Case 3 -

Bone, ilium, right, biopsy: Malignant lymphoma, Hodgkin lymphoma, nodular sclerosis Yasuaki Nakashima, M.D. Laboratory of Anatomic Pathology, Kyoto University Hospital Sakyo-ku, Kyoto 606-8507, JAPAN

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Patient Twenty-four year old female. Case History: The patient noted pain in the right flank to right hip, and consulted a local practitioner. On laboratory tests, however, there were no abnormal findings. Six months later, an elevated erythrocyte sedimentation rate was detected. Because of radiating pain from her right hip, through the right lower extremity, to the right toe, she consulted an orthopedic surgeon and an osteolytic lesion in the right ilium was identified. She also demonstrated a fever of 38 centigrade. Five months later, about one year after the onset of her initial symptom of pain in the right flank, she underwent biopsy of the lesion in the right ilium. Roentgenological Findings An osteolytic and destructive lesion was identified in the right ilium, with permeation into the adjacent bone medulla, accompanied by extraosseous extension in the soft tissue. In MRI, the lesion showed low intensity in T1-weighted images and high intensity in T2-weighted images. Use mouse to enlarge Pathological Findings The biopsy specimen was composed of several fragments, histologically showing variegated histologic features, including fibroblastic proliferation, mature lymphocytic mononuclear cells, many eosinophils and plasma cells, and histiocytic cells, In the granulation-like polymorphous background. There were haphazardly scattered large atypical cells with amphophilic dark-stained cytoplasm. In the large nucleus with an irregularly thickend nuclear membrane and coarsely aggregated chromatin, a single large nucleolus was prominent. Most of these atypical large cells demonstrated immunohistochemical profiles of CD15+, CD30+, CD3-, CD20-, CD1a-, S-100 protein-, CAM5.2-, and EBER-. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathological Diagnosis Bone, ilium, right, biopsy: Malignant lymphoma, Hodgkin lymphoma, nodular sclerosis. Treatment and Course On CT scan, swelling of the mediastinal and paraaortic lymph nodes was identified. In addition to positive findings in the ilium and lymph nodes, involvement of multiple bones and the spleen was suspected on FDG-PET. The patient was diagnosed as having stage IVB, and underwent chemotherapy with the ABVD regimen accompanied by 36 Gy radiation for the right ilium. Thirteen months after the initial diagnosis, the patient is well without residual lymph node swelling, and there are no positive findings on FDG-PET. Discussion Malignant lymphoma may involve the skeletal system either as a primary tumor or, far more commonly, as a manifestation of generalized disease, and the exact incidence of skeletal lymphoma is difficult to determine. If we adopt the definition of primary lymphoma of bone as biopsy-confirmed skeletal lesion associated without evidence of disease elsewhere even within 6 months after the diagnosis, cases of primary lymphoma exclusively affecting the bone are extremely rare, and, from a practical perspective, almost all cases of malignant lymphoma of the bone represent a secondary skeletal involvement of systemic disease. Lymphoma of bone, mainly of the large B-cell type, constituting approximately 7% of all skeletal sarcomas and about 5% of extranodal lymphomas, usually occurs in adults over the age of 30 years, and rarely affects children with an incidence equal to about 10% of that of Ewing sarcoma. There is a slight or modest predilection for males. The femur, pelvic bones, and spine are common sites of involvement, and the metaphysis or diaphysis of the long bone is frequently affected. Pain and/or swelling may be initial symptoms, and systemic or B symptoms including fever and night sweats are rare. Patients with involvement of the spine may demonstrate neurologic symptoms due to compression of spinal cord. Roentgenological change of the affected bone with combined sclerotic and lytic features is generally extensive. Patchy cortical destruction is frequent, and periosteal reaction is not common. Occasionally, findings on plain roentgenograms can be subtle or even negative and, if combined with positivity on isotope bone scan, suggest malignant lymphoma of bone. MRI may be useful for showing a permeative and destructive process difficult to identify on simple X-rays. Hematological investigation, including flow cytometry and cytogenetic studies, and immunohistochemistry are mandatory for the diagnosis of malignant lymphoma. From a practical perspective of routine general surgical pathology, in performing immunostaining as the initial approach to a suspected case, a battery of immunostaining including CD3, CD5, CD10, CD15, CD20 (L26), and CD30 (Ki-67, BerH2), may be recommended. Immunostaining for CD1a, CD43, CD45RO, CD56, CD68 (KP-1, PG-M1), CD79a, CD138, bcl-2, and cyclin D1, may be employed in some difficult cases as auxiliary procedures or for further investigations. Myeloperoxidase reaction may also be used for differential diagnosis for myeloid sarcoma. Immunostaining for CD45 (LCA) is frequently nonspecific and may be of less importance. On gross inspection, the tumor is pale to pinkish gray, with a granular and fish flesh-like appearance. Some lesions show osteosclerotic change, and identification of the lesion may be difficult. Extraosseous extension to the soft tissues and invasion into the surrounding muscles are frequent. Histologic appearances and morphologic spectrum of malignant lymphoma of the bone are fundamentally similar to those of nodal lymphomas or lymphomas in other extranodal locations, and diffuse large B-cell lymphomas are most common, and generally CD3-, CD5-, CD20+, and CD79a+ on immunostaining. Malignant cells infiltrate between bony trabeculae sometimes with reactive sclerotic bony change, and permeate within the fatty marrow. Crush artifact may be prominent in lymphoid cells, frequently causing difficulties in the identification of cytological characteristics. In addition to cases showing typical diffuse infiltration of large lymphoid cells, mixed proliferation of mature small lymphocytic cells, medium-sized cells, and large cells are frequent, producing a variegated polymorphous appearance. In some cases, fibrotic change is prominent and neoplastic lymphoid cells show spindle cell-like elongation, with even storiform arrangement, simulating sarcomatoid proliferation or granulation-like histologic features. Skeletal involvement of a low-grade or follicular lymphoma is extremely rare, and usually shows CD5-, CD10+, and bcl-2+ on immunohistochemistry. Anaplastic large cell lymphoma, null cell type or T-cell type, infrequently affects the skeleton, usually shows immunostaining of CD15-, CD30+, EMA+, ALK+ and granzyme B+, and the main differential consideration is Hodgkin lymphoma. Burkitt lymphoma, typically affects the jawbone, can also involves the long bones and pelvic bones, generally with EBER+ for EB virus. Lymphoblastic lymphoma of precursor B-cell type may produce a solitary skeletal involvement, histologically simulating Ewing sarcoma, with Immunohistochemical profiles of TdT+, CD43+, CD79a+, CD99+ and sometime CD20+. Hodgkin lymphoma can present with bone lesions in about 12% to 19% of the patients, mainly as a late manifestation of the disease, with multiple involvement in approximately 60 % of the cases, and not infrequently without symptoms. Vertebrae are the most common site, and involvement of the pelvis, rib, sternum, and femur can also be seen. Lymph node involvement, mediastinal and/or paraaortic, is almost always detected. Exceptionally, however, bone involvement is the initial presentation of Hodgkin lymphoma. Radiographically, osteolytic or mixed lytic and sclerotic appearance can be seen, and sclerotic change may prominent especially in spinal lesions. In approximately 50% of the cases, however, roentgenological findings may be unremarkable. Histologically, according to the latest WHO classification of lymphoid neoplasia, Hodgkin lymphomas are divided into nodular lymphocyte predominant Hodgkin lymphoma characterized by L&H cells (lymphocyte and/or histiocytic Reed-Sternberg cell variants) or popcorn cells, and classical Hodgkin lymphoma in which identification of typical Hodgkin and Reed-Sternberg cells (HRS cells) is the histological requisite for diagnosis. Hodgkin lymphoma of the bone can show the same histological features and variations as seen in classical Hodgkin lymphomas in the lymph nodes and extraskeletal soft tissue, with predominance of nodular sclerosis classical Hodgkin lymphoma and mixed cellularity classical Hodgkin lymphoma. Mixed cellular arrangement composed of mature lymphocytes, polymorphonuclear cells mainly of eosinophils, plasma cells, histiocytic cells, and other mesenchymal cell, in the granulation-like fibrosing background, is a common feature, and identification of classic HRS cells with large nucleus and big nucleoli may sometimes be difficult. Immunohistochemically, large cells are usually CD15+, CD30+, EMA-, and ALK-, and infiltration of reactive CD3+ T-lymphocyte may be prominent. Differential consideration for malignant lymphoma may usually concentrate on neoplastic and nonneoplastic lesions composed of small round cell proliferation. Clinical and roentgenological features of osteomyelitis can simulate those of malignant lymphoma, and histologic arrangement of mixed cellular infiltration of lymphoma may also be mistaken for chronic osteomyelitis. Even in small foci, however, lymphoma shows relatively monotonous or homogenous proliferation of atypical lymphoid cells, and complete effacement of the histology by granulation tissue is unusual in malignant lymphoma. Immunohistochemically, proliferation of CD3+ cells can occur even in reactive situations, and may be nonspecific. Prominent and monotonous proliferation of CD20+ or CD79+ lymphoid cells, however, suggests large B-cell lymphoma. Ewing sarcoma generally affects children, histologically showing a large lobular arrangement, separated by fibrous septa, with frequent central necrosis, whereas the mixed and polymorphic appearances frequently seen in malignant lymphomas are not found. Nuclear features are predominantly regular with a fine chromatin pattern, and differ from those see in malignant lymphomas frequently accompanied by somewhat polymorphic nuclear features with indentation, lobulation, or convolution, and showing prominent nucleoli. Scant cytoplasm with an indistinct cell border offers a good contrast to well defined, relatively abundant eosinophilic or amphophilic cytoplasm of malignant lymphomas. Negative Immunostaining for TdT and CD79a of Ewing sarcoma can be useful for differentiation from lymphoblastic lymphoma of precursor B-cell type with CD99+ in immunostaining. Acute leukemia, especially in children, frequently produce roentgenologically visible involvement, while the systemic and widespread nature of the lesions may cause slight problems in differentiating the disease from primary malignant lymphoma of bone. Myeloid sarcoma (granulocytic sarcoma) may present with acute myeloid leukemia or a myeloproliferative disorder, simultaneously or after the foregoing hematological findings, and can also occur de novo as an isolated lesion without leukemia or as the initial manifestation of myeloid disease. In addition to lymph node and skin, the subperiosteal bone structure is mainly affected, and the skull, paranasal sinuses, sternum, ribs, vertebrae, and pelvis are the most common sites of involvement. Histologic differentiation between malignant lymphoma and granulocytic sarcoma, especially the lytic type primarily composed of myeloblasts, or the immature type with myeloblasts, promyelocytes and eosinophilic myelocytes, may be difficult or even impossible simply in H&E stained sections. In immunohistochemistry, granulocytic sarcoma is generally CD3-, CD20-, and frequently CD43+, and positivity for lysozyme and myeloperoxidase may be the most important clue for the diagnosis. Plasma cell myeloma and plasmacytoma may show the same skeletal distribution of predominant involvement as seen in malignant lymphoma, namely, vertebrae, ribs, skull, pelvis, femur, clavicle and scapula, in order of frequency. Detection of monoclonal protein in serum and urine can establish the diagnosis of plasmacytic neoplasm. Radiologically, purely lytic change frequently showinga punched-out pattern, is usual, and sclerotic features sometimes found in malignant lymphoma are rare in plasma cell tumors, except in cases showing POEMS (Crow-Fukase) syndrome. Radioisotope scan is frequently negative and is useful for differentiation from malignant lymphoma usually visualized positively in scintigram. Eccentrically located nucleus with coarsely clumped chromatin in the amphophilic cytoplasm with perinuclear Hof produce typical cytological features of plasma cells, and binucleation is relatively common. Amyloid deposition in bone is generally considered a manifestation of plasma cell neoplasm. Immunohistochemically, tumor cells are usually CD20-, CD56+, CD79a+, CD138+, showing monoclonality for a kappa or lambda light chain of immunoglobulin. Anaplastic large cell lymphoma can histologically mimic metastatic undifferentiated carcinoma, especially large cell carcinoma. Cellular nest formation surrounded by desmoplastic dense fibrous septa highly suggests a metastatic carcinoma. Fibrosis in lymphoma is more diffuse and fine than that seen in fibrosing stroma with metastatic carcinoma. In addition to lymphoid markers, immunohistochemical stains for epithelial markers, including CAM5.2, AE1/3, CK group, etc., may be useful for differentiating between carcinoma and lymphoma, and for detecting the primary site of metastatic tumor, some immunohistochemical markers including CD10 for renal cell carcinoma, TTF1 for lung and thyroid cancers, PSA for prostate cancer, Hep-Par1 for hepatocellular carcinoma, CD56 for small cell (neuroendocrine cell) carcinoma of the lung or other organs, and progesterone and estrogen receptors for breast carcinoma, may sometimes be helpful. Langerhans cell histiocytosis commonly occurs in childhood, and can simulate the roentgenologic and histologic findings of Hodgkin lymphoma, producing a polymorphous histologic appearance composed of lymphocytes, plasma cells, neutrophils, and histiocytic cells including multinucleated giant cells, with frequent infiltration of eosinophils in granulation-like stroma. Histologically, patchy arrangement by relatively haphazard distribution of the dense aggregations of histiocytic cells in low power magnification is an important clue for the diagnosis. Langerhans cells have a characteristic oval nucleus with indentation and lobulation and frequent coffee bean-like feature due to the longitudinal nuclear groove in the abundant eosinophilic cytoplasm, showing CD1a (O10)+, S-100 protein+, and frequently CD68 (KP-1, PG-M1)+ immunostaining. Almost all malignant lymphomas of bone may be considered part of the systemic involvement of nodal disease, and chemotherapy with or without radiation is usually the treatment of choice. Both the stage and histologic cell type are the most important prognostic factors. In the most common type of skeletal malignant lymphoma of large B-cell type, the 5-year survival rate ranged from approximately 22% to 48% in several reported series. Tumors of centrocytic cleaved cell type may show a better prognosis, while the prognosis of anaplastic large cell lymphoma with CD30+, EMA+, and granzyme B+, ALK+ in immunoreactivity is generally poor. As a complication of treatment for malignant lymphoma of bone, osteonecrosis of the femoral head or humeral head can occur. References Boston HC, Jr., Dahlin DC, Ivins JC, Cupps RE. Malignant lymphoma (so-called reticulum cell sarcoma) of bone. Cancer 1974;34(4):1131-7. Reimer RR, Chabner BA, Young RC, Reddick R, Johnson RE. Lymphoma presenting in bone: results of histopathology, staging, and therapy. Ann Intern Med 1977;87(1):50-5. Mahoney JP, Alexander RW. Primary histiocytic lymphoma of bone: a light and ultrastructural study of four cases. Am J Surg Pathol 1980;4(2):149-61. Neiman RS, Barcos M, Berard C, Bonner H, Mann R, Rydell RE, et al. Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases. Cancer 1981;48(6):1426-37. Chan KW, Rosen G, Miller DR, Tan CT. Hodgkin's diseases in adolescents presenting as a primary bone lesion. A report of four cases and review of literature. Am J Pediatr Hematol Oncol 1982;4(1):11-7. Dosoretz DE, Raymond AK, Murphy GF, Doppke KP, Schiller AL, Wang CC, et al. Primary lymphoma of bone: the relationship of morphologic diversity to clinical behavior. Cancer 1982;50(5):1009-14. Newcomer LN, Silverstein MB, Cadman EC, Farber LR, Bertino JR, Prosnitz LR. Bone involvement in Hodgkin's disease. Cancer 1982;49(2):338-42. Kluin PM, Slootweg PJ, Schuurman HJ, Go DM, Rademakers LH, van der Putte SC, et al. Primary B-cell malignant lymphoma of the maxilla with a sarcomatous pattern and multilobated nuclei. Cancer 1984;54(8):1598-605. Bacci G, Jaffe N, Emiliani E, Van Horn J, Manfrini M, Picci P, et al. Therapy for primary non-Hodgkin's lymphoma of bone and a comparison of results with Ewing's sarcoma. Ten years' experience at the Istituto Ortopedico Rizzoli. Cancer 1986;57(8):1468-72. Ostrowski ML, Unni KK, Banks PM, Shives TC, Evans RG, O'Connell MJ, et al. Malignant lymphoma of bone. Cancer 1986;58(12):2646-55. Clayton F, Butler JJ, Ayala AG, Ro JY, Zornoza J. Non-Hodgkin's lymphoma in bone. Pathologic and radiologic features with clinical correlates. Cancer 1987;60(10):2494-501. Howat AJ, Thomas H, Waters KD, Campbell PE. Malignant lymphoma of bone in children. Cancer 1987;59(2):335-9. Falini B, Binazzi R, Pileri S, Mori A, Bertoni F, Canino S, et al. Large cell lymphoma of bone. A report of three cases of B-cell origin. Histopathology 1988;12(2):177-90. Pettit CK, Zukerberg LR, Gray MH, Ferry JA, Rosenberg AE, Harmon DC, et al. Primary lymphoma of bone. A B-cell neoplasm with a high frequency of multilobated cells. Am J Surg Pathol 1990;14(4):329-34. Chan JK, Ng CS, Hui PK, Leung WT, Sin VC, Lam TK, et al. Anaplastic large cell Ki-1 lymphoma of bone. Cancer 1991;68(10):2186-91. Baar J, Burkes RL, Bell R, Blackstein ME, Fernandes B, Langer F. Primary non-Hodgkin's lymphoma of bone. A clinicopathologic study. Cancer 1994;73(4):1194-9. Fairbanks RK, Bonner JA, Inwards CY, Strickler JG, Habermann TM, Unni KK, et al. Treatment of stage IE primary lymphoma of bone. Int J Radiat Oncol Biol Phys 1994;28(2):363-72. Pambuccian SE, Horyd ID, Cawte T, Huvos AG. Amyloidoma of bone, a plasma cell/plasmacytoid neoplasm. Report of three cases and review of the literature. Am J Surg Pathol 1997;21(2):179-86. Ozdemirli M, Fanburg-Smith JC, Hartmann DP, Shad AT, Lage JM, Magrath IT, et al. Precursor B-Lymphoblastic lymphoma presenting as a solitary bone tumor and mimicking Ewing's sarcoma: a report of four cases and review of the literature. Am J Surg Pathol 1998;22(7):795-804. Iravani S, Singleton TP, Ross CW, Schnitzer B. Precursor B lymphoblastic lymphoma presenting as lytic bone lesions. Am J Clin Pathol 1999;112(6):836-43. Ostrowski ML, Inwards CY, Strickler JG, Witzig TE, Wenger DE, Unni KK. Osseous Hodgkin disease. Cancer 1999;85(5):1166-78. Nagasaka T, Nakamura S, Medeiros LJ, Juco J, Lai R. Anaplastic large cell lymphomas presented as bone lesions: a clinicopathologic study of six cases and review of the literature. Mod Pathol 2000;13(10):1143-9. Huebner-Chan D, Fernandes B, Yang G, Lim MS. An immunophenotypic and molecular study of primary large B-cell lymphoma of bone. Mod Pathol 2001;14(10):1000-7. Vega F, Medeiros LJ. Marginal-zone B-cell lymphoma of extranodal mucosa-associated lymphoid tissue type: molecular genetics provides new insights into pathogenesis. Adv Anat Pathol 2001;8(6):313-26. de Leval L, Braaten KM, Ancukiewicz M, Kiggundu E, Delaney T, Mankin HJ, et al. Diffuse large B-cell lymphoma of bone: an analysis of differentiation-associated antigens with clinical correlation. Am J Surg Pathol 2003;27(9):1269-77. Barbieri E, Cammelli S, Mauro F, Perini F, Cazzola A, Neri S, et al. Primary non-Hodgkin's lymphoma of the bone: treatment and analysis of prognostic factors for Stage I and Stage II. Int J Radiat Oncol Biol Phys 2004;59(3):760-4. Cook JR, Shekhter-Levin S, Swerdlow SH. Utility of routine classical cytogenetic studies in the evaluation of suspected lymphomas: results of 279 consecutive lymph node/extranodal tissue biopsies. Am J Clin Pathol 2004;121(6):826-35. Gill P, Wenger DE, Inwards DJ. Primary lymphomas of bone. Clin Lymphoma Myeloma 2005;6(2):140-2. Bakshi NA, Ross CW, Finn WG, Valdez R, Ruiz R, Koujok K, et al. ALK-positive anaplastic large cell lymphoma with primary bone involvement in children. Am J Clin Pathol 2006;125(1):57-63. Glotzbecker MP, Kersun LS, Choi JK, Wills BP, Schaffer AA, Dormans JP. Primary non-Hodgkin's lymphoma of bone in children. J Bone Joint Surg Am 2006;88(3):583-94.