April 2015

A 26 year-old female with an enlarging left leg nodule

Matthew Szarko, MD, MPH and Flavia Rosado, MD

Overview

A 26-year-old Caucasian female presented with a 2.0 cm nodule on her left anterior leg. Imaging studies showed a solid-appearing soft tissue mass abutting the tibia, with underlying cortical bone thickening.  CT-guided biopsies were performed.

Microscopic Description

The biopsy showed a diffuse cellular infiltrate dissecting through skeletal muscle, with intervening large areas of necrosis (top left).  There was no overlying epidermis present for evaluation.

Sheets of neoplastic cells are seen in a fibrotic background. Crush artifact was prominent throughout the specimen.
On high magnification, the neoplastic cells were predominantly intermediate in size, and displayed oval nuclei, vesicular chromatin, occasional small nucleoli, and inconspicuous cytoplasmic borders. Numerous mitotic figures and apoptotic cells were noted.
By immunohistochemistry, the neoplastic cells were positive for CD20 and co-expressed BCL-6 and CD10. They were negative for CD5, CD3, CD43 (not shown), and BCL-2. Ki-67 (not shown) showed a high proliferation rate of greater than 95%.
A fluorescent in situ hybridization (FISH) study using break apart probes was positive for rearrangements involving the MYC gene on chromosome 8q24. FISH using dual fusion probes was negative for an IGH/MYC translocation (not shown) .

Diagnosis

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Answer

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Discussion

Burkitt lymphoma (BL) is a highly aggressive B-cell neoplasm first described by Denis Burkitt in 1958. It is the most common non-Hodgkin lymphoma (NHL) in children and adolescents, accounting for over 40% of NHL’s in those under the age of 20. [1,3,4,5] The three clinical variants of BL are endemic, sporadic and immunodeficiency-associated types. 

The endemic variant is found in the malaria belt of equatorial Africa and in Papua, New Guinea. The majority of these cases are EBV positive.  BL primarily affects extranodal sites, especially the jaw and orbit of children aged 4 to 7 years. The sporadic variant also more commonly affects children and young adults. However, in contrast to the endemic variant, the sporadic type is seen around the world, involvement of the jaw or orbit is unusual, and EBV positivity is present in less than 30% of cases.  The immunodeficiency-associated variant affects all ages, and is commonly seen in patients with the acquired immunodeficiency syndrome (AIDS), although it may occur in association with other types of immunosuppression, including primary and iatrogenic disorders. Bone marrow and nodal involvement are common, and EBV positivity is seen in 25% to 40% of cases.[2,3,4]

The characteristic t(8;14) MYC translocation involves the MYC gene (8q24) and the Ig heavy chain region (14q32), and is seen in 75-80% of cases.  Although rearrangements of MYC play a role in the pathogenesis of BL, the exact mechanism of disease has not been entirely elucidated. Overexpression of the MYC gene promotes cell proliferation and allows the tumor cells to evade host immune control tumor survival by downregulating expression of human leukocyte antigen (HLA) class I molecules. However, there have been studies suggesting that MYC overexpression alone is insufficient to cause lymphoma. [3,4] In addition, MYC gene rearrangements are not pathognomonic of BL, and may be found in other hematopoietic malignancies. [2,3]

Morphologically, BL presents as a diffuse infiltrate of monomorphic medium-sized cells that exhibit round nuclei, dispersed chromatin, and inconspicuous nucleoli. On imprint preparations, the cells show basophilic cytoplasm and frequent lipid vacuoles. The numerous mitotic figures and macrophages containing apoptotic debris reflect the tumor’s high proliferation rate, and gives a low power view reminiscent of a “starry sky”. [2,3] By immunophenotyping, BL is composed of CD 20-positive light chain restricted mature B-cells that co-express CD10, BCL6, CD19, and CD22, and are negative for BCL2.  The proliferation rate determined by Ki-67 expression is greater than 95% in nearly all tumors.

The overall survival is near 90% in children and 50-70% in adults.  Poor prognostic factors include bone marrow involvement, large tumors greater than 10 cm, and high LDH serum levels.  Relapses typically occur within the first year after diagnosis. CNS involvement is a common complication in patients that do not receive prophylactic CNS chemotherapy. [2,3,4]

In conclusion, BL is an aggressive, but curable mature B-cell malignancy.  The diagnosis of BL should be considered in biopsies of rapidly enlarging masses showing diffuse and monotonous infiltrate of medium-sized cells with high proliferation rate (greater than 95%).  Once BL is considered, the diagnosis can be confirmed with cytogenetic or FISH studies showing the typical MYC gene rearrangement. [2,3]

References

  1. Gattuso, P, Reddy, VB, David, O, et al. (2010) Differential Diagnosis in Surgical Pathology, 2e. Saunders Elsevier. Philadelphia, PA.
  2. Swerdlow, SH, Campo, E, Harris, NL, et al. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4ed. International Agency for Research on Cancer (IARC). Lyon, France.
  3. Jaffe, ES, Harris, NL, Vardiman, JW, Campo, E, Arber, DA. (2011) Hematopathology. Saunders Elsevier. St. Louis, Missouri.
  4. Gorczyca, W and Emmons, F. (2008) Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2ed. Genzyme Genetics, New York, NY.
  5. Said, JW. Aggressive B-cell lymphomas: How many categories do we need? Modern Pathology. 2013;26:542-556.