Case 4 -

Extranodal NK/T-cell Lymphoma, Nasal Type Primarily Involving the Skin and Lymph Nodes Leticia M. Quintanilla-Fend Eberhard Karls University of Tubingen Tubingen, Germany

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Clinical History: A 31 year-old Mexican woman presented with a hyperpigmented, firm, approximately 2 cm, painful lesion on the upper left thigh and inguinal lymphadenopathy on the same side. Biopsies of the skin and inguinal lymph node were taken. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 Skin lesion. The lymphoid infiltrate involves the epidermis, dermis and subcutaneous tissue. Case 4 - Figure 2 Skin lesion. At higher magnification the lymphomatous infiltrate has an angiocentric angiodestructive quality with extensive coagulative necrosis of the subcutaneous tissue. Case 4 - Figure 3 Subcutaneous tissue. Cytologically, the tumor is composed predominantly of medium-sized cells admixed with some pleomorphic large cells. Focally the neoplastic cells surround the fat cells. Case 4 - Figure 4 Skin lesion. The tumor cells are strongly positive for CD3 Case 4 - Figure 5 Subcutaneous tissue. Immunohistochemical staining for CD56 highlights the rimming of individual fat spaces by tumor cells. Case 4 - Figure 6 The neoplastic cells are strongly positive for granzyme B Case 4 - Figure 7 The neoplastic cells are strongly positive for TIA-1 Case 4 - Figure 8 In situ hybridization for EBV-encoded RNA (EBER) is positive in practically all neoplastic cells. Pathologic Features: Microscopically, the skin showed a lymphoid infiltrate involving mainly the dermis and the subcutaneous tissue. The lymphoid infiltrate had angiocentric, angiodestructive quality with extensive coagulative necrosis of the subcutaneous tissue. The tumor was composed predominantly of medium-sized cells admixed with large, pleomorphic cells. Focally there was rimming of individual fat spaces by tumor cells. The lymph node biopsy showed complete effacement of the architecture by a diffuse infiltration of mainly large lymphoid cells with open chromatin and prominent nucleolus with a high mitotic rate. Coagulative necrosis was prominent. Immunohistochemical analysis revealed that the neoplastic cells were positive for CD3, CD56, TIA-1, and granzyme B, and negative for CD4, CD8, and CD5. In situ hybridization for EBV encoded RNA (EBER) was positive in the majority of the tumor cells. Diagnosis: Extranodal NK/T-cell lymphoma, nasal type primarily involving the skin and lymph nodes. Clinical Follow-up: The patient refused treatment and was lost to follow-up. Seven months later she returned to the hospital complaining of epistaxis and periorbital edema, malaise, fever and 10 kg weight loss. A CT scan of the face revealed a tumor in the nasal cavity extending upwards to the right orbit, resulting in proptosis and downwards into the pharyngeal region. Additionally, there was hepatosplenomegaly and renal involvement by the tumor. The BM and the peripheral blood were free of disease. Differential diagnosis: The differential diagnosis includes all neoplasms expressing T and NK-cell markers with frequent cutaneous involvement. In this case, the presence of panniculitis-like changes with focal rimming of individual fat spaces by CD3+ tumor cells raises the possibility of a subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Although in SPTCL, vascular invasion may be seen with necrosis and karyorrhexis, the extensive involvement of the dermis and the expression of CD56 make this diagnosis unlikely. SPTCL is a cytotoxic T-cell lymphoma characterized by tumor cells expressing CD3, CD8 and cytotoxic molecules, but lacking CD56 expression. The neoplastic cells in SPTCL show rearrangement of T-cell receptor genes, and are negative for EBV. CD56 positive hematological neoplasias involving the skin and subcutaneous tissue include, 1) primary cutaneous γδ T-cell lymphoma, 2) blastic plasmacytoid dendritic cell neoplasm, rarely 3) acute myeloid leukemia, and 4) extranodal NK/T-cell lymphoma, nasal type: 1) Primary cutaneous γδ T-cell lymphoma (TCL) can present morphologically and immunophenotypically very similar to this case. Due to the extensive involvement of the subcutaneous tissue, as well as the dermis and epidermis, these cases previously known as SPTL with a gamma/delta phenotype are now classified, in the new WHO classification of tumors of hematopoietic and lymphoid tissues, as part of the cutaneous peripheral T-cell lymphomas. The neoplastic cells in primary cutaneous γδ TCL are generally medium to large in size with clumpy chromatin and inconspicuous nucleoli. Angioinvasion is often observed accompanied by apoptosis and necrosis. A hemophagocytic syndrome commonly occurs. The tumor cells show a mature activated g/d cytotoxic T-cell phenotype with CD3+CD2+CD56+ and are negative for b F1, CD4 and usually CD8. The most important distinguishing features are that the neoplastic cells show clonal rearrangement of TCRg and TCRd genes and that EBV is negative. 2) The blastic plasmacytoid dendritic cell neoplasm (BPDC), previously known as blastic NK cell lymphoma, is a rare hematologic neoplasm with a predilection for the skin, followed by bone marrow and peripheral blood. In contrast to this case, BPDC is characterized by a diffuse monomorphous infiltrate of medium-sized blast cells with fine chromatin and irregular nuclei. The cutaneous infiltrate is predominantly in the dermis sparing the epidermis, but eventually extending to the subcutaneous fat. Angioinvasion and coagulative necrosis are absent. Tumor cells express CD4, CD43, CD56, TCL1 and CD123. TdT is positive in a third of the cases. CD3, CD8 and EBV are negative. 3) Skin infiltration of CD56+ AML might be the first manifestation of an AML, usually of the myelomonocytic type, or present with concurrent bone marrow, lymph node and blood involvement. The tumor cells are usually monomorphous medium to large-size with round nuclei and fine, blastic, diffuse chromatin. The infiltrate is located mainly in the middle and deep dermis, and like in BPDC, angioinvasion and coagulative necrosis are absent. Although the tumor cells are CD56+, they also express one or several myelomonocytic markers (CD43, CD33, CD68 and MPO). CD3, CD30, TIA-1 and EBV are negative. In this submitted case, the morphological features (angioinvasion, angiodestruction and coagulative necrosis) together with CD56 and EBER positivity are rather characteristic of extranodal NK/T-cell lymphoma. Extranodal NK/T-cell lymphoma, nasal type is more common in Asia, and in the Native American population of Mexico, Central and South America. Although it occurs predominantly in the upper aerodigestive tract, extranasal involvement is not infrequent. Preferential sites of extranasal involvement include the skin, gastrointestinal tract, soft tissue and testis. Rarely, these cases are accompanied by secondary lymph node involvement, as was present in this case. The skin is the second most common site of involvement and may be a primary or secondary manifestation of the disease. Patients present with multiple plaques or tumors preferentially on the trunk and extremities; ulceration is common. The presentation as a unique tumor lesion with lymph node involvement is rather unusual. Systemic symptoms like fever, malaise and weight loss may be present, sometimes complicated by a hemophagocytic syndrome. Extranodal NK/T-cell lymphoma occurring outside the nasal cavity is highly aggressive, with short survival times. Skin disease often pursues a rapidly progressive course and additional sites of disease appear rapidly within weeks to months, as seen in this case. Response to multi-agent chemotherapy is often poor and the median survival is 3.5 months (1 week to 3 years). Morphologically, the neoplastic cells infiltrate preferentially the dermis and often the subcutaneous tissue, although epidermotropism may occur. The cytological spectrum is very broad, but in most cases the lymphoma is composed either of medium-sized cells or a mixture of small and large cells. An angiocentric and angiodestructive growth pattern is usually present. Coagulative necrosis and apoptotic bodies are very common findings and a clue to the diagnosis. By definition, the neoplastic cells show CD56 expression and cytoplasmic CD3e with negative surface CD3, although in rare cases, CD56 might be weak or even negative. EBER is positive virtually in every neoplastic cell, and is a prerequisite for the diagnosis. LMP1 is often negative. Cytotoxic molecules (granzyme B, perforin and TIA-1) are positive. Other T- and NK-cell markers such as CD4, CD5, CD2, CD16, CD57, CD43, CD45RO, TCR d and bF1 are negative. Occasional cases are positive for CD8, CD7 or CD30. An interesting feature in this case is that even though the disease was left to its natural course, and the patient had systemic disease, there was no involvement of the BM and/or PB. It has been proposed that aggressive NK/T-cell leukemia, a CD56+EBV+ neoplasia, represents the leukemic manifestation or advanced stage of extranodal NK/T-cell lymphoma, however, there are several distinguishing features: 1) aggressive NK/T-cell leukemia, in contrast to extranodal NK/T cell lymphoma, occurs rarely in Mexico and central America and is prevalent only in Asia, 2) the age of presentation is more than a decade younger, 3) high frequency of peripheral blood, bone marrow and hepatosplenic involvement, 4) frequent expression of CD16, and 5) lymphadenopathy and skin lesions are very uncommon in aggressive NK/T-cell leukemia. Take Home Points Dermal and subcutaneous lymphomatous infiltration can be caused by a variety of primary cutaneous or systemic T-cell and NK-cell lymphomas. Complete immunophenotype including CD56 and EBV is mandatory for all cases with a TIA-1 and/or granzyme B positive cytotoxic phenotype. Angiocentricity with extensive coagulative necrosis is a helpful morphologic feature in the differential diagnosis. In contrast to other skin lymphomas, the neoplastic infiltrate might involve the epidermis, dermis and the subcutaneous tissue. References: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. (Eds.): WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. IARC: Lyon 2008 (4th Edition) Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al., WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105:3768-3785 Chan JKC, Sin VC, Wong KF, Ng CS, Tsang WYW, Chan CH, Cheung MMC, Lau WH. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood 1997; 89:4501-4513 Assaf C, Gellrich S, Whittaker S, Robson A, Cerroni L, Massone C, et al. CD56-positive haematologic neoplasms of the skin: a multicenter study of the cutaneous lymphoma project group of the European Organization for Research and treatment of Cancer. J Clin Pathol 2007; 60:981-989 Stokkermans-Dubois J, Jouary T, Vergier B, Delaunay MM, Taieb A. A case of primary cutaneous nasal type NK/T-cell lymphoma and a review of the literature. Dermatology 2006;213:345-349 Willemze R, Jansen PM, Cerroni L, Berti E, Santucci M, Assaf C, et al. Subcutaneous panniculitis-like T-cell lymphoma: definition, classification and prognostic factors. An EORTC Cutaneous Lymphoma Group study of 83 cases. Blood 2007;111:838-845