Hepatic Infiltration with Malignant T-cells Manifesting as Impending Acute Liver Failure in Sezary Syndrome
Received: August 14, 2019
Accepted: December 16, 2019
Mediterr J Hematol Infect Dis 2020, 12(1): e2020007 DOI 10.4084/MJHID.2020.007
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describe a case of impending acute liver failure in a patient with
Sézary syndrome (SS). The three-phase computed tomography (CT) of the
liver showed neither mass nor hepatomegaly. Liver biopsy confirmed
infiltration with malignant CD4+ clonal T-cells. Prompt administration
of combination chemotherapy, consisting of gemcitabine, dexamethasone,
and cisplatin (GDP), resulted in full recovery of liver function. To
the best of our knowledge, this is the first report of liver failure
from SS. Commercial next-generation sequencing panel identified 11
clinically relevant mutations. Interestingly, the identified ARID2
mutation, frequently observed in hepatocellular carcinoma, rarely
occurs in hematologic malignancies. Further studies are necessary to
elucidate the role of ARID2 mutations in the biological behavior of
Sezary cells, such as a propensity to infiltrate liver parenchyma.
Patients with hematologic malignancies infrequently develop acute liver failure (ALF). The main mechanisms for ALF include tumor infiltration, drug-induced hepatotoxicity, and reactivation of viral hepatitis. ALF has not been reported in SS. Here, we report a case of impending ALF secondary to hepatic involvement of SS. The patient had full recovery of the liver function after initiation of chemotherapy.
While being treated for his symptoms, he developed worsening of transaminitis and anasarca on hospital day (HD) 4. Despite stopping potentially hepatotoxic agents including allopurinol and gabapentin, his LFTs rose exponentially. On HD 6, his AST/ALT/ALP were 1570/1442/660 IU/L, respectively, total bilirubin was 6.7 mg/dL, and INR was 1.3. Work-up included negative infectious etiologies (hepatitis A, hepatitis B, hepatitis C, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, and herpes simplex virus); negative hemophagocytic lymphohistiocytosis markers; negative antinuclear antibody and anti-mitochondria antibody. Anti-smooth muscle antibody was mildly elevated (38 units, normal range 0-19 units), which was more consistent with liver injury than autoimmune hepatitis. Abdominal Doppler ultrasound and triple-phase CT scan of the liver were negative for liver pathology or hepatomegaly (Figure 1).
|Figure 1. Triple-Phase CT scan of the liver. No focal lesions were present in the liver or spleen. Hepatosplenomegaly was absent. Generalized edema was seen diffusely.|
A trial of steroids was initiated. However, the AST/ALT continued to increase rapidly to the 2000s IU/ml by HD 7. His jaundice and mental status worsened. Despite the absence of liver abnormalities on imaging studies, ALF secondary to hepatic involvement of SS was suspected. He was referred for diagnostic core needle liver biopsy. The final pathology report of the liver biopsy confirmed malignant hepatic infiltration with Sézary cells. Cytomorphology showed dense portal infiltrate by mostly small mature atypical lymphocytes without large cell transformation; immunohistochemical staining revealed CD4+ T cells with loss of CD7 (Figure 2); flow cytometry and T-cell receptor gene rearrangement studies of the tissue confirmed monoclonal T cell population. Next-Generation Sequencing (NGS) of peripheral blood (Foundation One Inc. Cambridge, MA) showed a high mutation burden (25 mutations/Mb) and identified 31 genetic alternations. Seven clinically relevant mutations included CCND3 P203L, STAT3 D661Y, ARID2 G70Fs*20, ASXL1 T822fs*11, CBL C3965, CD58 Q32*, CDKN2a splice site 151-1G>A, CIITA Q909*, EP300 Q641*, MAPK1 E322K, and TNFAIP3 loss.
He was treated with a chemotherapy regimen consisting of gemcitabine, dexamethasone, and cisplatin (GDP). The patient’s LFTs and mental status started to improve on the second day of GDP.
His LFTs normalized and erythroderma resolved during the 1-month follow-up. He completed two additional cycles of GDP, followed by maintenance gemcitabine. Restaging PET/CT showed complete remission. Unfortunately, he passed away six months later due to myocardial infarction.
To the best of our knowledge, the present case is the first report of liver injury from malignant hepatic infiltration of SS. This case showed that the prompt administration of chemotherapy could result in the complete recovery of liver function and prevent progression into ALF. The diagnostic dilemma included the lack of abnormalities in multiple imaging modalities and concerns for recurrent disease of the previously treated DLBCL. Homogeneous infiltration of malignant cells in the liver occasionally makes it difficult to detect with imaging studies and can result in a delay in diagnosis. High clinical suspicion should trigger liver biopsy and molecular studies.
A high mutation burden in NGS may potentially explain the aggressiveness of the disease. Among the identified mutations, TNFAIP3 mutations have been reported in CTCL previously. CCND3, STAT3, ASXL1, CBL, CDKN2A, EP300, and MAPK1 have been reported in adult T cell lymphoma/leukemia and other types of mature T cell lymphomas (COSMIC 2017).
ARID2 mutation has rarely been reported in hematologic malignancy (prevalence: 0.5%), but frequently described in hepatocellular carcinoma (prevalence: 5-20%).[5,7] ARID2 encodes a subunit of the SWI/SNF-B (PBAF) chromatin remodeling complex, which assists in mediating gene expression and double-strand DNA gene repair. ARID2 functions as a tumor suppressor gene and is associated with loss-of-function mutations in most cases. In the absence of ARID2, cells are sensitized to DNA damage secondary to ultraviolet light and other carcinogens. In the present case, ARID2 mutation was a frameshift mutation of G70fs*20 in the splice site, likely resulting in loss of function. The ARID2 mutation possibly predisposes Sezary cells to acquire more mutations and aggressive features. Further studies are necessary to elucidate the role of ARID2 mutations in the biological behavior of Sezary cells, such as a propensity to infiltrate liver parenchyma.
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