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2011 — September Case of the Month

Posted September 20, 2011

CLINICAL SUMMARY: Spleen  

CAP Foundation September 2011 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

An 85-year-old woman presented with weakness and abdominal pain. Evaluation revealed pancytopenia, peripheral blood lymphocytosis, and massive splenomegaly. A splenectomy was performed. The 2,227 g spleen had cut surfaces that were dark red-brown and homogeneous. Flow cytometric immunophenotyping revealed a CD45 bright lymphoid population that expressed B cell antigens, FMC7, CD11c, and CD103. CD5, CD10, and CD23 were not expressed.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 32, and is hairy cell leukemia.

Criteria for Diagnosis and Comments: Sections show diffuse infiltration of the red pulp by a population of small-intermediate size lymphoid cells. The combined clinical, morphologic, and immunophenotypic features of this proliferation are diagnostic of hairy cell leukemia. Hairy cell leukemia (HCL) typically is most frequently observed in middle-aged to older males with a mean age at diagnosis of 54 years; the male: female ratio is 4:1. Patients typically present with cytopenias, including monocytopenia, which is very characteristic, and splenomegaly, the latter present in up to 85% of patients. Due to the combination of these defects, patients usually present with infection secondary to neutropenia, as well as fatigue related to anemia and bruising or bleeding secondary to thrombocytopenia.

The diagnosis of HCL is predominantly made in the peripheral blood in which lymphocytes with round to “bean-shaped” nuclei and pale grey-blue cytoplasm with circumferential cytoplasmic projections are noted. In the bone marrow, HCL is evident as nodular, interstitial, or paratrabecular lymphoid aggregates. Typically, the lymphoid cells of HCL are described as having a “fried egg” appearance in tissue sections due to the abundant clear cytoplasm and the non-overlapping, evenly spaced nuclei. Often, the diagnosis must be made in the tissue core, as many marrows will be a “dry tap” due to the presence of abundant reticulin. In the spleen, HCL shows diffuse infiltration of the red pulp. In contrast to other low grade B cell lymphoproliferative disorders involving the spleen, the white pulp is often decreased. In some cases, the extent of red pulp infiltration effaces the white pulp entirely. A characteristic, but not specific, finding in the spleen is the presence of “blood lakes", pseudosinuses filled with red blood cells and lined by neoplastic cells.

The characteristic immunophenotype of HCL is CD19, CD20 and CD22 positive; CD5, CD10, CD23 are negative. CyclinD1 is generally positive but due to variability and intensity it is not of diagnostic utility. The markers CD11c, CD25 and CD103 are all typically expressed on the cells of HCL, and uncommonly in other small B lymphocyte proliferations, providing a relatively specific immunophenotypic profile. Immunohistochemical evaluation with DBA-44, which is not specific to this entity but does highlight the presence of the cytoplasmic projections, and antibodies to tartrate-resistant acid phosphatase (TRAP) provide additional useful diagnostic adjuncts in paraffin sections when flow cytometry is not available. Recently antibodies to CD123 and annexin A1 have been shown to be sensitive and specific markers of HCL.

Once myeloid proliferations, principally chronic myeloproliferative disorders with their associated splenic trilineage hematopoiesis, have been excluded morphologically, the primary differential diagnosis of HCL involving the spleen is with other B cell lymphoma/leukemias. Large B cell lymphoma is easily excluded based on the cell size and the propensity to form a mass lesion. All other B cell lymphoma/leukemias except HCL preferentially involve the white pulp with a nodular architecture. In some cases, however, the involvement may be sufficiently extensive to obscure the architectural differences; flow cytometric immunophenotyping, using the markers above or paraffin section immunophenotyping using a limited panel as indicated in the table below will resolve the vast majority of cases.

 

HCL

SMZL

SLL/CLL

MCL

FL

CD20

+

+

+

+

+

CD5

-

-

+

+

-

CD10

-

-

-

-

+

CD23

-

-

+

-

-

Cyclin D1

+

-

-

+

-

TRAP

+

-

-

-

-

Abbreviations: HCL – Hairy cell leukemia, SMZL – Splenic marginal zone lymphoma, SLL/CLL – Small lymphocytic lymphoma/chronic lymphocytic leukemia, B cell type, MCL – Mantle cell lymphoma, FL – Follicular lymphoma, TRAP – Tartrate-resistant acid phosphatase

Some patients remain asymptomatic and do not require therapy. Currently, most patients with hairy cell leukemia are first treated with Cladribine (2-CdA), a purine-nucleoside analog; a single 7-day infusion will typically result in a very high complete remission rate and a prolonged duration of response. Pentostatin (DCF) is also highly effective as a second line therapy. Splenectomy is reserved for those patients with symptomatic, massive splenomegaly or cytopenias refractory to medical therapy. Ultimately, 30-40% of patients will relapse and, in this setting the salvage therapy of choice is the anti-CD20 antibody, rituximab, or other, less widely available biologic agents such as anti-CD25 and anti-CD22. While most patients are never cured of HCL, as evidenced by persistent minimal residual disease in the bone marrow, long term remissions and extended survival are common.

Supplementary Questions:
For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which of these lymphoma/leukemias characteristically shows a CD20 (+), CD11c (+), CD25 (+), CD103 (+) immunophenotype? A. Chronic myeloid leukemia
B. Hairy cell leukemia
C. Large B-cell lymphoma
D. Mantle cell lymphoma
E. Small lymphocytic lymphoma/chronic lymphocytic leukemia
E. Splenic marginal zone lymphoma
2. Which hematolymphoid proliferation most commonly shows positivity for CD5 and FMC7 typically and also expresses Cyclin D1? A. Chronic myeloid leukemia
B. Hairy cell leukemia
C. Large B-cell lymphoma
D. Mantle cell lymphoma
E. Small lymphocytic lymphoma/chronic lymphocytic leukemia
E. Splenic marginal zone lymphoma
3. Which of these lymphoma/leukemias most commonly preferentially involves the red pulp of the spleen with relative sparing of the white pulp? A. Chronic myeloid leukemia
B. Hairy cell leukemia
C. Large B-cell lymphoma
D. Mantle cell lymphoma
E. Small lymphocytic lymphoma/chronic lymphocytic leukemia
E. Splenic marginal zone lymphoma

References

  1. Bitter MA. Hairy cell leukemia and related disorders. In: Knowles DM, ed. Neoplastic Hematopathology, 2nd ed. Philadelphia: Lippincott, Williams, and Wilkins. 2001; 1531-1556.
  2. Dogan A, Isaccson PG. Splenic marginal zone lymphoma. Sem Diagn Pathol. 2003; 20:121-127.
  3. Gidron A, Tallman MS. Hairy cell leukemia: towards a curative strategy. Hematol Oncol Clin North Amer. 2006; 20:1153-1162.
  4. Hsi ED. B-cell leukemias of mature lymphocytes. In: Hsi, ED, ed. Hematopathology. New York: Churchill Livingstone. 2007; 376-380.
  5. Rao DS, Said JW. Small lymphoid proliferations in extranodal locations. Arch Pathol Lab Med. 2007; 131:383-396.
  6. Sharpe RW, Bethel KJ. Hairy cell leukemia: diagnostic pathology. Hematol Oncol Clin North Amer. 2006; 20:1023-1049.

Author:
2008
Richard W. Brown, MD, FCAP
Surgical Pathology Committee
Memorial Hermann Healthcare System
Houston, TX