Case presentation:

A 47-year old Chinese man who enjoyed good past health presented with pyrexia of unknown origin for 4 months associated with liver derangement. Physical examination showed small cervical lymph nodes and hepatosplenomegaly. Complete blood counts showed: haemoglobin 9.5 g/dL, white blood cells 2.6 X 109/L, and platelets 13 X 109/L. Liver function test showed (normal range in parenthesis): albumin 32 g/L (42-54), globulin 30 g/L (24-36), bilirubin 247 mmol/L (7-19), alkaline phosphatase 226 IU/mL (49-138), alanine transaminase 403 IU/L (6-53), aspartate transaminase 717 (13-33), g-glutamyl transferase 69 IU/mL (8-37) and lactate dehydrogenase 1390 IU/L (197-401). No infection cause was identified. Viral serology including hepatitis B and C was negative. An extensive panel of immune markers was negative. Cervical lymph node biopsy was inadequate for diagnosis, and bone marrow aspiration showed reactive changes. HIV testing was negative. Empirical anti-TB therapy was instituted, but without response. A PET scan was negative. The patient developed acute renal failure, coma and bilateral clonus that necessitated intubation and mechanical ventilation. A CT scan of the abdomen showed hepatosplenomegaly only with no focal lesion detected. He ran a downhill course and succumbed to multi-organ failure and uncontrolled sepsis despite aggressive inotropic support.

A repeat trephine biopsy before death showed abnormal lymphoid infiltration of the bone marrow in a nodular pattern associated with focal coarsening of reticulin fibres. There were large mononuclear cells (Figures 1 & 2) showing inclusion-like nucleolus and abundant amphophilic cytoplasm. On immunostaining, these large lymphoid cells were positive for CD30 and hence stood out prominently (Figure 3). The CD30 staining was localized to the cell membrane as well as the Golgi zone (Figure 4). Other markers including LCA, EMA, L26 and CD3 were negative. In-situ hybridization study showed that the abnormal lymphoid cells are positive for EBER (Figure 5)

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Post-mortem examination showed multiple lymphadenopathy affecting the mediastinal, para-aortic and peri-pancreatic lymph nodes as well as those around the common bile duct region. Microscopic examination showed complete effacement of lymph node architecture and replacement by an infiltrate of abnormal lymphoid cells within a fibrosclerotic background (Figure 6). These cells had prominent nucleoli resembling Reed-Sternberg (RS) cells (Figure 7). Lymphocytes, histiocytes and a few eosinophils are present in the background. Immunohistochemical studies revealed that these cells were positive for CD30 and CD15, but were negative for epithelial marker AE1/3, leucocyte common antigen (CD45), B-cell marker CD79a, T-cell marker CD3 and anaplastic lymphoma marker ALK-1. Additionally, the liver (2763 grams in weight), spleen (726 grams in weight) and both adrenal glands (9 and 10 grams respectively) were enlarged. Microscopic examination showed lymphomatous infiltration in all these organs, and in the spleen there was marked expansion of the white pulp due to lymphoma involvement (Figure 8).

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Diagnosis

Disseminated Hodgkin's Lymphoma, lymphocytic depletion type, involving the bone marrow, liver, spleen and both adrenal glands in addition to multiple lymph node regions.

Discussion

Lymphocytic depletion is the least common form of Hodgkin's lymphoma, found in approximately 1% of cases. Controversy surrounding this subtype is reflected by the various proposals in the WHO classification as to whether lymphocytic depletion should be a category of anaplastic large cell lymphoma (ALCL). It is retained in the latest WHO classification and includes cases that previously were considered Hodgkin's-like ALCL but currently reinterpreted as ALCL-like Hodgkin's lymphoma, which usually behaves aggressively.

Histologically, lymphocytic depletion comprises diffuse fibrosis and reticular types. Diffuse fibrosis, as observed in the present case, is characterized by a disorganized proliferation of non-birefringent connective tissue of non-collagenous type. In addition to connective tissue, the lymph node is usually depleted of cells, particularly of lymphocytes, although rare cellular areas may be observed. The reticular type of lymphocytic depletion is characterized by two essential patterns: one resembling mixed cellularity but with a predominance of RS cells, and the other showing increased RS cells that appear pleomorphic and almost sarcomatous.

The clinical characteristics of lymphocytic depletion include the following:

1. Older age at onset.
2. Constitutional symptoms such as fever and wasting.
3. Hepatic dysfunction.
4. Advanced stage disease: subdiaphragmatic disease (liver, spleen, retroperitoneal lymph nodes) and bone marrow involvement.
5. More aggressive clinical course.

The differential diagnosis of lymphocytic depletion Hodgkin's lymphoma include, in addition to ALCL, other forms of Hodgkin's lymphoma particularly nodular sclerosis grade II and syncytial variant, and the mixed cellularity type with increased numbers of mononuclear variants of RS cells. Distinction from ALCL proves to be most difficult, because there appears to be a continuous spectrum between these disorders with much clinical morphologic and immunologic overlap. Immunohistochemistry is very useful in resolving these cases but may not always settle the ambiguity. In general, lymphocytic depletion tends to be CD15+, CD45-, T-cell-, and EMA-, whereas the opposite is true for ALCL. However, CD15 expression is lacking in 15% of Hodgkin's lymphoma, and other markers may also show a range of reactivities. Tumour expression of t(2;5) or ALK-1 supports ALCL, but most cases with overlapping features of ALCL and Hodgkin's lymphoma are ALK-1 negative. Therefore, despite evaluation of morphology, immunophenotype and molecular genetic marker, a small number of cases still defy classification. These patients, nevertheless, respond to chemotherapy for high-grade non-Hodgkin's lymphoma and to conventional Hodgkin's disease treatment.

Finally, lymphoma cases with initial presentation in the bone marrow as encountered in our patient usually manifest as protracted fever of unknown origin, cytopenia and liver derangement. The possibility of an underlying lymphoma should always be kept in mind for these cases in addition to cryptic infections and autoimmune disorders, and an early diagnosis may translate into a better chance of survival for the patient.