Pathology – Research and Practice 210 (2014) 127–129

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Teaching Case

Composite ALK-negative anaplastic large cell lymphoma and small lymphocytic lymphoma involving the right inguinal lymph node Paul Persad, Changlee S. Pang ∗ Department of Pathology, Wake Forest University Baptist Medical Center, USA

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Article history: Received 9 July 2013 Received in revised form 13 August 2013 Accepted 18 September 2013 Keywords: Composite lymphoma ALK-negative anaplastic large cell lymphoma Small lymphocytic lymphoma Chronic lymphocytic leukemia

a b s t r a c t Anaplastic large cell lymphoma and small lymphocytic lymphoma are two lymphoid malignancies with completely distinct morphologies and natural histories. We present a rare case of composite anaplastic large cell lymphoma and small lymphocytic lymphoma in an inguinal lymph node of an otherwise healthy 47-year-old male patient. Immunohistochemical and molecular studies identified the two populations clearly. Their separation is imperative as anaplastic large cell lymphoma can be an aggressive neoplasm and easily overlooked in cases of small lymphocytic lymphoma with a small population of anaplastic large cell lymphoma cells. © 2013 Elsevier GmbH. All rights reserved.

Introduction Composite lymphomas (CL) are rare phenomena defined as two distinct tumor clones occurring concurrently or sequentially at a single site [1]. Anaplastic large cell lymphoma (ALCL) is a neoplasm of T or null cells characterized by sheets of bizarre lymphocytes with ample cytoplasm and pleomorphic nuclei, including horseshoe shapes (so-called hallmark cells) [2]. CD30 is consistently expressed in a membranous and perinuclear (Golgi complex) pattern [3]. Two categories of ALCL have been described depending on the presence or absence of anaplastic lymphoma kinase (ALK) expression, a 200-kDa transmembrane receptor similar to leukocyte tyrosine kinase [4]. ALK-positive ALCL neoplasms often demonstrate the 2;5 translocation, which results in a 80-kDa fusion protein termed NPM-ALK. Homodimers of this chimeric protein are felt to activate the ALK catalytic domain, resulting in increased mitotic activity and eventual neoplasia [4]. While ALK-positive ALCL is well characterized histologically and immunophenotypically, ALK-negative ALCL is a less well understood, more heterogeneous entity that requires careful morphologic and phenotypic examination to distinguish from Hodgkin lymphoma or peripheral T-cell lymphoma, not otherwise specified [5,6].

∗ Corresponding author at: Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston Salem, NC 27157, USA. Tel.: +1 336 716 2650; fax: +1 336 716 7595. E-mail address: [email protected] (C.S. Pang). 0344-0338/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.prp.2013.09.006

We present an extremely rare case of a composite ALK-negative anaplastic large cell lymphoma and small lymphocytic lymphoma occurring in the inguinal lymph nodes.

Case report A 47-year-old white male presented for bilateral groin swelling for over a year and half. The patient had initially presented with this complaint at a walk in clinic but was not given a definitive diagnosis. The patient presented again several months later because of failure of the swelling to abate. He had noted night sweats but denied fever or weight loss. CT scan imaging revealed multiple inguinal lymph nodes, with the largest measuring 2.4 cm × 1.7 cm. A right inguinal lymph node biopsy was performed at an outside institution and reviewed by the authors at consultation. The lymph node demonstrated a prominent dual population. The lesion was predominantly involved by a diffuse proliferation of monomorphic small lymphocytes, and focally surrounded by a minor population of large atypical lymphocytes. Bilateral bone marrow core biopsies showed a normocellular marrow with atypical interstitial and paratrabecular lymphoid aggregates. A peripheral blood smear was not available for review; however, reported CBC data indicated no absolute lymphocytosis. The hematoxylin and eosin (H and E) sections of the right inguinal lymph node demonstrated diffuse effacement of nodal architecture by small to medium sized atypical lymphocytes with clumped chromatin, inconspicuous nuclei and round nuclear contours. At the periphery of this small lymphocytic proliferation, there was a thin rim of cohesive large pleomorphic cells with prominent

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P. Persad, C.S. Pang / Pathology – Research and Practice 210 (2014) 127–129

Fig. 1. (a) H&E, diffuse proliferation of SLL (right upper) with peripheral rim of ALK-negative ALCL (left). Inlet shows clusters of large pleomorphic lymphocytes with atypical mitotic figure. (b) Strong and uniform expression of CD30 in ALCL; (c) Ki-67 indicates High proliferation rate in ALCL; (d) variable expression of granzyme B in ALCL; (e) CD20 highlights predominant involvement by SLL; (f) aberrant coexpression of CD5 in SLL.

nucleoli and multinucleation. Hallmark cells as well as increased mitotic figures were identified (Fig. 1a). The large pleomorphic lymphocytes comprised less than 5% of all tumor cells. Bilateral bone marrow biopsies demonstrated atypical intersitial and paratrabecular lymphoid aggregates composed of monomorphic small lymphocytes, consistent with chronic lymphocytic leukemia (CLL). No large anaplastic lymphocytes or Hallmark cells were observed in the bone marrow. Immunohistochemical studies (Fig. 1b–f) revealed small atypical lymphocytes positive for CD20 and PAX5 with coexpression of CD5, CD43, and BCL-2. They were negative for CD10 and cyclin D1. Ki-67 showed 10–20% proliferation. The findings were diagnostic of small lymphocytic lymphoma (SLL). The large atypical lymphocytes were positive for CD30 (strong, uniform), granzyme B, BCL-2 (weak), and CD43 with aberrant expression of CD23. CD2, CD4, and CD45 showed variable focal weak staining. They were negative for CD3, CD5, CD7, CD8, ALK, EBER, beta F1, CD56, CD57, CD10, CD15, CD20, PAX5, and cytokeratin AE1/AE3. Ki-67 staining revealed a high proliferation index (Fig. 1c). These findings were consistent with an ALK-negative anaplastic large cell lymphoma. Flow cytometric analysis of the lymph node performed at an outside institution detected a lambda light chain restricted B cell population that expressed CD19, CD20 (dim), CD5, CD23, and HLADR without expression of CD10, CD38, and FMC7. A minor subset of events reportedly expressed CD4 and CD38 with increased cell size, which is presumably ALCL population. Flow cytometric analysis of the bone marrow material revealed a monoclonal B-cell

Fig. 2. (a) Lane A, molecular weight (ladder); Lane B, SLL, patient sample; Lane C, polyclonal control; Lane D, positive control; and (b) Lane E, ALCL, patient sample; Lane F, negative control; Lane G, positive control; Lane H, molecular weight (ladder).

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population with the same phenotype. No aberrant CD30-positive events were reportedly detected. Fluorescent in situ hybridization (FISH) revealed no abnormalities at loci examined on chromosomes 6, 11, 12, 13, and 17 (Fig. 2). Polymerase chain reaction (PCR)-based IG heavy chain gene (IGH) and T cell receptor (TCR) gene rearrangement analyses were attempted on extracted DNA of the lymph node biopsy material. Macrodissection of the CD30-positive, ALK-negative ALCL and CD20-positive SLL was performed. Clonal gene rearrangement of the IGH chain was detected only in the SLL not in the ALCL tumor cells. TCR gene rearrangement showed negative findings in both neoplasms. The patient had received four cycles of R-EPOCH (Rituximab, Etoposide, Prednisone, Vincristine, Doxorubicin, and Cyclophosphamide) with subsequent autologous stem cell transplant. He is currently in complete remission. Discussion Composite lymphomas, defined as two distinct clonal populations of lymphoid cells occurring at the same site, are being increasingly detected due to the wide spread use of molecular characterization methods. The pathogenic mechanism is uncertain; proposed theories include clonal selection, genomic instability, and immature precursor cells developing along separate pathways [7]. Reported combinations include: B-cell/T-cell lymphomas, multiple B-cell lymphomas, Non-Hodgkin lymphoma (NHL)/Hodgkin lymphoma (HL), and T-cell lymphoma/HL. Our case demonstrates an extremely rare composite lymphoma of ALK-negative anaplastic large cell lymphoma (ALCL) and small lymphocytic lymphoma (SLL). ALCL is an aggressive T cell neoplasm characterized by pleomorphic nuclei, abundant cytoplasm, and uniform expression of CD30. Morphologic variants include: common, lymphohistiocytic, small cell, Hodgkin-like and giant cell rich. This disorder can be grouped further classified by the expression of the anaplastic lymphoma kinase (ALK) protein. ALK-negative cases tend to occur in older individuals with advanced clinical stage and extra-nodal involvement. The differential diagnosis includes Hodgkin’s Lymphoma (HL), diffuse large B cell lymphoma (DLBCL), peripheral T-cell lymphoma, melanoma, and metastatic carcinoma. From the morphological point of view, ALK-negative ALCL can be difficult to be distinguished from classical Hodgkin lymphoma, especially when there are associated features of sclerosis and/or eosinophilia. However, with the complete immunophenotyping and molecular studies, ALK-negative ALCL can be distinguished from classical Hodgkin lymphoma in virtually all cases. PAX5 immunohistochemistry is essential in making these distinctions. In contrast to the characteristically weak nuclear staining of PAX5 in Hodgkin and Reed-Sternberg (HRS) cells in the majority of classical Hodgkin lymphoma cases, PAX5 is consistently negative in ALK-negative ALCL cases. Additionally, HRS cells contain

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clonal immunoglobulin gene rearrangement in more than 98% of cases and clonal T-cell receptor gene rearrangement in rare cases. Whereas the majority of ALK-negative ALCL cases show clonal rearrangement of T-cell receptor genes, whether or not they express T-cell antigens. Small lymphocytic lymphoma (SLL) is an indolent B cell neoplasm of small lymphocytes with bland nuclear features and a wisp of cytoplasm. Immunohistochemically, SLL stains positively for B cell markers, including CD19, CD20, and CD79a with characteristic expression of CD5 and CD23. Our case was remarkable for a diffuse proliferation of small lymphocytes, morphologically and phenotypically consistent with SLL. Notably, the periphery of this neoplasm had a focal thin rim of a second proliferation of large atypical T cells demonstrating characteristic features of ALCL, including horseshoe nuclei (Hallmark cells), uniform staining for CD30 and granzyme B. Additionally, the ALCL cells in this case had aberrant expression of CD23, which has not been described in the literature. Our PCR gene rearrangement studies, however, only revealed the IGH clonality of the SLL population. The search for TCR rearrangements, unfortunately, was unsuccessful in identifying the ALCL cells. This most likely represents a false-negative result due to low numbers of ALCL tumor cells. Nonetheless, the morphologic features and immunohistochemical staining pattern clearly point to ALCL. In summary, we report a rare case of a combination lymphoma composed of SLL and ALK-negative ALCL. When dealing with SLL or other indolent lymphomas, the existence of combination lymphomas should be kept in mind especially when atypical morphologic features are encountered. Conflict of interest The authors declare that they have no conflict of interest. References [1] T.G. Papathomas, I. Venizelos, C.H. Dunphy, J.W. Said, M.L. Wang, E. Campo, S.H. Swerdlow, et al., Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications, Hum. Pathol. 43 (April (4)) (2012) 467–480. [2] A.J. Ferreri, S. Govi, S.A. Pileri, K.J. Savage, Anaplastic large cell lymphoma, ALKpositive, Crit. Rev. Oncol. Hematol. 83 (August (2)) (2012) 293–302. [3] H.M. Amin, R. Lai, Pathobiology of ALK+ anaplastic large cell lymphoma, Blood 110 (October (7)) (2007) 2259–2267. [4] H. Stein, H.D. Foss, H. Durkop, T. Marafioti, G. Delsol, K. Pulford, et al., CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features, Blood 96 (December) (2000) 3681–3695. [5] N.M. Mokhtar, Review article composite lymphoma, J. Egypt Natl. Canc. Inst. 19 (September (3)) (2007) 171–175. [6] L.J. Mederios, K.S.J. Elenitoba-Johnson, Anaplastic large cell lymphoma, Am. J. Clin. Pathol. 127 (May (5)) (2007) 707–722. [7] C. Campidelli, E. Saattini, M. Piccioli, M. Rossi, D. DeBlasi, E. Miragilia, Simultaneous occurrence of peripheral T-cell lymphoma unspecified and B-cell small lymphocytic lymphoma. Report of 2 cases, Hum. Pathol. 38 (May (5)) (2007) 787–792.

Composite ALK-negative anaplastic large cell lymphoma and small lymphocytic lymphoma involving the right inguinal lymph node.

Anaplastic large cell lymphoma and small lymphocytic lymphoma are two lymphoid malignancies with completely distinct morphologies and natural historie...
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