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The first malignant primary hepatic glomus tumor: A case report

Highlights • This is the first malignant primary hepatic glomus tumor.• Glomus tumor diagnosis involves morphologic and immunohistochemical features.• Our glomus tumor had an inactivating TP53 mutation.• Consider glomus tumors when evaluating heterogeneous liver masses.


Introduction
Glomus tumors (GTs) are rare neoplasms derived from modified smooth-muscle cells of thermoregulatory glomus bodies. While GTs most frequently originate from within the dermis of the distal extremities, they can occasionally arise from visceral organs [1,2]. All seven previously reported primary hepatic GTs were benign [3][4][5][6][7][8][9]. Additionally, the molecular profile of malignant GTs has not been extensively characterized. Here we present the literature's first malignant primary hepatic GT and next-generation sequencing results from this rare tumor. This work has been reported in line with the SCARE criteria [10].

Clinical course
A 60-year-old male with a history of ulcerative colitis presented with weight loss, early satiety, night sweats, and abdominal distention. Imaging revealed a large mass abutting the stomach, duodenum, and head of the pancreas exerting mass effect on the portal vein and inferior vena cava (Fig. 1A). Biopsy of the mass revealed a morphologically undifferentiated epithelioid and spindle cell tumor with indeterminate staining patterns. This sample was deemed nondiagnostic after histopathologic evaluation at multiple institutions. The patient was seen and denied an operation at multiple tertiary referral centers around the United States.
We evaluated the patient and offered him resection of the mass. Intraoperatively, we found that the tumor replaced the caudate lobe and was adhered to the gastric antrum. We performed a caudate lobe resection, antrectomy, and Bilroth II gastrojejunostomy. The operation required skeletonization of much of the periportal vas-  cular anatomy and repair of multiple venotomies due to the tumor's adherence to the inferior vena cava (Fig. 1B). The patient tolerated the procedure well. Postoperatively he did experience a mild flare of his ulcerative colitis that resolved with medical therapy, but his course was otherwise unremarkable. He has demonstrated no evidence of recurrent disease and continues to follow up with our service.

Pathology
Grossly, the resected specimen consisted of a large tan-brown mass measuring 18 cm in greatest dimension and weighing 890 g (Fig. 1C). There were solid and cystic components. The solid portion was dense, nodular, and tan-brown, with focal areas of necrosis. The cystic portion lacked an epithelial lining and contained bloody fluid with brown-gray coagulated material ( Fig. 2A). Microscopic examination revealed plump, epithelioid round cells with eosinophilic, smooth cytoplasm and oval, hyperchromatic nuclei arranged in a trabecular pattern. The slits between the trabeculae were lined with thin endothelial cells (Fig. 2B-D). The mitotic count was 17 mitoses/50 high-powered fields, and atypical mitotic figures were identified (Fig. 2E). The tumor cells demonstrated smooth muscle actin (SMA) positivity by immunohistochemistry (Fig. 2F).
The tumor's site of origin and histomorphology prompted the consideration of a broad differential diagnosis that included primary hepatic sarcoma, angiosarcoma, leiomyosarcoma, hepatocellular carcinoma, cholangiocarcinoma, perivascular endothelial cell tumor (PEComa), hemangioendothelioma, primary hepatic neuroendocrine carcinoma, and gastrointestinal stromal tumor (GIST). While several diagnoses were less likely based on tumor morphology alone, immunohistochemical analyses further defined the neoplasm. Specifically, the tumor lacked the diffuse CD34 staining characteristic of angiosarcoma, the HMB-45 staining distinctive of PEComa, or the c-kit/CD117 staining typical of GIST. Although the tumor did demonstrate focal synaptophysin positivity, the absence of "salt and pepper" chromatin and a nest/chord arrangement ruled out the diagnosis of neuroendocrine tumor. Ultimately, the trabecular arrangement of distinctive, endothelial-lined epithelioid cells combined with positive SMA staining were typical of GT and secured the diagnosis. Furthermore, the tumor's extensive necrosis, atypical mitoses, elevated mitotic index, and vascular invasion were all suggestive of potential malignant behavior.
The GT's molecular profile was analyzed using a clinicallyvalidated next-generation targeted sequencing assay (TruSight Oncology 500, Illumina, San Diego, CA), which detected six somatic mutations (Table 1). Among the detected variants, TP53 I254T is a known inactivating mutation. The remaining variants are not well characterized, and their significance is unknown.

Discussion
Here we report the literature's first malignant primary hepatic GT and its molecular profile using a targeted panel of common cancer-causing mutations. While hepatic GT are exceedingly uncommon diagnoses, they should not be forgotten when evaluating heterogeneous liver lesions. GTs can originate from various visceral sites and can metastasize when malignant [1,2]. Metastatic GT can involve the liver, and the exclusion of a metastatic process is crucial when managing any liver tumor. Our patient demonstrated no findings suggestive of additional pathology on physical exam, cross-sectional imaging, or metabolic imaging, which led us to conclude that his malignant GT was a primary hepatic process.
Survival implications due to the GT's malignant classification are unknown. Two prior GT series posited criteria for GT malignancy that included the presence of atypical mitotic figures and at least five mitoses per 50 high-powered fields [1,2]. Our patient's hepatic GT demonstrates both of these histomorphological criteria, in addition to clear vascular invasion, making it the only GT in the literature to do so. Additionally, while the GT's histopathologic findings suggest potential malignant behavior, the tumor's molecular profile provides little prognostic insight. Aside from an inactivating TP53 mutation at amino acid 254, the GT demonstrated five variants that are poorly characterized, have not been described in malignant glomus tumors, and could represent either oncogenic mutations, passenger mutations, or private single nucleotide polymorphisms. Notably, our assay did not detect a NOTCH2 translocation or BRAF V600E mutation, both of which are present in our panel assay and were reported in prior malignant GT genomic studies [11,12].

Conclusion
Overall, our case represents the first reported primary malignant hepatic GT and posed a diagnostic and surgical challenge. Close follow-up will be important to document the course of the patient's disease and plan any subsequent interventions in a timely fashion.

Conflicts of interest
The authors have no financial, personal, or organizational conflicts of interest.

Sources of funding
All funding support for this study was provided by the Intramural Research Program, National Cancer Institute, at the National Institutes of Health.

Ethical approval
Not applicable, the patient has given written informed consent for the publication of his case.

Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request.