Paraneoplastic Anti-Tif1-gamma Autoantibody-positive Dermatomyositis as Clinical Presentation of Hepatocellular Carcinoma Recurrence

Abstract

Hepatocellular carcinoma (HCC) is rarely associated with autoimmune paraneoplastic syndromes. We report a case of anti-transcriptional intermediary factor-1 gamma (TIF1-γ)-positive dermatomyositis (DM) as clinical presentation of HCC recurrence in a 72-year-old male patient admitted to our hospital due to fatigue, myalgia, and typical skin rash. His medical history was notable for hepatitis C-related cirrhosis, successful treatment with direct-acting antiviral agents, and previously efficacious treatment of HCC. Laboratory testing showed significant rhabdomyolysis with anti-TIF1-γ antibodies at high titer, and DM was diagnosed. After a careful diagnostic workup, HCC recurrence was diagnosed. After first-line corticosteroid treatment, azathioprine and intravenous immunoglobulin treatments were administered; unfortunately, he mounted only partial response. Owing to the compromised performance status, no HCC treatment was feasible, and, according to international guidelines, he received only best supportive care. Here, we discuss the diagnostic, prognostic, and pathogenic roles of anti-TIF1-γ antibodies associated with paraneoplastic DM and the scant literature data on its occurrence in HCC patients. Considering the TIF1 gene family's established role in oncogenesis, we also review the role of TIF1-γ as a tumor-related neoantigen, leading to the development of clinically overt anti-TIF1-γ antibodies-positive DM.

Keywords: Anti-transcriptional intermediary factor-1 gamma (tif1-γ) antibodies; Dermatomyositis; Hepatocellular carcinoma; Paraneoplastic syndrome.

Fig. 1. Skin biopsy.

Hematoxylin-eosin staining showing superficial and perivascular infiltrate predominantly of lymphocytes, vacuolar alteration at the dermo-epidermal junction, and papillary dermis edema. The basement membrane is thickened, and there is an increased connective-tissue mucin (magnification 200×).

Fig. 2. Laboratory tests when under immunosuppressive therapy.

Left axis represents creatine-kinase (U/L); right axis represents AST, ALT and LDH (U/L).

Fig. 3. CEUS features of the HCC nodule at segment II (CEUS LI-RADS LR5).

(A) CEUS arterial phase showing hyperenhancement of the nodule. (B) CEUS late phase showing wash-out of the nodule. (C) Hilar metastatic lymphadenopathy (20 mm × 35 mm). CEUS, contrast-enhanced ultrasound; HCC, hepatocellular carcinoma.

Fig. 4. Abdominal contrast-enhanced computed tomography.

(A–B) Enlargement of segment II lesion (arrow). (B–C) New intrahepatic lesions at segment II (arrow). (D–E) Segment VI (arrow). (F–G) Extrahepatic HCC progression, characterized by enlargement of hepatic hilar lymph node (arrow). Arterial (A, C, E, G) and venous (B, D, F, H) phases are shown. HCC, hepatocellular carcinoma.

Fig. 5. Hypothetical mechanisms of the pathogenesis that underlie the association between HCC and TIF1-γ-positive DM.

Mutations develop in the TIF1 genes of HCC cells which could elicit an immune response (anti-TIF1γ antibodies) against the resulting mutated protein (tumor neoantigen). The cross-reactivity to the wild-type antigen could injure specific tissues, such as skin and muscle, leading to clinically overt DM. DM, dermatomyositis; HCC, hepatocellular carcinoma; TIF1-γ, transcriptional intermediary factor-1 gamma.