Hepatic failure as a rare cause of death in Cowden syndrome: A case report and literature review

Dear Editor, Here, we report a case of Cowden syndrome (CS) with atypical presentation of hepatocellular carcinoma (HCC) and liver cirrhosis in a female patient with multiple neoplasms, including breast cancer, thyroid cancer, and gastrointestinal hamartomas. Although HCC and liver cirrhosis are rarely associated with CS, the association is significant as it can lead to substantial morbidity. We emphasize the importance of surveillance for liver disease in the management of CS. A 44-year-old Taiwanese woman presented with punctate keratoderma-like hyperkeratotic lesions on her acral skin that had been present since childhood. Physical examination revealed pin-head-sized skin-colored flat-topped papules on both the palms and soles [Figure 1a and b]. The patient had no history of smoking, alcohol consumption, or drug abuse. The patient was diagnosed with right adrenal cortical carcinoma and underwent right adrenal excision at 15 years of age. Two years later, abdominal sonography revealed a tumor in the right lobe of the liver, and the patient underwent a right lobectomy. The final pathologic report confirmed the diagnosis of HCC. She underwent left skin-nipple-preserving mastectomy plus adjuvant chemotherapy and hormonal therapy at the age of 27 years due to an infiltrating ductal carcinoma (T1N3M0, Stage IIIc) with axillary lymph node metastasis. In the following year, the patient developed multiple enlarging toxic nodular goiters. A total thyroidectomy with radioiodine ablation was performed for thyroid follicular carcinoma (Stage I) at 28 years of age. Incisional biopsy for one painless nodule over the right breast revealed proliferative fibrocystic change without atypia at 31 years of age.Figure 1: Pin-head to pea-sized skin-colored flat-topped papules on the bilateral palms and soles (a and b), Histological findings (c) Orthokeratosis with acanthosis (H and E, ×40), (d) minimal expression of phosphatase and tensin homolog in immunohistochemical staining.Biopsy for two papules over the tongue revealed reactive fibroblastic and myofibroblastic reactions. Skin biopsy over the bilateral palms showed orthokeratosis with acanthosis [Figure 1c]; however, the phosphatase and tensin homolog (PTEN) immunohistochemical study revealed only scattered minimal nuclear expression in basal keratinocytes (<0.5% in number) [Figure 1d]. Despite the absence of a PTEN gene analysis, the patient met the diagnostic criteria for CS according to the International CS Consortium.[1] Gastroscopy and colonoscopy revealed numerous hamartomatous polyps with a cobblestone appearance over the esophagus, stomach, duodenum, and colon to rectum [Figure 2a and b].Figure 2: Cobblestone appearance was found endoscopically in the esophagus and colon (a), Hamartomatous polyps were found in the gastric body, gastric antrum, and duodenum (b).Unfortunately, the patient had progressive liver cirrhosis with splenomegaly since the age of 43 years. There was no evidence of viral hepatitis, autoimmune hepatitis, nonalcoholic steatohepatitis (NASH), or other metabolic disease-related cirrhosis. Owing to the severe complications of hepatic failure such as portal hypertension, hepatic encephalopathy, and hepatorenal syndrome, the patient died 1 year after the skin biopsy. CS, a rare autosomal-dominant hamartoma tumor syndrome, first described in 1963 by Lloyd and Dennis, is part of the spectrum disorder of germline PTEN mutations.[2,3] This disorder is characterized by a wide collection of mucocutaneous abnormalities (multiple acral keratosis, facial trichilemmomas, and oral papillomatosis) and runs a high risk for developing multiple neoplasms involving breast, endometrium, thyroid, and gastrointestinal and genitourinary system.[2-4] In the literature, breast cancer is the most common malignancy and the most common cause of death in CS.[3] In summary, our patient fulfilled the criteria for multiple palmoplantar keratosis, breast carcinoma, thyroid follicular carcinoma, gastrointestinal hamartomas, and fibrocystic breast disease. Notably, our patient was diagnosed with HCC and liver cirrhosis, which are rarely reported in CS cases. The pathogenesis of CS has been studied extensively. PTEN acts as a tumor suppressor gene that downregulates the expression of phosphatidylinositol-3-kinases. PTEN mutation activates the serine-threonine kinase protein kinase B/Akt signaling pathway and leads to cellular hyperplasia.[2,5,6] In an animal study, dysfunction of PTEN has been demonstrated to increase the expression of PPARg and SREBP1c in hepatocytes. The overexpression of PPARg and SREBP1c has been implicated in both increased oxidative stress and elevated adipogenic gene expression in the hepatocytes.[6] In addition, elevated oxidative stress disrupted the cell membrane of hepatocytes and caused oxidative DNA damage, thereby contributing to hepatitis and hepatic tumorigenesis. Therefore, PTEN mutation could be significant in the development of hepatic neoplasm and liver fibrosis. To the best of our knowledge, there is only one report for HCC possibly originating from NASH in a patient with CS.[2] Our patient is the first case of CS with HCC, who died of liver failure. Conventionally, cancer screening for CS is targeted at breast cancer, endometrial cancer, thyroid cancer, gastrointestinal hamartomas, and renal cancer. Further studies with more multicenter case series are warranted to establish the prevalence rate of HCC and hepatic failure-induced mortality in CS. We suggest performing serum liver enzyme test and abdominal sonography annually for screening on the diagnosis of CS. If there is an abnormal finding, serum alpha-fetoprotein or abdominal-enhanced CT is recommended. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent form. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed. Data availability statement Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Financial support and sponsorship This study was supported by the grants from CMUH (DMR-111-056). Conflicts of interest There are no conflicts of interest.