidly enlarging lesions on his calf, thigh, and cheek. Three months prior, he had noticed a small nodule on his calf, with no overlying skin changes or tenderness. This progressed to a tender, nodular plaque while other lesions appeared. The patient denied other signs or symptoms. His medical history included Parkinson disease, for which he took no medication. Laboratory findings showed an elevated lactate dehydrogenase (LDH) level at 439 U/L (reference range, 118-242 U/L) (to convert LDH to microkatals per liter, multiply by 0.0167). Results from serum chemical analyses, complete blood cell count, and tests of liver functions were normal. Physical examination revealed a healthy-appearing man with a 4.0 × 4.0-cm pink, firm, tender nodular plaque on his left calf (Figure, A), a 5.0-cm firm, subcutaneous mass on his right thigh, and a 0.5 × 0.5-cm subcutaneous nodule on his left cheek. There was no cervical, axillary, or inguinal lymphadenopathy. A punch biopsy specimen was obtained from each lesion (Figure, B and C). Figure. View LargeDownload A, Clinical photograph of the nodular plaque on the left lateral calf. B and C, Histopathologic images from the punch biopsy specimen demonstrating angiocentrism. B, The large atypical lymphoid cells can be seen infiltrating a vessel (outlined by arrowheads) (hematoxylin-eosin, original magnification ×400). C, Histopathologic image from the punch biopsy specimen showing positive EBER in situ hybridization. The atypical lymphocytic infiltrate is strongly positive for EBV, as shown by EBV-encoded RNA in situ hybridization (original magnification ×600). Read the Discussion. Box Section Ref ID What Is the Diagnosis? Cutaneous anaplastic large cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Blastomycosis Subcutaneous panniculitis-like T-cell lymphoma Discussion Diagnosis B. Extranodal NK/T-cell lymphoma, nasal type Microscopic Findings and Clinical Course Histopathologic examination demonstrated a dense diffuse infiltrate in the dermis and panniculus composed of large atypical lymphoid cells with vesicular chromatin, conspicuous nucleolus, and variable cytoplasm. Frequent mitoses and apoptosis were noted. Infiltration of blood vessel walls by atypical lymphocytes and geographic areas of necrosis were observed. The immunophenotype was CD2+, CD3+, CD5−, CD7−, CD4−/+, CD8−, CD30−, CD56−, TIA1+, and ALK1−. The infiltrate was strongly EBV positive (Figure 1C) (EBER in situ hybridization). The Ki-67 proliferation index was 95%. Polymerase chain reaction was positive for clonal γ T-cell receptor gene rearrangement. This process consists of a cytotoxic T-cell infiltrate with EBV expression and angiocentrism. Positron emission tomographic–computed tomographic (PET-CT) imaging from skull base to mid-thigh found high-grade hypermetabolic activity in the left cheek nodule and inguinal lymph nodes with intermediate activity in other draining lymph nodes and within several muscle groups. Results from peripheral blood T-cell receptorgene rearrangement and flow cytometry were normal. The patient was diagnosed as having extranodal NK/T-cell lymphoma, nasal type (ENKTL) and referred to the hematology-oncology service for further workup. A bone marrow biopsy found no abnormalities. The patient began EPOCH chemotherapy (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), which was well tolerated with clinical remission achieved after 2 cycles. After 4 cycles, PET-CT imaging showed new hypermetabolic areas in the lung, and patient was switched to treatment with methotrexate, dexamethasone, ifosfamide, etoposide, and L-asparaginase (SMILE) for 2 cycles. Complete clinical and radiologic remission was achieved, and patient recently underwent autologous stem cell transplant. Extranodal NK/T-cell lymphoma, nasal type, is an aggressive, primarily extranodal lymphoma of NK-cell or, rarely, cytotoxic T-cell origin.1 Most primary lesions are in the nasal cavity and nasopharynx. These patients present with sinonasal symptoms, including nasal obstruction or facial swelling, or with destructive midfacial tumors, previously known as lethal midline granuloma.1,2 The primary extranasal sites of involvement are also the preferential locations for metastasis of primary nasal disease: skin, intestine, testis, lung, and soft tissue.1,3 Patients with skin involvement most frequently present with multiple lesions on the trunk or extremities, although solitary lesions and lesions on the head and neck have been reported.4,5 Cutaneous ENKTL most commonly appears as subcutaneous nodules with overlying erythema, erythematous papules, or ulcerative lesions.5,6 On histologic examination, the diffuse lymphomatous infiltrate of ENKTL is typically characterized by angiocentricity, angiodestruction, coagulative necrosis, and ulceration. Lymphoma cells are infected by Epstein-Barr virus (EBV), best demonstrated by in situ hybridization for EBV-encoded RNA (EBER-ISH); therefore, EBER-ISH is critical when considering ENKTL. Immunohistochemical analysis is also essential for diagnosis. The most common immunophenotype is CD2+, CD56+, surface CD3−, and cytoplasmic CD3ε+ (surface and cytoplasmic CD3 proteins are distinguishable only on fresh or frozen tissue). However, the presence of NK-cell marker CD56 is neither specific nor required for diagnosis of ENKTL. Lymphomas that are CD56− and CD3ε+ are classified as ENKTL if they are also positive for both EBV and cytotoxic molecules (eg, TIA1, granzyme B, perforin). TCR genes are generally in germline configuration but may show clonal rearrangement.1 Prognosis is poor but variable, with a 23.5% 5-year overall survival for patients with cutaneous ENKTL in 1 case series.6 Treatment with SMILE has recently become the preferred chemotherapeutic regimen because these agents are not affected by the abundant NK-cell expression of multidrug resistance protein 1, which confers resistance to many other chemotherapeutic agents, including anthracyclines.7,8 Hematopoietic stem cell transplant may improve outcome if performed during complete remission.7 Back to top Article Information Corresponding Author: Jaehyuk Choi, MD, PhD, Department of Dermatology, Yale University School of Medicine, PO Box 208059, New Haven, CT 06520-8059 (jaehyuk.choi@yale.edu). Published Online: August 13, 2014. doi:10.1001/jamadermatol.2014.1045. Conflict of Interest Disclosures: None reported. Section Editor: Molly A. Hinshaw, MD; Assistant Section Editors: Soon Bahrami, MD; Nicole Fett, MD, MSCE; Anna K. Haemel, MD; Arni K. Kristjansson, MD; Lori D. Prok, MD. References 1. Chan JK, Quintanilla-Martinez L, Ferry JA, Peh SC. Extranodal NK/T-cell lymphoma, nasal type. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.4th ed. Lyon, France: International Agency for Research on Cancer; 2008:285-288. 2. Li S, Feng X, Li T, et al. Extranodal NK/T-cell lymphoma, nasal type. Am J Surg Pathol. 2013;37(1):14-23.PubMedGoogle ScholarCrossref 3. Au WY, Weisenburger DD, Intragumtornchai T, et al; International Peripheral T-Cell Lymphoma Project. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma. Blood. 2009;113(17):3931-3937.PubMedGoogle ScholarCrossref 4. Mraz-Gernhard S, Natkunam Y, Hoppe RT, LeBoit P, Kohler S, Kim YH. Natural killer/natural killer-like T-cell lymphoma, CD56+, presenting in the skin. J Clin Oncol. 2001;19(8):2179-2188.PubMedGoogle Scholar 5. Wang TT, Xu C, Liu SL, et al. Clinicopathology, immunophenotype, T-cell receptor gene rearrangement, Epstein-Barr virus status, and p53 gene mutation of cutaneous extranodal NK/T-cell lymphoma, nasal-type. Chin Med J (Engl). 2013;126(7):1281-1287.PubMedGoogle Scholar 6. Ahn HK, Suh C, Chuang SS, et al. Extranodal natural killer/T-cell lymphoma from skin or soft tissue. Ann Oncol. 2012;23(10):2703-2707.PubMedGoogle ScholarCrossref 7. Tse E, Kwong YL. How I treat NK/T-cell lymphomas. Blood. 2013;121(25):4997-5005.PubMedGoogle ScholarCrossref 8. Kwong YL, Kim WS, Lim ST, et al. SMILE for natural killer/T-cell lymphoma. Blood. 2012;120(15):2973-2980.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Dermatology American Medical Association

Rapidly Enlarging Nodular Plaque on the Leg

Little, Alicia J.; Subtil, Antonio; Choi, Jaehyuk
JAMA Dermatology , Volume 150 (10) – Oct 1, 2014
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Publisher
American Medical Association
Copyright
Copyright © 2014 American Medical Association. All Rights Reserved.
ISSN
2168-6068
eISSN
2168-6084
DOI
10.1001/jamadermatol.2014.1045
pmid
25133474
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Abstract

Case A white man in his 60s was referred to our dermatology clinic for rapidly enlarging lesions on his calf, thigh, and cheek. Three months prior, he had noticed a small nodule on his calf, with no overlying skin changes or tenderness. This progressed to a tender, nodular plaque while other lesions appeared. The patient denied other signs or symptoms. His medical history included Parkinson disease, for which he took no medication. Laboratory findings showed an elevated lactate dehydrogenase (LDH) level at 439 U/L (reference range, 118-242 U/L) (to convert LDH to microkatals per liter, multiply by 0.0167). Results from serum chemical analyses, complete blood cell count, and tests of liver functions were normal. Physical examination revealed a healthy-appearing man with a 4.0 × 4.0-cm pink, firm, tender nodular plaque on his left calf (Figure, A), a 5.0-cm firm, subcutaneous mass on his right thigh, and a 0.5 × 0.5-cm subcutaneous nodule on his left cheek. There was no cervical, axillary, or inguinal lymphadenopathy. A punch biopsy specimen was obtained from each lesion (Figure, B and C). Figure. View LargeDownload A, Clinical photograph of the nodular plaque on the left lateral calf. B and C, Histopathologic images from the punch biopsy specimen demonstrating angiocentrism. B, The large atypical lymphoid cells can be seen infiltrating a vessel (outlined by arrowheads) (hematoxylin-eosin, original magnification ×400). C, Histopathologic image from the punch biopsy specimen showing positive EBER in situ hybridization. The atypical lymphocytic infiltrate is strongly positive for EBV, as shown by EBV-encoded RNA in situ hybridization (original magnification ×600). Read the Discussion. Box Section Ref ID What Is the Diagnosis? Cutaneous anaplastic large cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Blastomycosis Subcutaneous panniculitis-like T-cell lymphoma Discussion Diagnosis B. Extranodal NK/T-cell lymphoma, nasal type Microscopic Findings and Clinical Course Histopathologic examination demonstrated a dense diffuse infiltrate in the dermis and panniculus composed of large atypical lymphoid cells with vesicular chromatin, conspicuous nucleolus, and variable cytoplasm. Frequent mitoses and apoptosis were noted. Infiltration of blood vessel walls by atypical lymphocytes and geographic areas of necrosis were observed. The immunophenotype was CD2+, CD3+, CD5−, CD7−, CD4−/+, CD8−, CD30−, CD56−, TIA1+, and ALK1−. The infiltrate was strongly EBV positive (Figure 1C) (EBER in situ hybridization). The Ki-67 proliferation index was 95%. Polymerase chain reaction was positive for clonal γ T-cell receptor gene rearrangement. This process consists of a cytotoxic T-cell infiltrate with EBV expression and angiocentrism. Positron emission tomographic–computed tomographic (PET-CT) imaging from skull base to mid-thigh found high-grade hypermetabolic activity in the left cheek nodule and inguinal lymph nodes with intermediate activity in other draining lymph nodes and within several muscle groups. Results from peripheral blood T-cell receptorgene rearrangement and flow cytometry were normal. The patient was diagnosed as having extranodal NK/T-cell lymphoma, nasal type (ENKTL) and referred to the hematology-oncology service for further workup. A bone marrow biopsy found no abnormalities. The patient began EPOCH chemotherapy (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), which was well tolerated with clinical remission achieved after 2 cycles. After 4 cycles, PET-CT imaging showed new hypermetabolic areas in the lung, and patient was switched to treatment with methotrexate, dexamethasone, ifosfamide, etoposide, and L-asparaginase (SMILE) for 2 cycles. Complete clinical and radiologic remission was achieved, and patient recently underwent autologous stem cell transplant. Extranodal NK/T-cell lymphoma, nasal type, is an aggressive, primarily extranodal lymphoma of NK-cell or, rarely, cytotoxic T-cell origin.1 Most primary lesions are in the nasal cavity and nasopharynx. These patients present with sinonasal symptoms, including nasal obstruction or facial swelling, or with destructive midfacial tumors, previously known as lethal midline granuloma.1,2 The primary extranasal sites of involvement are also the preferential locations for metastasis of primary nasal disease: skin, intestine, testis, lung, and soft tissue.1,3 Patients with skin involvement most frequently present with multiple lesions on the trunk or extremities, although solitary lesions and lesions on the head and neck have been reported.4,5 Cutaneous ENKTL most commonly appears as subcutaneous nodules with overlying erythema, erythematous papules, or ulcerative lesions.5,6 On histologic examination, the diffuse lymphomatous infiltrate of ENKTL is typically characterized by angiocentricity, angiodestruction, coagulative necrosis, and ulceration. Lymphoma cells are infected by Epstein-Barr virus (EBV), best demonstrated by in situ hybridization for EBV-encoded RNA (EBER-ISH); therefore, EBER-ISH is critical when considering ENKTL. Immunohistochemical analysis is also essential for diagnosis. The most common immunophenotype is CD2+, CD56+, surface CD3−, and cytoplasmic CD3ε+ (surface and cytoplasmic CD3 proteins are distinguishable only on fresh or frozen tissue). However, the presence of NK-cell marker CD56 is neither specific nor required for diagnosis of ENKTL. Lymphomas that are CD56− and CD3ε+ are classified as ENKTL if they are also positive for both EBV and cytotoxic molecules (eg, TIA1, granzyme B, perforin). TCR genes are generally in germline configuration but may show clonal rearrangement.1 Prognosis is poor but variable, with a 23.5% 5-year overall survival for patients with cutaneous ENKTL in 1 case series.6 Treatment with SMILE has recently become the preferred chemotherapeutic regimen because these agents are not affected by the abundant NK-cell expression of multidrug resistance protein 1, which confers resistance to many other chemotherapeutic agents, including anthracyclines.7,8 Hematopoietic stem cell transplant may improve outcome if performed during complete remission.7 Back to top Article Information Corresponding Author: Jaehyuk Choi, MD, PhD, Department of Dermatology, Yale University School of Medicine, PO Box 208059, New Haven, CT 06520-8059 (jaehyuk.choi@yale.edu). Published Online: August 13, 2014. doi:10.1001/jamadermatol.2014.1045. Conflict of Interest Disclosures: None reported. Section Editor: Molly A. Hinshaw, MD; Assistant Section Editors: Soon Bahrami, MD; Nicole Fett, MD, MSCE; Anna K. Haemel, MD; Arni K. Kristjansson, MD; Lori D. Prok, MD. References 1. Chan JK, Quintanilla-Martinez L, Ferry JA, Peh SC. Extranodal NK/T-cell lymphoma, nasal type. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.4th ed. Lyon, France: International Agency for Research on Cancer; 2008:285-288. 2. Li S, Feng X, Li T, et al. Extranodal NK/T-cell lymphoma, nasal type. Am J Surg Pathol. 2013;37(1):14-23.PubMedGoogle ScholarCrossref 3. Au WY, Weisenburger DD, Intragumtornchai T, et al; International Peripheral T-Cell Lymphoma Project. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma. Blood. 2009;113(17):3931-3937.PubMedGoogle ScholarCrossref 4. Mraz-Gernhard S, Natkunam Y, Hoppe RT, LeBoit P, Kohler S, Kim YH. Natural killer/natural killer-like T-cell lymphoma, CD56+, presenting in the skin. J Clin Oncol. 2001;19(8):2179-2188.PubMedGoogle Scholar 5. Wang TT, Xu C, Liu SL, et al. Clinicopathology, immunophenotype, T-cell receptor gene rearrangement, Epstein-Barr virus status, and p53 gene mutation of cutaneous extranodal NK/T-cell lymphoma, nasal-type. Chin Med J (Engl). 2013;126(7):1281-1287.PubMedGoogle Scholar 6. Ahn HK, Suh C, Chuang SS, et al. Extranodal natural killer/T-cell lymphoma from skin or soft tissue. Ann Oncol. 2012;23(10):2703-2707.PubMedGoogle ScholarCrossref 7. Tse E, Kwong YL. How I treat NK/T-cell lymphomas. Blood. 2013;121(25):4997-5005.PubMedGoogle ScholarCrossref 8. Kwong YL, Kim WS, Lim ST, et al. SMILE for natural killer/T-cell lymphoma. Blood. 2012;120(15):2973-2980.PubMedGoogle ScholarCrossref

Journal

JAMA Dermatology – American Medical Association

Published: Oct 1, 2014

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