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Atypical CLL/SLL vs. CLL/SLL

History:

An 89 year-old female with generalized adenopathy underwent left cervical neck lymph node biopsy.

Microscopic Findings:

Lymph node architecture was completely effaced by small well differentiated lymphocytes with irregular, variably interspersed and expanded “pale” zones containing small, medium and few larger cells with nucleoli. There was mild increase in background capillary sized blood vessels. No preserved germinal centers, subcapsular sinuses, or medullary spaces were seen. Focally, tumor cells extended beyond the capsule into surrounding adipose.

Special Studies:

A. Flow cytometry - 59% CD5+ monoclonal B-cell population, compatible with malignant B cell lymphoma with an immunophenotype suggestive of mildly atypical chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), requiring morphologic subclassification

a. CD45+ (moderate), CD19+, CD20+ (heterogeneous), CD5+, CD10-, CD23+, FMC7-, CD38+ , sIg kappa+ (bright)

B. Immunohistochemistry - Paraffin immunohistochemical stains highlighted a mixture of PAX5+ B cells and nearly equal numbers of CD3+ T cells. Relative to PAX5+ B cell staining, there was a 40-50% Ki67 index. Tumor cells were p53 negative.

C. FISH -

a. Deletion of 11q22.3(ATM) in 78% of cells.

b. Gain of CEP 12 in 32% of cells.

c. Gain of CEP 12 concurrent with deletion 13q14 in 16% of cells.

d. NEGATIVE for BCL1(CCND1)/IGH/ t(11;14)

- two non-rearranged copies of BCL1(CCND1) and IGH; two non-rearranged copies of 6q23, 11q13, 13q34, 14q32 and 17p13.1

Differential Diagnosis: Atypical CLL/SLL vs. CLL/SLL undergoing large cell (Richter’s) transformation vs. atypical mantle cell lymphoma vs. “paraimmunoblastic” lymphoma

Diagnosis: “Accelerated” small lymphocytic lymphoma/ chronic lymphocytic leukemia with increased proliferation centers and unfavorable cytogenetic features.

Educational comments: Typically, small lymphocytic lymphoma/chronic lymphocytic leukemia undergoes “transformation” in two forms, either large cell (Richter’s) transformation or prolymphocytic transformation. The concept of “accelerated” CLL/SLL is less clearly defined in pathologic terms. Historically, there have been scattered, murky reports describing atypical small lymphocytic lymphomas such as this case, that were confused by blurred distinctions between prolymphocytes, paraimmunoblasts, and large cells. Many or most of those earlier reports seem to better described as “accelerated” small lymphocytic lymphomas with "increased proliferation centers" (see reference). Although it is tempting to equate increased proliferation centers in tissue samples with increased prolymphocytes in circulating blood, it is not certain that these are equivalent features of disease progression in CLL/SLL.

In tissue sections, “accelerated” small lymphocytic lymphomas with "increased proliferation centers" lack features off large cell transformation and demonstrate increased numbers of expanded proliferation zones, intermediate levels of Ki67 staining (5-30%) and intermediate prevalence of positive p53 staining when compared to nonaccelerated CLL/SLL and diffuse large B cell lymphoma.

In support of an accelerated form of disease, which is associated with unfavorable overall survival, this tumor demonstrated adverse cytogenetic features deletion 11q22.3(ATM) and trisomy 12.

References: Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (“accelerated” chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica 2010;95(9):1526-1533

Fig. 1 - Conventional region of usual CLL/SLL (H&E)

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Fig 2 - Proliferation zone (H&E)

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Fig. 3 - Proliferation zone (Ki67)

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Fig. 4 - del 11q22.3 (ATM) [MYBx2(Aqua),ATMx1(Green), p53x2(Orange)]

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Fig. 5 - trisomy 12 [CEP12x3(Green), 13q14x2(Orange), 13q34x2(Aqua)]

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Mastocytosis

History:

A 45 year old man presents with occasional episodes of sweating, diarrhea, tachycardia, flushing, and syncope over previous four years. Laboratory data shows an increased tryptase level. A bone marrow biopsy was performed.

Microscopic Findings:

Bone marrow examination revealed few small paratrabecular lymphoid aggregates consisting of small unremarkable lymphocytes with admixed cells with spindle-shaped nuclei and well-defined cytoplasmic borders in a fibrotic stroma. The aggregates also contained an infiltrate of unremarkable eosinophils. Aspirate smear morphology was unremarkable with no aggregates seen.

Gastroesophageal Junction Adenocarcinoma

HER2 negative GIST

Invasive poorly differentiated gastroesophageal junction adenocarcinoma with signet ring cell features
- NEGATIVE for HER2 (immunohistochemistry)

HER2 gene amplification and/ or HER2 protein overexpression have been demonstrated in colon, bladder, ovarian, endometrial, lung, cervical, head and neck, esophageal, and gastric carcinomas, which represent non-mammary candidate targets for Herceptin therapy. The need for Herceptin therapy is augmented in aggressive, high stage cancers for which highly effective drugs are not available.

The recent Trastuzumab for Gastric Cancer (or so-called ToGA) clinical trial established benefit from Herceptin (trastuzumab) in combination with chemotherapy as first-line therapy for HER2 positive gastric or gastroesophageal junction carcinomas.

Myeloid Neoplasm with Eosinophilia and PDGFR-alpha Rearrangement

FISH deletion 4q12

Hypereosinophilia represents a diagnostic challenge. As in the past, one must clinically exclude benign secondary reactive causes such as infection, hypersensitivity, paraneoplastic reaction, pulmonary and autoimmune diseases. If there is persistent, unexplained eosinophilia lasting more than 6 months without attributable cause, one might consider myeloproliferative neoplasms with dominant eosinophilia, chronic eosinophillic leukemia, rare myeloid and lymphoid neoplasms with recurrent genetic abnormalities or the shrinking category of hypereosinophilia syndrome.

Enteropathy-Associated T-cell Lymphoma

enteropathy associated T-cell lymphoma malignant lymphocytes

The majority of Enteropathy-associated T-cell lymphomas (EATL) are associated with adult onset gluten-sensitive enteropathy with which they have a similar geographic distribution, which are usually CD56- CD103+. A minor subset of EATLs (Type II; monomorphic variant) is not as clearly associated with gluten-sensitive enteropathy. These subsets are typically CD56+ CD8+. Both subtypes are CD4-, and >80% positive for chromosomal gains at chromosome 9q31.3. In the case of Type II EATL, clinical correlation is required to exclude unlikely secondary GI involvement by an unusual CD56+ peripheral T-cell lymphoma, NOS.

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