A case of composite lymphoma and multiple cancer diagnoses in an individual heterozygous for FANCI variant Free

Here we report a case of multiple malignancies in a patient with a history of superficial basal cell carcinoma (BCC) and seborrheic keratosis. After three years of persistent hematuria and an initial unrevealing workup, a computed tomography (CT) scan revealed an intramural exophytic left bladder mass and an enlarged, left iliac lymph node. Microscopic analysis demonstrated a dense, small infiltrate of atypical lymphocytes with cleaved nuclei in a follicular and diffuse pattern involving the smooth muscle wall and adjacent fibroadipose tissue. The follicles were small, and no germinal centers were identified. The atypical cells were positive for CD10, CD20, BCL-2 and BCL-6, and negative for Cyclin-D1 and CD43. Ig heavy chain gene rearrangement (IGHV) studies identified a monoclonal population. A diagnosis of low-grade follicular lymphoma was favored according to the 4^th edition of the WHO classification system. Subsequent imaging performed two years later due to urinary urgency, revealed an enlarged prostate and a round, solid/heterogenous left kidney mass. Due to his history of elevated PSA, prostatectomy and urinary bladder biopsy were performed and were negative for neoplasia. A partial nephrectomy was later performed. The mass was consistent with renal cell carcinoma (RCC), clear cell type (Fuhrman grade 2/4) stage pT1aNX.

The following year, the patient was admitted due to dyspnea. A chest CT showed a right pleural effusion and a large right anterior mediastinal mass. A biopsy demonstrated a diffuse proliferation of small lymphocytes and rare large cells with irregular nuclear contours. Flow cytometry demonstrated two separate κ-restricted B-cell populations. The two different lymphocytic populations had immunophenotypes consistent with the flow cytometric analysis: one population consisted of CD5-negative and CD10-positive B-cells, distributed in nodules; the other population was a diffuse infiltrate of small B-cells that were CD10-positive and CD5-negative. The neoplastic cells were all Cyclin-D1 negative. The morphology was most consistent with low-grade nodular follicular lymphoma, and the inter-nodular infiltrating population best resembled small lymphocytic lymphoma (SLL). While clonality revealed two rearranged IGH clones, it did not aid in distinguishing between a common or separate clonal origin. The chronic lymphocytic leukemia (CLL) FISH panel did not identify any abnormalities. A bone marrow biopsy performed demonstrated involvement by small mature lymphocytes. The atypical lymphoid aggregate contained cells were positive for CD5, CD20 and PAX5, and negative for Cyclin D1. Flow cytometric analysis detected a κ-restricted population of B-cells expressing CD5, CD19, dim CD20, and CD23. FISH analysis revealed trisomy 12. The combination of findings was most consistent with involvement by CLL/SLL. In the subsequent years, the patient was later diagnosed with infiltrating nodular type BCC and cervical lymph node involvement by kappa-restricted follicular lymphoma.

Targeted panel and whole exome sequencing were performed on tissues from the bladder follicular lymphoma, clear cell RCC, CLL/SLL, mediastinal composite lymphoma, and non-neoplastic tissue to establish a possible overlap among these tumors. Variants from exome sequencing data were compared with the variants for the ACMG 81 genes to rule out cancer predisposing variants. Copy number variants (CNV) were derived from the exome data.

Targeted panel sequencing detected a FANCI C777R variant in all samples and there were no other overlapping variants detected. Analysis from the exome data detected CNV along chromosome 3, 5, 10, 14 and 20 in the clear cell RCC. Clustering analysis of variants indicated that the bladder lymphoma, CLL/SLL, and composite lymphoma were more closely related compared to the RCC.

Various factors may be involved in the pathogenesis of this patient's numerous malignancies. This case illustrates the importance of obtaining an accurate history at the time of initial diagnosis to identify important risk factors and prognostic indicators to assist in determining the most appropriate treatment strategies. Through comprehensive genomic analysis we ruled out known likely/confirmed cancer predisposing variants.