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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 51  |  Issue : 2  |  Page : 186-189
Clinically unsuspected Hodgkin's lymphoma diagnosed primarily from bone marrow trephine biopsy: Report of six cases


Department of Hematology, AIIMS, New Delhi 110 029, India

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   Abstract 

Bone marrow may be the initial or rarely the only site of involvement in Hodgkin's lymphoma. A high index of suspicion is required to pick up the histopathological changes of Hodgkin's lesions in the bone marrow like necrosis, presence of Reed-Sternberg cell or its variant in a polymorphic background infiltrate, focal fibrosis and myxoid change especially in the absence of classical clinical picture. Bone marrow with immunohistochemistry has a valuable role in the staging and in the diagnosis of primary medullary Hodgkin's lymphoma. B-symptoms may easily masquerade as an infectious process as in all our cases the patients had fever as a presenting feature, in four of them tuberculosis was suspected clinically and two had received antitubercular therapy elsewhere. We report six human immunodeficiency virus-negative patients diagnosed over a period of 5 years in which the initial diagnosis of Hodgkin's lymphoma was suggested from bone marrow histology.

Keywords: Bone marrow, Hodgkin′s lymphoma, trephine biopsy

How to cite this article:
Kar R, Dutta S, Tyagi S. Clinically unsuspected Hodgkin's lymphoma diagnosed primarily from bone marrow trephine biopsy: Report of six cases. Indian J Pathol Microbiol 2008;51:186-9

How to cite this URL:
Kar R, Dutta S, Tyagi S. Clinically unsuspected Hodgkin's lymphoma diagnosed primarily from bone marrow trephine biopsy: Report of six cases. Indian J Pathol Microbiol [serial online] 2008 [cited 2019 Dec 8];51:186-9. Available from: http://www.ijpmonline.org/text.asp?2008/51/2/186/41675



   Introduction Top


A primary extranodal presentation of Hodgkin's lymphoma (HL) is rare occurring in <0.25% of patients with Hodgkin's lymphoma. [1] As the bone marrow lacks lymphatics, infiltration of bone marrow by Hodgkin's lymphoma indicates vascular dissemination of the disease (stage IV). However, primary Hodgkin's lymphoma of the bone is also reported (stage IE). [1],[2] The incidence of bone marrow involvement in Hodgkin's lymphoma varies with the histologic subtype: 10% in classical Hodgkin's mixed cellularity, approximately 1% in lymphocyte predominant Hodgkin's and lymphocyte rich classical Hodgkin's lymphoma, [3],[4] and 3% in Nodular Sclerosis subtype. [5] Although lymphocyte depleted Hodgkin's lymphoma is the rarest subtype, it often shows selective extranodal presentation including involvement of bone marrow with relative sparing of peripheral lymphnodes. [4] Hodgkin's lymphoma diagnosed primarily from trephine biopsy histology is reported in the literature. [6] Diagnosis by bone marrow biopsy is relatively frequent in human immunodeficiency virus (HIV)-positive patients, who often present with stage IVB disease. [7] Herein we report six cases from our institute diagnosed over a period of 5 years in which the initial diagnosis of Hodgkin's lymphoma was suggested from bone marrow histology.


   Materials And Methods Top


This was a retrospective study in which all the cases of Hodgkin's lymphoma diagnosed primarily from bone marrow trephine biopsies on the basis of hematoxylin and eosin (H and E)-stained sections over the past 5 years were reviewed. Immediate follow-up and confirmation by lymph node biopsy was possible in three patients. Immunohistochemistry (IHC) using standard technique was performed in four cases. Postchemotherapy follow-up was available in one patient. The brief clinical summary of the cases is presented.

Case 1

A 45-year-old female presented with 3 months history of anemia, fever, weakness, fatigability and hematuria. On examination, she had hepatosplenomegaly (liver - 4 cm, spleen - 3 cm) and no peripheral lymphadenopathy. Computed tomography (CT) scan showed small mediastinal lymph nodes (0.5 cm). Herroutine hemogram showed hemoglobin 93 g/l, total leukocyte count (TLC) 5.5 10 9 /l and platelet count (PC) 140 10 9 /l. Bone marrow examination was done for pyrexia of unknown origin (PUO) work-up.The trephine biopsy showed effacement of the normal marrow architecture by a diffuse polymorphic infiltrate and a necrotic background. Occasional large binucleate cells with moderate amount of cytoplasm and prominent eosinophilic nucleoli (Reed-Sternberg, RS cells) and few large cells with vesicular nuclei and prominent eosinophilic nucleoli (variant RS cells) were identified. Focal areas of fibrosis were seen. Acid fast bacilli (AFB) stain on the marrow section was negative. Immunohistochemistry done on the bone marrow (BM) trephine biopsy section showed these cells to be CD15+ and CD30−. With this, a diagnosis of Hodgkin's lymphoma was made.

Case 2

A 5-year-old male child presented with 6 months history of fever and anemia. On examination, he had hepatosplenomegaly (liver - 4 cm, spleen - 12 cm), bilateral cervical and axillary lymphadenopathy and anasarca. He had received antituberculosis treatment (ATT) for tuberculosis from outside, further details of which were not available. His routine hemogram showed hemoglobin 71 g/l, TLC 5.6 10 9 /l and PC 101 10 9 /l. Bone marrow examination was done for PUO work-up.The trephine biopsy was cellular with increased lymphocytes, occasional typical RS cells and few variant RS cells. The background was polymorphous with large areas of necrosis. No granuloma was seen and AFB stain on the marrow section was negative. A morphological diagnosis of Hodgkin's lymphoma was made and lymph node biopsy was advised. The lymph node biopsy confirmed the diagnosis of Hodgkin's lymphoma-mixed cellularity.

Case 3

A 45-year-old male presented with 10 months history of anemia, fever off and on, weakness and loss of weight. On examination, he had splenomegaly (2 cm), but no hepatomegaly or lymphadenopathy. The routine hemogram showed pancytopenia with hemoglobin 87 g/l, TLC 22 10 9 /l and PC 16 10 9 /l. Bone marrow examination was done for suspected disseminated fungal/tubercular infection and to rule out myelodysplastic syndrome (MDS). The trephine biopsy showed large areas of necrosis along with a polymorphous infiltrate of neutrophils, eosinophils and a few plasma cells. Small lymphoid follicles were seen. No typical RS cells were seen; however, occasional variant RS cells were identified. AFB stain on the marrow section was negative and bone marrow culture was sterile for fungal and bacterial cultures. Immunohistochemistry done on the BM trephine biopsy section showed these cells to be CD15− and CD30+. A bone marrow diagnosis suggestive of Hodgkin's lymphoma was made. Two weeks later, the patient developed cervical lymphadenopathy, biopsy from which confirmed the diagnosis of Hodgkin's lymphoma-nodular sclerosis subtype.

Case 4

A 19-year-old male presented with 1-year history of fever, cough, weight loss and anemia. On examination, he had mild hepatosplenomegaly (liver - 2 cm, spleen - just palpable) and no peripheral lymphadenopathy. The routine hemogram showed bicytopenia with hemoglobin 50 g/l, TLC 8.5 10 9 /l and PC 118 10 9 /l. Bone marrow examination was done for suspected disseminated tuberculosis and to rule out lymphoma. The trephine biopsy showed multifocal areas of necrosis along with a polymorphous infiltrate comprising plasma cells, eosinophils, neutrophils and lymphocytes. Few typical RS cells and mononuclear Hodgkin cells were seen scattered. There were focal areas of fibrosis. Atypical mitotic figures were also seen. AFB stain on the marrow section was negative. Immunohistochemistry done on the BM trephine biopsy section showed these cells to be CD30+ and CD15 was positive in few of the cells. With this, a diagnosis of Hodgkin's lymphoma was made.

Case 5

A 48-year-old male was investigated for progressive fall in hemoglobin and fever following splenectomy. The patient had been symptomatic since 3 years with history of anemia, weakness, dyspnoea and lump in the left hypochondrium. He was having pallor, jaundice, hepatosplenomegaly (liver - 2 cm, spleen - 7 cm) and no peripheral lymphadenopathy. His counts progressively fell to hemoglobin 73 g/l, TLC 2.3 10 9 /l and PC 18 10 9 /l. No cause of splenomegaly was detected even on extensive investigation. Bone marrow examination was done twice during this period and showed cellular marrow with normoblastic erythroid hyperplasia. He subsequently underwent splenectomy for hypersplenism which showed fibrocongestive splenomegaly. Postsplenectomy, after 4 months his counts were hemoglobin 78 g/l, TLC 14.5 10 9 /l and PC 239 10 9 /l. CT scan done showed the presence of multiple intraabdominal lymph nodes. Bone marrow examination was done for suspected tuberculosis. The trephine biopsy showed effacement of the normal marrow architecture by a diffuse polymorphic infiltrate with marked prominence of eosinophils. Focal areas of necrosis were seen. Megakaryocytes were prominent and occasional lymphoid follicles were seen. Scattered large cells with vesicular nuclei and prominent eosinophilic nucleoli (mononuclear variant of RS cells) were identified. AFB stain on the marrow section was negative. Immunohistochemistry done on the BM trephine biopsy section showed these cells to be CD15+ and CD30+ . With this, a diagnosis of Hodgkin's lymphoma was made.

Case 6

A 15-year-old male presented with 6 months history of fever off and on, cough for 1 month, weakness and loss of weight. On examination, he had no hepatosplenomegaly and right axillary lymphadenopathy (1.5-3 cm). He had received ATT for tuberculosis from outside for 2 months without any improvement. His routine hemogram showed hemoglobin 81 g/l, TLC 20.5 10 9 /l and PC 315 10 9 /l. Fine needle aspiration cytology (FNAC) from the lymph node was suspicious of Hodgkin's disease. Bone marrow examination was done for PUO work-up.The trephine biopsy was paucicellular and showed loose connective tissue background with stromal edema, myxomatous change and focal fibrosis. No granuloma or RS cells, or necrosis was seen. The possibility of Hodgkin's lymphoma was strongly suggested. The lymph node biopsy confirmed the diagnosis of Hodgkin's lymphoma-mixed cellularity. Contrast-enhanced computed tomography (CECT) scan showed multiple lymph nodes in the lower neck, right axilla, mediastinum and paraaortic areas along with multiple areas of consolidation and small nodules in bilateral lungs which was likely to be de to lymphomatous infiltration.

The patient is receiving chemotherapy with Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) which he has tolerated well and his current chest X-ray is normal.


   Results Top


The salient clinicopathologic features of all the six cases are presented in [Table 1]. All our six cases were HIV negative. Most of the cases presented with fever, anemia, weakness and fatiguability of duration ranging from 3 months to 1 year while in case 5, patient was investigated for progressive fall in hemoglobin and fever following splenectomy for hypersplenism which showed fibrocongestive spleen on histopathology. Bone marrow examination was done either for PUO work-up or suspected disseminated tuberculosis in the majority. Mild-to-moderate hepatosplenomegaly was present in two patients, splenomegaly in one patient and hepatomegaly in one patient. Peripheral lymphadenopathy was present in only two patients at presentation while in case 3, the patient developed cervical lymphadenopathy 2 weeks later, biopsy from which confirmed the diagnosis. Radiological evidence of mediastinal or intraabdominal lymph nodes were seen in three cases. Multiple areas of consolidation and small nodules in bilateral lungs were seen in case 6 which resolved on chemotherapy. On evaluation, most patients had bicytopenia or only decreased hemoglobin level. The bone marrow aspirates were generally of low cellularity with prominent mature lymphocytic infiltrate in two cases. The trephine biopsy mostly showed effacement of the normal marrow architecture. Bone marrow histologic features [Figure 1] which were striking in raising the diagnostic possibility were bone marrow necrosis seen in five cases, presence of RS cell or its variant in a polymorphic background infiltrate seen in five of the six cases, focal fibrosis in three cases and myxoid change in one case. Small lymphoid follicles were seen in two cases. AFB stain done on the marrow section in five cases where necrosis was present was negative. The diagnosis was confirmed by bone marrow IHC in four cases. Tissue diagnosis in the form of lymph node biopsy was possible only in three patients of which two were mixed cellularity and one was nodular sclerosis.


   Discussion Top


Hodgkin's lymphoma diagnosed primarily from trephine biopsy histology is reported. The biopsies usually were done for the investigation of pancytopenia or of systemic symptoms such as fever. [8] Nonspecific B symptoms have been described as initial presentation in clinically unsuspected Hodgkin's disease. [9] All the six cases reported by us had fever as a presenting feature, in four cases tuberculosis was suspected clinically and two had received antitubercular therapy elsewhere before presenting to us. Marrow involvement mostly results from widely disseminated disease and an Indian study [10] of bone marrow involvement in Hodgkin's disease found lymphadenopathy in all the cases and hepatosplenomegaly in the majority unlike in the present study.

In the bone marrow, the presence of typical R-S cells or mononuclear variant in a cellular background typical of Hodgkin's lymphoma with such cells in other specimens is definitive of involvement; presence of atypical cells lacking features of R-S cells or mononuclear variant in a cellular background typical of Hodgkin's lymphoma with histologically proven disease elsewhere is highly suspicious of involvement; foci of fibrosis in the absence of typical R-S cells or mononuclear variant with Hodgkin's lymphoma diagnosed elsewhere is suspicious of involvement. [11] Hodgkin's lesions in bone marrow are usually cellular but in some instances, hypocellularity with loose sparsely cellular connective tissue with scattered cells is seen as was seen in the last case. Necrosis is usually seen posttherapy, [11] but in our cases it was present at diagnosis in the majority. Fibrosis is a common finding in Hodgkin's lesions in bone marrow and is not limited to the nodular sclerosis or lymphocyte depletion variants. [11] Immunohistochemistry was used to confirm the diagnosis in four of our cases.

The role of trephine biopsy has been considered nonmandatory by some authors [12] especially in stage IA disease where it is justifiable to avoid trephine biopsy and rarely patients with stage IB and some patients with stage II disease require bone marrow examination because the results of the investigation might determine the choice of treatment. [8] However in the light of our findings, it may be possible to revise the concept of not performing BM trephine biopsy in early stage Hodgkin's to making bone marrow with IHC mandatory for staging as has been stated in another study [13] where its value is considered irreplaceable in the staging of HL and in the diagnosis of primary medullary HL.

If bone marrow examination is required in Hodgkin's disease, a trephine biopsy is essential because, even when the marrow is involved, it is rare for neoplastic cells to be detected in an aspirate [8] as aptly illustrated in this study. It is important to have a high index of suspicion and pick up the histopathological changes of Hodgkin's lesions in the bone marrow as marrow may be the initial or sometimes the only site of involvement. Moreover, nonspecific B symptoms may easily masquerade as an infectious process even though the patient is harboring a lymphoma.


   Conclusions Top


Bone marrow may sometimes be the only or initial site of involvement in Hodgkin's lymphoma. It is important to pick up the histopathological findings of Hodgkin's lymphoma in a bone marrow trephine section with a normal aspirate and absence of any clinical indicators. The IHC has a role in such cases in confirming the diagnosis.

 
   References Top

1.Fried G, Arieh Y, Haim N, Dale J, Stein M. Primary Hodgkin's disease of bone. Med Pediatr Oncol 1995;24:204-7.  Back to cited text no. 1    
2.Citow JS, Rini B, Wollman R, Macdonald RL. Isolated primary extranodal Hodgkin's disease of the spine: Case report. Neurosurgery 2001;49:453-7.  Back to cited text no. 2    
3.Siebert H, Stucky JH, Kurtin PJ, Banks PM. Extranodal lymphocyte predominance Hodgkin's disease. Clinical and pathologic features. Am J Clin Pathol 1995;103:485-91.  Back to cited text no. 3    
4.Stein H, Delsol G, Pileri S, et al. World Health organization classification of tumors. Pathology and Genetics of tumors of hematopoetic and lymphoid tissues. Lyon: IARC Press; 2001. p. 244-53.  Back to cited text no. 4    
5.Munker R, Hasenclever D, Brosteanu O, Hiller E, Diehl V. Bone marrow involvement in Hodgkin's disease: An analysis of 135 consecutive cases. J Clin Oncol 1995;13:403-9.  Back to cited text no. 5    
6.Noguchi Y, Haseawa Y, Nakazawa M, Yoda Y, Abe T, Mori N. Hodgkin's disease diagnosed from numerous Reed-Sternberg cells in the bone marrow. Rinsho Ketsueki 1989;30:731-5.  Back to cited text no. 6    
7.Karcher DS. Clinically unsuspected Hodgkin disease presenting initially in the bone marrow of patients infected with the human immunodeficiency virus. Cancer 1993;71:1235-8.  Back to cited text no. 7    
8.Bain BJ. Bone marrow trephine biopsy. J Clin Pathol 2001;54:737-42.  Back to cited text no. 8    
9.Jain A, Gupta HL. Primary Hodgkin's disease of bone marrow. JIACM 2002;3:395-6.  Back to cited text no. 9    
10.Chopra R, Kumar S, Rana R, Zachariah A. Bone marrow involvement in Hodgkin's disease-clinicopathological study of seven cases. Indian J Pathol Microbiol 1995;38:267-71  Back to cited text no. 10    
11.Brunning RD. Bone marrow. In : Rosai and Ackerman's surgical pathology, vol 2, Mosby; 2004. p. 2094.  Back to cited text no. 11    
12.Ellis ME, Diehl LF, Granger E, Elson E. Trephine needle biopsy in the initial staging of Hodgkin disease: Sensitivity and specificity of the Ann Arbor staging procedure criteria. Am J Hematol 1989;30:115-20.  Back to cited text no. 12    
13.Franco V, Tripodo C, Rizzo A, Stella M, Florena AM. Bone marrow biopsy in Hodgkin's lymphoma. Eur J Haematol 2004;73:149-55  Back to cited text no. 13    

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Correspondence Address:
Seema Tyagi
Department of Hematology, AIIMS, New Delhi 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.41675

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