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A 39-year-old woman presented with increasing fatigue, abdominal fullness, nausea, upper abdominal left quadrant pain, menometrorrhagia, and bruising. Evaluation revealed moderate pancytopenia (Hb: 9.2 gm/dL; HCT: 28%; WBC: 3,800/uL; Differential count: neutrophils: 67%; monocytes: 0%; lymphocytes: 28%; atypical lymphocytes: 5%). An enlarged spleen extending across the umbilicus was palpable. Splenectomy revealed a 1,535 g spleen measuring 27.0 x 17.0 x 9.0 cm. Grossly, there was red pulp expansion without any lesions. Immunohistochemically, the lesional cells are positive for CD20, CD10, and DBA.44 and negative for CD3 and CD43. Flow cytometry revealed a neoplastic B-cell population, monotypic kappa, positive for CD19, CD20, CD22, CD11c, CD25, and CD103.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2010, case 17, and is a hairy cell leukemia.
Histologic sections show diffuse expansion of the red pulp by a population of mostly small lymphoid cells with moderate eosinophilic cytoplasm and somewhat irregular nuclear membrane contours. This histologic picture in combination with the clinical presentation of splenomegaly and pancytopenia (characteristically monocytopenia), the immunohistochemical phenotype, and the flow cytometric findings are diagnostic of hairy cell leukemia (HCL).
HCL is a rare neoplasm of small mature B-cells with oval nuclei and abundant cytoplasm showing ‘hairy’ cytoplasmic projections. It involves the peripheral blood and diffusely infiltrates the bone marrow and the splenic red pulp, rarely involving lymph nodes. HCL predominantly affects middle-aged to elderly adults with a median age of diagnosis of 52 years, although rarely it has been diagnosed in young adults. The male: female ratio is approximately 5:1. HCL most commonly presents with cytopenias and splenomegaly. As a result, clinical symptoms often include weakness and fatigue, fever, left upper quadrant pain, and bleeding.
The diagnosis of HCL is best made on peripheral blood smear examination in conjunction with bone marrow aspirate and biopsy; occasionally a diagnosis is made on tissue. In the bone marrow, HCL present as an infiltrate of widely-spaced lymphoid cells with oval or indented (bean-shaped) nuclei. The abundant eosinophilic cytoplasm and prominent cell borders give the cells a ‘fried-egg’ appearance on H&E stain. Occasionally the infiltrate is sparse and may be missed on core biopsy. If truly hypocellular, HCL may result in a ‘dry tap’. Analysis of the peripheral blood will show a minority population of abnormal small to medium-sized lymphoid cells with oval or indented nuclei and abundant pale blue cytoplasm with circumferential ‘hairy’ cytoplasmic projections, leading to the given nomenclature.
In the spleen, HCL shows diffuse infiltration of the red pulp, rarely showing complete effacement of the white pulp. ‘Blood lakes’ in the spleen are a characteristic but non-specific finding in HCL and consist of collections of red blood cells surrounded by neoplastic lymphoid cells.
The classic immunophenotype (by flow cytometry) of HCL consists of bright monotypic surface immunoglobulin, bright co-expression of CD20, CD22, and CD11c, and expression of CD103, CD25, CD123, and DBA.44 (frequently by IHC). Negative markers include CD5, CD10, CD23, and cyclinD1. Most importantly, positive CD25, CD11c, and CD103 in the setting of a CD20 positive lymphoid disorder is diagnostic of HCL. DBA.44 immunohistochemical stain may highlight the presence of the characteristic cytoplasmic projections. Immunohistochemical or cytochemical stains for tartrate-resistant acid phosphatase (TRAP), frequently done on peripheral blood, is an additional clue to the diagnosis; TRAP should be positive in HCL.
The primary differential diagnosis of HCL of the spleen is other B-cell lymphomas/leukemias, including splenic marginal zone lymphoma and small lymphocytic lymphoma/chronic lymphocytic leukemia. These other B-cell neoplasms preferentially involve the splenic white pulp in a nodular fashion whereas HCL diffusely infiltrates the red pulp, primarily sparing the white pulp. Similar to HCL, splenic marginal zone B-cell lymphoma has cytoplasmic projections when it involves peripheral blood. But in contrast to HCL with its circumferential fine projections, splenic marginal zone lymphoma is described to have ‘bi-polar’ cytoplasmic projections. Rarely, other B-cell neoplasms may involve the spleen extensively enough to obscure the splenic architecture entirely, making a morphologic diagnosis less straightforward. Other differential diagnoses include the metabolic disorder Gaucher disease and extramedullary hematopoiesis involving the spleen. Gaucher disease can result in massive splenomegaly with diffuse expansion of the red pulp by numerous histiocytes with fine abundant cytoplasm, and relative preservation of the white pulp. However, the histiocytes can be readily distinguished by the lack of the characteristic nuclei of HCL, and through flow cytometry/IHC markers. Splenic extramedullary hematopoiesis will also show expansion of the red pulp, but the histologic picture should show complete trilineage hematopoiesis with myeloids, erythroids and occasional megakaryocytes, rather than a monomorphic lymphoid cell population. To resolve these difficult cases, flow cytometric immunophenotyping or paraffin section immunohistochemical staining using the previously mentioned markers in a limited panel is warranted. CD68 immunostain will highlight the histiocytic infiltrate of Gaucher disease. Large B-cell lymphoma is usually easily excluded from the differential due to the difference in cell size and its typical presentation as a mass or nodular lesion. Occasionally HCL may resemble a myeloid proliferation, specifically chronic myelogenous leukemia, but a myeloid lesion such as CML should be easy to exclude by peripheral blood/bone marrow examination and characteristic t(9;22) translocation.
The overall 10-year survival rate for HCL exceeds 90%, and many patients remain asymptomatic without treatment. HCL is uniquely sensitive to either α-interferon or purine analogs. Current first line therapy in most patients is cladribine (2-CdA), and pentostatin is highly effective as a second line therapy. Splenectomy is generally reserved for patients with symptomatic massive splenomegaly, or in those patients with refractive cytopenias. Over time, 30-40% of HCL patients will relapse and require salvage therapy with agents such as rituximab (anti-CD20), or more experimental biologic agents such as anti-CD22 and anti-CD25. HCL remains an indolent lymphoid neoplasm, with extended remissions and long-term survival.