Cystic Hepatic Lesions in c-Kit Negative Systemic Mastocytosis

Abstract

Purpose: Systemic mastocytosis (SM) is a rare disorder characterized by infiltration of mast cells in visceral organs. We present a 70 year old male with a c-kit negative mutation and aggressive SM presenting as multiple cystic liver lesions and non-cirrhotic portal hypertension. He had presented with worsening dyspnea on exertion, increased abdominal girth and weight loss. He had no history of alcohol, tobacco, IV drug use, transfusion, tattoos or familial liver disease. On exam, he had a fluid wave and hepatomegaly. Labs showed a WBC 3.9 × 10(9)/L with 35% monocytes, hemoglobin 9.7 g/dL, platelets 110 × 10(9)/L, alkaline phosphatase 201 U/L and INR of 1.3. Electrophoresis revealed a polyclonal gammopathy. Viral and autoimmune etiologies were excluded. Ascitic fluid showed a SAAG of 1.6 with total protein of 5 g/L and 89 neutrophils. Cytology showed histiocytes and mesothelial cells. Serum tryptase level was 150 ng/dL (nl<11.5). Imaging showed splenomegaly, ascites, recanalization of the umbilical vein, innumerable cystic liver lesions without arterial enhancement and multiple lytic rib lesions. Bone marrow biopsy revealed hypercellular marrow with an infiltrate of atypical spindle cells, compromising 30-40% of the cellularity. Immunohistochemical staining of the atypical cells was positive for CD117, mast cell tryptase, and CD25. Liver biopsy showed a similar infiltrate of atypical spindle cells, involving the portal areas and dispersed through the sinusoids with associated focal fibrosis. He was treated with one cycle of cladribine with persistent pancytopenia and no response in his bone and hepatic involvement. Genomic analysis, following the initiation of chemotherapy, revealed the absence of the D816V KIT mutation. The patient was enrolled in a trial with midostaurin (PKC412). Discussion: In a majority of adult cases of mastocytosis, including cases with hepatic manifestations, the somatic mutation Asp816Val (D816V) has been described in the catalytic domain of the KIT proto-oncogene. As in our case, patients with negative KIT mutations do not respond to imatinib mesylate. In the progression of mastocytosis, the KIT mutant D816V may disappear as a result of the clonal selection and transformation of more malignant subclones derived from a primitive neoplastic stem cell population. In our patient, the loss of the D816V mutation is possibly explained by clonal selection subsequent to the chemotherapeutic induction. The radiologic findings of cystic liver lesions are uncommon but may be related to obstructed sinusoids from infiltrated mast cells leading to portal hypertension.