Vanishing bile duct syndrome associated with peripheral T cell lymphoma, not otherwise specified, arising in a posttransplant setting

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A 23-year-old man with end-stage renal disease of uncertain etiology underwent deceased donor renal transplant. Seven years later, the patient presented complaining of increasing abdominal girth as well as bilateral upper quadrant pain and nausea. Physical examination was significant for cachexia, scleral icterus, and massive ascites. The posttransplant clinical course was reportedly free of cytomegalovirus infection and rejection. Although scleral icterus and ascites were new findings, the patient had reportedly experienced progressive cachexia with intermittent fever of unknown origin (despite an extensive infectious disease work-up) over the preceding two years.

Serum chemistries were remarkable for an alanine aminotransferase level of 94 U/L, an aspartate aminotransferase level of 110 U/L, alkaline phosphatase level of 237 U/L, and a total bilirubin level of 5.1 mg/dL. Typical viral hepatitides (A, B, C) were excluded by serological and polymerase chain reaction-based testing, although Epstein-Barr virus was detected by polymerase chain reaction (<1000 copies/mL serum). Results from coagulation testing were abnormal (international normalized ratio = 2.0). The creatinine was markedly elevated (4.68 mg/dL) and there was evidence of metabolic acidosis. The complete blood count was normal except for slight leukocytosis (14.9 × 109 cells/L) and neutrophilia (12.7 × 109 cells/L). Computed tomography imaging confirmed massive ascites and identified mesenteric and retroperitoneal lymphadenopathy. Ultrasound did not detect hepatobiliary abnormalities and specifically, there was no evidence of portal hypertension (further supported by a serum-ascites albumin gradient of 0.7). To further assess the etiology of acute liver dysfunction, a transjugular liver biopsy was performed.

Histological sections of the liver core biopsy show hepatic parenchyma with severe (grade 3) macrovesicular steatosis and a primarily portal-based lymphohistiocytic infiltrate (Fig. 1A). Relatively monomorphous small-to-intermediate size lymphocytes, with dark smudgy chromatin, infiltrate the endothelium and focally extend into lobular parenchyma (Fig. 1B). Cholestasis and ductopenia were appreciated (0 of 13 [0%] portal tracts with interlobular bile ducts) (Fig. 1C); the latter was confirmed by absence of cytokeratin-7 immunostaining. Steatosis in this biopsy may reflect the patient's nutritional state, particularly given that the overall features do not appear characteristic of steatohepatitis and that the patient did not have other risk factors for fatty liver disease. The infiltrate was composed predominantly of T cells (CD3/CD4-positive) with aberrant loss of CD7 (Fig. 1D), and without coexpression of Epstein-Barr virus (as determined by Epstein-Barr virus-encoded RNA in situ hybridization), CD30, or CD20. This immunophenotype was consistent with flow cytometric findings obtained concurrently from a retroperitoneal lymph node fine-needle aspirate (and also from ascites fluid, thereby supporting an etiologic role for malignancy in this patient's massive ascites) with the lack of CD20 expression arguing against a diagnosis of B cell lymphoma and the lack of CD30 expression arguing against classification as an anaplastic large cell lymphoma. Aberrant loss of CD7 expression and identification of clonal rearrangement of the T cell receptor gamma chain gene, determined by polymerase chain reaction amplification, further support consideration of a neoplastic T cell population and, taken together with the morphology, other immunophenotypic findings, and clinical context, are consistent with a peripheral T cell lymphoma, not otherwise specified, arising in a posttransplant setting (i.e., a monomorphic T cell posttransplant lymphoproliferative disorder). An etiologic role for immunosuppression is unclear in this setting.

Figure 1.

Hematoxylin and eosin stained sections of a liver core biopsy showing a portal based lymphohistiocytic infiltrate and severe steatosis (A, 100× magnification); a medium size artery with infiltration by lymphoma cells, an arrow highlights the infiltrating atypical lymphocytes (B,400× magnification); a portal tract without an apparent interlobular bile duct, arrows highlight interlobular hepatic arterioles (C, 400× magnification); and a CD3 immunohistochemical stain highlighting a T-cell predominant infiltrate (D, 100× magnification).

Vanishing bile duct syndrome (i.e., “idiopathic adulthood ductopenia”) has been histologically defined as the absence of interlobular bile ducts in at least 50% of portal tracts1 and has been well described in association with classical Hodgkin lymphoma,2, 3 either from direct damage by lymphoma cells or more likely through paraneoplastic bile duct destruction by lymphoma-derived cytokines.4 In at least one report, these histologic findings are reversible with successful chemotherapy.5 Other ductopenic entities in the differential diagnosis in adults would primarily include primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune cholangiopathy, sarcoidosis, and drug-induced injury.

This case represents the first report of posttransplant peripheral T cell lymphoma, not otherwise specified, in association with bile duct paucity. Although a cytokine-mediated paraneoplastic effect could represent the underlying mechanism, direct damage may be likely given the extent of portal-based involvement in this case. Following treatment with a single dose of cyclophosphamide, this patient experienced catastrophic decline in all organ functions and died 5 weeks after admission to the hospital.

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