Angiotropic Large Cell Lymphoma (Intravascular Lymphomatosis) Occurring After Follicular Small Cleaved Cell Lymphoma

Case Report Angiotropic Large Cell Lymphoma (Intravascular Lymphomatosis) Occurring After Follicular Small Cleaved Cell Lymphoma DAVID K. CARTER, M.D.,* KENNETH

P. BATTS, M.D., PIET C. DE GROEN, M.D., AND PAUL J. KURTlN, M.D.

Angiotropic large cell lymphoma is a rare, aggressive type of malignant lymphoma that primarily involves intravascular spaces and most often has clinical manifestations in the skin and central nervous system. Virtually any organ can be affected, however, including the lymph nodes and spleen. Peripheral blood involvement is usually not detectable morphologically. Conventional lymphoma in association with this entity has also been described. Herein we present a case of angiotropic lymphoma of B-cell lineage that affected

Angiotropic large cell lymphoma (angiotropic lymphoma [ALl. intravasc ula r lymphomatosis , or malignant angioendotheliomatosis) is a rare , aggressive malignant lymphoma that is characterized morphologically by intravascular collections of large neopla stic lymphocytes and clinically most often as multiple cutaneous lesions or neurologic deficits.'? As noted by Molina and associates," Pfleger and Tappeiner' first described this disease in 1959 as angioendotheliomatosis proliferans systemisata. For many years, it was thought to be a primary endothelial disorder, and its relationship to reactive angioendotheliomatosis has often been addressed>" Subsequently, however, this entity has been clearly demonstrated to be a peculiar malignant hematolymphoid disorder. 2•3•8•9 Lymphadenopathy is not commonly present; however, if lymph nodes are involved, they demonstrate focal infiltration or effacement by large cell lymphoma, cytologically identical to the intravascular malignant cells. Herein we describe a patient with untreated low-grade follicular lymphoma who later had hepatic and cutaneous involvement by AL. To our knowledge, this is the first report of AL occurring after untreated low-grade follicular lymphoma. From the Division of Anatomi c Pathology (D.K.C., K.P.B .), Division of Ga stroenterology and Internal Medi cine (P.C.d.G.) , and Division of Hematopathology (PJ.K.), Mayo Clinic Roche ster, Rochester, Minnesota. *Current address : Santa Fe Pathology Services, Santa Fe, New Mexico. Address reprint requests to Dr. K. P. Batts, Division of Anatomic Pathology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo C/in Proc 1996; 71:869-873

the liver and skin. Reanalysis of a lymph node specimen that had been excised 3 years previously demonstrated a follicular small cleaved cell lymphoma. To our knowledge, this is the first reported case of possible evolution of follicular lymphoma to large cell lymphoma of angiotropic type. (Mayo Clin Proc 1996; 71:869-873) AL =angiotropic lymphoma

REPORT OF CASE A 63-year-old woman was first examined at Mayo Clinic Rochester in July 1993 because of a lO-month history of chronic cough, intermittent fevers (up to 39.4°C), severe night sweats, 11.3-kg weight loss, possible depression, and tender lower extremity skin nodules. Her medical history included reportedly benign cervical lymphadenopathy in 1990. Her condition had progressively worsened while she was taking corticosteroid therapy for suspected adult Still's disease. The work-up at Mayo included numerous negative serologic test results and cultures for viral, bacterial, fungal, and parasitic organisms; a tuberculin skin test was also nonreactive. The patient had anemia (hemoglobin concentration, 9 g/dL) , the erythrocyte sedimentation rate was greater than 100 mm in 1 hour, and the serum antinuclear antibody was 1:80 with a speckled pattern. Histopathologic review of the cervical lymph node biopsy specimen obtained in 1990 disclosed follicular small cleaved cell lymphoma. A bone marrow aspirate and biopsy were then performed, findings of which showed no evidence of lymphoma, including negative flow cytometric and molecular genetic test results for clonal B- or T-cell populations. No adenopathy was evident on chest and abdominal computed tomographic scans . Abdominal exploration was refused. No chemotherapy was instituted at that time . In December 1993, the patient returned with worsening symptoms, including more prominent subcutaneous leg nodules. During further work-Up, a gastroenterology consultant 869

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ANGIOTROPIC LARGE CELL LYMPHOMA

detected subtle hepatomegaly, and a subsequent magnetic resonance imaging scan demonstrated a slight increase in signal diffusely in the T2-weighted images, a suggestion of infiltration by a neoplasm. AL was diagnosed on the basis of ultrasound-guided liver needle biopsy and right lower leg skin biopsy (see below). Currently, the patient is being treated with ProMACECytaBOM-trimethoprim (cyclophosphamide, doxorubicin, etoposide, cytosine arabinoside, bleomycin, vincristine, methotrexate, leucovorin, prednisone, and trimethoprim). PATHOLOGY Tissues were fixed in neutral-buffered formalin, and 3- to 511m sections were stained with hematoxylin-eosin and Masson's trichrome by conventional methods. Immunohistochemical stains (Table I) were performed by using a labeled streptavidin-biotin peroxidase method, as previously described. 10 Liver Specimen.-A polymorphous, mononuclear inflammatory cell infiltrate was present predominantly in portal areas but also involving sinusoids of the liver (Fig. I). Rare, cytologically abnormal large lymphocytes were present in lobular sinusoids and adjacent to portal vein endothelium in an intravascular location. The large cells were immunoreactive for the B-cell lineage-associated antigens CD20 (L26) and CD45RA (4KB5) (Fig. 2); however, they failed to stain for K or A immunoglobulin light chains. The T-cell lineage-associated antigens CD45RO (UCHL-l) and CD3 decorated most of the nonatypical portal and sinusoidal lymphocytes, but the large cells remained unstained (Fig. 2). Angiotropic B-cell lymphoma was suspected; however, in view of the paucity of B cells in the T-cell rich infiltrate, additional supportive evidence was sought.

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Table l.-Immunoperoxidase Stains* Used on Tissue Specimens From Patient With Angiotropic Lymphoma Antibody

CD designation

Dilution

L26 4KB5 Kt At UCHL-I

CD20 CD45RA

1:60 1:20 1:1,000 1:1,000 1:60 1:200 1:10

cm

bcl-2

CD45RO

cm

*Dako Corporation, Carpenteria, Califomia. tPolyclonal.

Skin Specimen.-The skin biopsy specimen contained large lymphocytes, similar to those seen in the liver but in more abundant intravascular collections, predominantly in the deep dermis and subcutis (Fig. 3). This finding was associated with a mild panniculitis consisting of a diffuse collection of macrophages in a histologically nonspecific, predominantly lobular pattern. The large lymphocytes were of B-cell lineage (positive for CD20), and the histopathologic features were believed to be sufficient to warrant an unequivocal diagnosis of AL. The neoplastic cells showed strong staining with antibodies against the bel2 oncogene product. Lymph Node Specimen.-Review of the right cervical lymph node biopsy specimen obtained 3 years previously showed features diagnostic of follicular small cleaved cell lymphoma (Fig. 4). Morphologically, the lymph node was effaced by closely apposed neoplastic follicles lacking the usual mantle cell layer. The follicles were composed of a monomorphous population of small cleaved lymphocytes.

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•

Fig. 1. Liver biopsy specimen showing angiotropic large cell lymphoma. A, Polymorphous lymphocytic infiltrate and endotheliitis in portal and sinusoidal regions. B, Some lymphocytes contain enlarged, atypical nuclei (arrows). (A and B, Hematoxylin-eosin; original magnification, x433.)

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ANGIOTROPIC LARGE CELL LYMPHOMA

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ular lymphoma;" immunohistochemical light chain restriction was absent.

A

t B

•

t

••

Fig. 2. Immunohistochemical appearance of hepatic angiotropic large cell lymphoma. Atypical lymphocytes (closed arrows) are positive for B-eell markers CD20 (A) and 4KB5 (B) and negative forT-ceilmarkerCD3 (C). Associated reactive T-celllymphocytes (open arrows) stainpositively with CD3 antibodies (C). CA, B, and C, x250.)

Small cleaved cells also were present in paracortical regions, a finding associated with collagen sclerosis. The intrafollicular neoplastic lymphocytes were strongly positive for the bcl-2 oncogene product, supporting a diagnosis of follic-

DISCUSSION Our patient was diagnosed as having AL of B-cell phenotype associated with untreated follicular small cleaved cell lymphoma. Although concomitant lymph node involvement by lymphoma occurs in patients with AL, most often the cells within the lymph node have morphologic features (that is, large cells) similar to the intravascular component. 3,5,8,12,13 To our knowledge, this is the first report of AL occurring in the setting of an untreated follicular center cell lymphoma. The positive staining for bcl-2 oncogene product is compatible with origin from a follicular neoplasm, albeit not definitivel y. Most cases of AL are of B-cell lineage, ' although a few cases of T-cell origin have been described.v" Immunohistochemical and cytogenetic evidence demonstrates that AL is truly an intravascular lymphoma rather than a peculiar intravascular spread of carcinoma or a multifocal vascular neoplasrn.P :" In a review of 15 cases of AL by Wick and colleagues ,' 6 were associated with focal or diffuse lymph node involvement, but all the cases were of the large cell type. Splenic involvement was also described in seven of their cases. In a study by Bhawan and coworkers," a 77year-old patient with AL was found to have malignant lymphoma of the jejunum, but this case was also of large cell type, similar to the atypical cells within vascular spaces . Other reports 8,12,13,16- 18 have shown cytologic similarities between lymphoma cells in the involved lymph nodes (or other organs with gross pathologic masses) and the systemic intravascular spaces. We were able to identify only one other case in the English literature of low-grade lymphoma and subsequent AL. In the series by Glass and associates'? in 1993, one case involved a 75-year-old man who had development of AL after a bone marrow diagnosis of small lymphocytic lymphoma with Waldenstrom's macroglobulinemia. In that case, however, the AL was ofT-cell lineage, evolving after cessation of a 6-year course of chlorambucil. Therefore, the diseases in that report were unlikely of a single clonal origin, as remains probable in the current case. Low-grade lymphomas of B-cell phenotype may undergo transformation to a higher grade lymphoma, most often a diffuse large cell type; this occurs in up to 25% of cases." In the current case, proving a common clonal lineage of the neoplastic cells in the 1990 lymph node specimen and the current intravascular lymphoma is not possible other than the circumstantial common B-celllineage. Fresh tissue from the 1990 lymph node specimen is not available for phenotyping or for studies of the immunoglobulin gene configuration,

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tion chemotherapeutic protocols offer the only hope of remission or cure." Hepatic involvement in AL ranges from previously asymptomatic microscopic vascular involvement noted at autopsy':" to multifocal hemorrhagic ischemic necrosis." The liver has also been the site of extravascular tumor (lymphoma) in a patient with systemic clinical manifestations of AL.17

• I

....

Fig. 3. Skin biopsy specimendemonstrating angiotropic large cell lymphoma. Atypical intravascular lymphocytes and thrombi are evident. (Hematoxylin-eosin; originalmagnification, x250.) which might provide further evidence of a common clonal origin of the neoplastic cells. The actual origin of the malignant cells in AL is as yet unknown; AL may represent a secondary dissemination of an occult lymphoma or an actual primary intravascular lymphoid malignant lesion. Ferry and colleagues" reported that three of six cases of AL stained with recently developed monoclonal antibodies to vascular homing receptors; however, as they pointed out, this finding alone was insufficient for explaining the peculiar small vessel trapping of neoplastic lymphocytes in this disorder. Regardless of the current lack of histogenetic proof of origin, this is clearly an aggressive malignant disease, and appropriately directed combina-

CONCLUSION The patient described herein had development of B-cell AL associated with untreated follicular small cleaved cell lymphoma. The common B-celllineage of these processes is intriguing and lends further support to the observations that so-called malignant angioendotheliomatosis is an aggressive lymphoma, often of B-celliineage. In the current case, AL possibly represents a large cell transformation of low-grade follicular small cleaved cell lymphoma. REFERENCES 1. Helm TN, Bergfeld WF, Elston D. Angiotropic lymphoma: malignant angioendotheliomatosis. Cutis 1992; 50:204206 2. Molina A, Lombard C, Donlon T, Bangs CD, Dorfman RF. Immunohistochemical and cytogenetic studies indicate that malignant angioendotheliomatosis is a primary intravascular (angiotropic) lymphoma. Cancer 1990; 66:474479 3. Wick MR, Mills SE, Scheithauer BW, Cooper PH, Davitz MA, Parkinson K. Reassessment of malignant "angioendotheliomatosis": evidencein favor of its reclassification as "intravascularlymphomatosis." Am J Surg Pathol 1986; 10:112-123

A

" I

-

Fig. 4. Lymph node biopsy specimens showing follicular small cleaved cell lymphoma, possible precursor to angiotropic large cell lymphoma. A, Neoplastic intrafollicular lymphocytes are immunoreactive for bel-L. (Anti-bcl-2; original magnification, x42.5.) B, Numerous small cleaved cells are present in a follicular center and adjacentmantle region. (Hematoxylin-eosin; originalmagnification, x240.)

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ANGIOTROPIC LARGE CELL LYMPHOMA

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Pfleger L, Tappeiner J. Zur Kenntnis der systemisierten Endotheliomatose der cutanen Blutgefasse (Reticuloendotheliose?). Hautarzt 1959 ; 10:359-363 Dominguez FE, Rosen LB, Kramer HC. Malignant angioendotheliomatosis proliferans: report of an autopsied case studied with immunoperoxidase. Am J Dermatopathol 1986;

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Martin S, Pitcher D, Tschen J, Wolf JE Jr. Reactive angioendotheliomatosis. J Am Acad Dermatol 1980; 2: 117-123 7. Wick MR, Rocamora A. Reactive and malignant "angioendotheliomatosis": a discriminant clinicopathological study. J Cutan Pathol 1988; 15:260-271 8. Ferry JA, Harris NL, Picker LJ , Weinberg DS, Rosales RK, Tapia J, et aJ. Intravascular lymphomatosis (malignant angioendotheliomatosis): a B-cell neoplasm expressing surface homing receptors. Mod Pathol 1988 ; 1:444-452 9. Setoyama M, Mizoguchi S, Orikawa T, Tashiro M. A case of intravascular malignant lymphomatosis (angiotropic largecell lymphoma) presenting memory T cell phenotype and its expression of adhesion molecules. J Dermatol 1992; 19:263-

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Kurtin PJ, Roche PC. Immunoperoxidase staining of nonHodgkin's lymphomas for T-cell lineage associated antigens in paraffin sections: comparison of the performance characteristics of four commercially available antibody preparations. Am J Surg Pathol 1993 ; 17:898-904 11. Said JW, Pinkus GS, Lones MA, Preston M, Shintaku IP. Expression of bcl-2 oncogene protein in malignant lymphomas, including Hodgkin 's disease and non-Hodgkin 's lymphomas of T-cell phenotype. .Appl Immunohistochem

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Lopez-Gil F, Roura M, Umbert I, Umbert P. Malignant proliferative angioendotheliom atosis or angiotropic lymphoma associated with a soft-tissue lymphoma. J Am Acad Dermatol 1992; 26: 101-104 Sheibani K, Battifora H, Winberg CD, Burke JS, Ben-Ezra J, Ellinger GM, et al. Further evidence that "malignant angioendotheliomatosis" is an angiotropic large-cell lymphoma. N Engl J Med 1986; 314:943-948 Bhawan J, Wolff SM, Ucci AA, Bhan AK. Malignant lymphoma and malignant angioendotheliomatosis: one disease. Cancer 1985; 55 :570-576 Braverman 1M, Lerner AB. Diffuse malignant proliferation of vascular endothelium : a possible new clinical and pathological entity. Arch Dermatol 1961; 84 :22-30 Kayano H, Katayama I. Primary hepatic lymphoma representing as intravascular lymphomatosis. Arch Pathol Lab Med 1990; 114:580-584 Scott PW , Sil vers DN, Helwig EB . Proliferating angioendotheliomatosis. Arch Pathol 1975; 99 :323326

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Glas s J, Hochberg FH, Miller DC . Intravascul ar lymphomatosis: a systemic disease with neurologic manifestations. Cancer 1993; 71: 3156-3164 Harris NL, Ferry JA. Follicular lymphoma and related disorders (germinal center lymphomas). In: Knowles DM, editor. Neoplastic Hematopathology. Baltimore: Williams & Wilkins, 1992: 645 -674 Stroup RM, Sheibani K, Moncada A, Purdy U , Battifora H. Angiotropic (intravascular) large cell lymphoma: a clinicopathologic study of seven cases with unique clinical presentations. Cancer 1990 ; 66 : I 781-1788 Nakanuma Y, Kumabashiri 1. Neoplastic angioendotheliomatosis with multifocal hemorrhagic necrosis of the liver. Am J Gastroenterol 1988 ; 83:1180-1182

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