RESEARCH AND PRACTICE
© Gustav Fischer Verlag
Anaplastic Large Cell Lymphoma of the Spleen Gisela A. Nai, Beria Cabello-Inchausti and Saul Suster Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, and the University of Miami School of Medicine, Miami, Florida
Summary A case is presented of CD30+ anaplastic large celllymphoma of the spleen. The patient, a 61 year old woman with a history of chronic lymphocytic leukemia (CLL) was seen for the sudden development of splenomegaly with thrombocytopenia. A splenectomy was performed which showed massive replacement of the spleen by a population of large atypical lymphoid cells showing bizarre nuclear forms and multinucleated tumor cells reminiscent of Reed-Sternberg cells. Immunohistochemical studies showed strong membrane and dot-like paranuclear positivity in the majority of the atypical cells for CD30, with coexpression in many of the cells for CDI5. Additionally, the cells also strongly reacted with CD3, UCHL-l, EMA and LCA. The present case illustrates an unusual variant of anaplastic (CD30+) large cell lymphoma sharing histologic and immunophenotypic features that overlap with those of Hodgkin's disease. The history in this patient of CLL with sudden development of splenomegaly raises the possibility of transformation of CLL into a high-grade lymphoma (Richter's syndrome). The possible pathogenetic implications of this phenomenon are discussed. Key words: Anaplastic (CD30+) large cell lymphoma Hodgkin's disease - Richter's syndrome
Introduction Richter's syndrome is the development of a high grade lymphoma in a patient with preexisting CLL. Although the majority of cases described in the literature have been shown to represent a clonal "progression" of the disease, i.e. loss of differentiation with transformation to a higher grade lymphoma arising from the same clone of CLL cells, several instances have been reportPathol. Res. Pract. 194: 517-522 (1998)
ed in which a heterogeneous or phenotypically unrelated malignancy has supervened against the background ofCLL. Herein we describe a case of anaplastic (CD30+) large cell lymphoma of the spleen arising in a patient with CLL. The possible relationship of this unusual variant of malignant lymphoma with the CLL is discussed.
Case Report A 61-year-old woman was seen on December 1995 for the development of left abdominal fullness and weakness. She had a history of CLL diagnosed in 1992 which had been treated with several courses of fludarabine. On her current admission, the patient complained of weakness and rectal pain secondary to a rectal fissure. No skin lesions or peripheral lymphadenopathy were noted. A bone marrow aspirate done in May 1995 at another institution showed hypercellularity with lymphocytosis consistent with CLL. Her most recent blood count showed a hemoglobin of 11.1, hematocrit 31, white blood cell count of 10,000, and platelets 45,000. Because of the progressive splenomegaly and thrombocytopenia, she was scheduled for splenectomy. At the time of surgery, the surgeon noted a few enlarged nodes in the abdominal cavity and slight enlargement of the liver. The patient recuperated uneventfully after splenectomy; however, due to her state of weakness it was elected not to administer any further chemotherapy until her condition improved. The patient has been lost to follow-up since.
Address for correspondence: Saul Suster, M.D., Department of Pathology, Mount Sinai Medical Center, 4300 Alten Rd., Miami Beach, FL, USA. E-mail: [email protected]
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Material and Methods Representative tissue sections from the spleen were fixed in neutral-buffered formalin and embedded in paraffin. Tissue sections were stained with hematoxylin and eosin (H&E) for routine microscopy. For immunohistochemical studies, paraffin-embedded tissue sections were incubated with antibodies against kappa light chains (Dako, Carpinteria, CA), lambda (Dako), EMA (Dako), Leu-MI (CDl5) (Beckton-Dickinson, San Jose, CA; I: 10), L26 (CD20) (Dako; I: 100), LCA (Dako; 1:30), UCHL-I (Dako; 1:30), MT-I (CD43) (Clonab, 1:5), CD3 (Dako; 1:50), CD30 (Behr-H2) (Dako; I:30) and KPI (CD68) (Dako; I:50) by the avidin-biotin peroxidase complex (ABC) technique. Tissue sections were incubated with nonimmune mouse and rabbit serum for negative controls. Appropriate positive controls were run concurrently for all antibodies tested.
Pathologic Findings The resected spleen measured 20xl4x9 cm and weighed 1245 gm. The capsule was intact and glistening, and cut section showed a homogeneous red-brown surface without any distinct nodularity. Histologic examination showed disruption of the normal splenic architecture by a diffuse infiltrate predominantly expanding the white pulp (Fig. 1). On higher magnification the infiltrate was characterized by a proliferation of large, atypical lymphoid cells with bizarre nuclei and prominent eosinophilic nucleoli surrounded by abundant cytoplasm resembling pleomorphic Reed-Sternberg cells (Fig. 2). Many of the atypical cells were multinucleated showing an occasional "wreath-like" arrangement of nuclei (Fig. 3A), whereas others showed multilobated nuclei with irregular nuclear contours. The atypical mononuclear cells showed prominent nuclear convolutions and indentations with often large, eosinophilic nucleoli, and were surrounded by a rim of abundant amphophilic cytoplasm (Fig. 3B). Mitoses were numerous, averaging 12 per 10 high power field. Admixed with the atypical cell population there were also many scattered small lymphocytes, plasma cells, neutrophils and eosinophils. Immunohistochemical studies showed strong membrane and dot-like paranuclear cytoplasmic positivity in the majority (>80%) of the large, pleomorphic tumor
Fig. I. Scanning magnification showing replacement of the white pulp by a population of large cells with abundant cytoplasm (H&E, x40). Fig. 2. Higher magnification showing population of large, often multilobated arid multinucleated cells with abundant cytoplasm admixed with scattered small lymphocytes, plasma cells, and eosinophils (H&E, xlOO).
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Fig. 3. A) Higher magnification showing large, multinucleated tumor cell with wreath-like, peripheral arrangement of nuclei (H&E, x4(0); B) Higher magnification showing atypical mononuclear cell with prominent indentation of nuclei ("horseshoe nucleus") surrounded by abundant cytoplasm (H&E, x4(0).
Fig. 4. A) Strong membrane and dot-like paranuclear positivity of large, atypical cells with CD30 antibody (x400); B) Membrane positivity is seen in scattered large, multinucleated, atypical cells with CD1S antibody (x400).
cells with CD30 antibodies (Fig. 4A), and focal strong positivity in a subpopulation of those cells (-30%) with CDl5 (Fig. 4B). The large atypical cells also showed strong membrane positivity with antibodies against LCA, EMA, CD3 and UCHL-l (Fig. 5A, 5C). Stains for kappa, lambda, L26, KPI and MT-l were negative in the large, atypical cells (Fig. 5B). The background small lymphocyte population strongly labeled with LCA and L26 and showed variable staining for kappa and lambda.
Discussion Primary splenic lymphomas are unusual and generally characterized by symptoms of splenomegaly, ab-
sence of lymphoma in extrasplenic sites, and negative liver and mesenteric/paraaortic lymph node biopsies on laparotomy [8, 11). The most common symptoms include left upper quadrant pain, weight loss, fever, and a palpable spleen. There is a predominance in females (male:female ratio 1: 1.7), and the mean age is around 65 years [20, 36). At laparotomy the spleen is generally enlarged, with a mean splenic weight of around 900 g [11, 15, 17,20). On cut section, the spleen often shows multiple nodules with focal areas of hemorrhage and necrosis, but may also present with diffuse involvement of splenic parenchyma without the formation of discrete tumor masses. Nearly all histologic subtypes of malignant lymphoma have been reported arising in the spleen. The
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Fig. 5. A) Strong membrane positivity of large, multinucleated cell with CD45 (LCA) antibody (x400); B) Immunoperoxidase stain for B-cell marker CD20 (L26), showing strong membrane positivity in residual small B-Iymphocytes, and negative staining of the surrounding large atypical cells (x200); C) Immunoperoxidase stain for UCHL-l (T-cell associated marker) showing membrane positivity in large atypical cell (center) and in a few small lymphocytes (x200).
most frequent type in most series, however, has been small lymphocytic lymphoma, followed by diffuse large cell lymphoma [15, 20, 34, 36]. The prognosis of primary splenic lymphoma does not appear to significantly differ from that of nodal-based lymphomas, and will generally depend on the histologic subtype [11, 20, 34, 36]. Some patients, however, have been shown to do well and enjoy long term survival after splenectomy even with the more aggressive subtypes . Anaplastic (CD30+) large cell lymphoma (ALCL) is a relatively new histologic type of lymphoma which is defined by a neoplastic proliferation of large, atypical lymphoid cell displaying anaplastic nuclear morphology and expressing the activation marker CD30 in over 70% of its cells [1, 19J. Many different morphologic types have been described, including monomorphic and pleomorphic types [6J, basophilic cell type [5J, sarcomatoid [4J, and a small cell predominant variant . Such tumors have a predilection for lymph nodes and skin, and can also present in solid organs at extranodal sites, but will rarely show involvement of bone marrow or central nervous system [1, 6, 19, 33]. Splenic involvement by ALCL is a highly unusual location for this particular type of lymphoma. Review of the literature disclosed only two previous instances of splenic ALCL [2, 13J. The first case was described in a 50 year old man with splenomegaly and no other manifestation of disease; the spleen contained a lymphoma that typed as a CD3Q+ ALCL of B-cell type . The second case was described in a 39 year old HIV+ man who presented with left upper quadrant pain, night sweats, and
splenomegaly without lymphadenopathy. The resected spleen weighed 900 g and showed multiple necrotic lesions which were histologically characterized by a proliferation of large, atypical cells with pleomorphic nuclei and prominent eosinophilic nucleoli. Immunohistochemical studies showed that the tumor cells corresponded to CD3Q+ B-lymphocytes . The case reported herein appears to represent another rare instance of the development of ALCL in the spleen. Several features of our case, however, were of interest and differed from those reported in the two previous cases. First of all, in addition to the anaplastic morphology displayed by the tumor cells and the intense CD30 positivity, a subset of these cells also showed strong positive staining for CD15 (Leu-Ml). This feature, coupled with the abundance of pleomorphic, multinucleated tumor cells which closely resembled Reed-Sternberg cells, and the background population of smalllymphocytes, plasma cells and eosinophils, strongly suggested the possibility of Hodgkin's disease (HD). The relationship of ALCL and HD is currently uncertain and remains a controversial topic. Many workers believe that the two conditions may be closely related and correspond to different ends within a single spectrum of disease while other believe they represent two separate conditions which merely show some overlap in antigenic determinants [22, 28, 29]. In recent years, a variant of ALCL showing close morphologic and immunophenotypic overlap with HD has been described under the designation of "Hodgkin-related" or "Hodgkin-like" ALCL [30, 35]. This category is cur-
Anaplastic Large Cell Lymphoma of the Spleen . 521
rently regarded as a provisional entity in the Revised European American Lymphoma Classification . Such tumors are characterized by variable expression of LCA (CD45), EMA, and a variety ofT and B-cell markers, in addition to positivity for CD30 and CD15 in the anaplastic tumor cells. Recent studies [10, 21, 27, 32J have shown that the expression of p80NMP/ALK, a chimeric protein that is activated by the t(2;5)(p23;q35) translocation, may play an important role in the pathogenesis of ALCL. Expression of this protein, however, was not found in cases of Hodgkin-related ALCL in a recent study [27 J. In the present case, the coexpression of CD30/CD15 together with demonstration of LCA, EMA, CD3 and UCHL-l positivity in the anaplastic tumor cells is more in-keeping with ALCL, Hodgkinrelated type, than with HD. The present tumor is thus currently best designated as an example of Hodgkinlike ALCL of the spleen. Another unusual feature in the present case was the previous history of CLL. The development of a high grade lymphoma supervening in CLL is a well known phenomenon which has been known in the literature under the eponym of Richter's syndrome (RS) [14, 23, 24]. Although RS generally has been thought to arise from clonal progression of B-cells originating from the preexisting CLL, several studies have documented the heterogeneity that can often be encountered within the cell population comprising these neoplasms [12, 14, 38]. Additionally, examples of what were believed to represent HD arising from patients with CLL have also been described in the literature [7, 9, 38]. In fact, the presence of large, atypical, multinucleated cells resembling ReedSternberg cells has been frequently cited as an accompanying feature in lymph nodes of patients with eLL [3, 31], as well as in malignant lymphomas developing in patients with RS [12, 14,23,25,26]. The majority of such studies, however, were carried out prior to the availability of commercially available CD30 and CD15 antibodies. The possibility therefore exists that some of those cases may have correspond to a similar phenomenon as the one here described, i.e. the development of Hodgkin-related ALCL against the background of CLL. Despite the history of CLL in our patient, clonal progression from CLL could not be documented in the splenic lymphoma. Because tissues were not available from her original diagnostic studies it was not possible to compare the original immunophenotype of the CLL with the present tumor. A diagnosis of Richter's syndrome therefore cannot be established with certainty. An alternate possibility in this case, however, is that the splenic lymphoma represents a second primary unrelated to the CLL. In any event, splenic involvement by anaplastic large cell lymphoma should be added to the list of diagnostic possibilities in patients with unexplained splenomegaly in the absence of peripheral lymphadenopathy.
Acknowledgements. The authors are grateful to Dr. Frederick C. Lancet of AMI Palmetto General Hospital, Hialeah, FL, for loan of the paraffin blocks for immunohistochemical studies. This work was done while Dr. G. A. Nai was a visiting fellow in pathology at Mount Sinai Medical Center of Greater Miami. Dr. Nai's current address is: Department of Pathology, Faculdade de Medicina, UNESP, Botucatu, Brazil.
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Received: December 9, 1997 Accepted in revised form: May 12, 1998