Answer: A - Epithelioid hemangioendothelioma (EHE)

This is an epithelioid hemangioendothelioma (EHE). Microscopically, the duodenal tumor is composed of epithelioid and spindled cells with numerous mitoses and occasional intracytoplasmic lumina. Tumor is positive for CD31, FLI-1, CK AE1/ AE3, WT-1 and patchy positive for ERG but negative for GATA3, CK7, CD34, synaptophysin, CD117, calretinin, mucicarmine, D2-40, DOG1, S-100, desmin, CAM 5.2, etc. See Figure C (H&E) and Figure D (representative immunostain). Morphology in view of staining pattern is consistent with a high-grade vascular tumor; in particular, a malignant/ high risk epithelioid hemangioendothelioma (EHE). The tumor is generally positive for vascular markers (e.g. CD31, CD34, ERG); however, there can be variability in expression as seen with the CD34 negativity in this case .  EHE is characterized by a translocation between chromosomes 1 and 3 resulting in WWTR1 and CAMTA1 gene fusion in majority of cases. A small subset of cases, however, are characterized by YAP1-TFE3 gene fusion (1,2). In our patient, a follow-up CT-scan depicted an increase in duodenal tumor size, and additionally, evidence of hepatosplenic involvement.

In comparison to this case, malignant GI neuroectodermal tumor (GNET) would be positive for S100 and synaptophysin, and negative for DOG1, CD117 and cytokeratin. Also known as clear cell sarcoma-like tumor of the gastrointestinal tract,  GNET is a rare malignant tumor that grows in sheets or cords and harbors EWSR1 translocation. In its conventional form, GIST has a spindled morphology and is positive for DOG1, CD117, and CD34, while negative for S100, desmin, and cytokeratin, amongst others. Mesothelioma is positive for cytokeratin stains including AE1/AE3, CK7 and CAM5.2, and in addition is typically positive for calretinin, WT-1 and D2-40.

EHE is a rare tumor with a prevalence of one in one million, more likely presents in middle-aged adults than children or elderly, and has a predication for lung, soft tissue, liver, and bone (1-4). The course of disease can be difficult to predict. In soft tissue, a risk stratification system based on mitotic index (cut-off 3 mitoses per 50 high power field) and size (cut-off 3.0 cm) has been proposed to aid in prognostication (5). In small intestine, EHE is exceedingly rare, with only a limited number reported, and as such, it can pose a clinicopathologic dilemma (6-9). The tumor may be only observed, but in patients with symptomatic or localized disease it can be surgically removed (1). For patients with unresectable or metastatic disease, systemic therapy is often utilized, and in addition to cytotoxic chemotherapy, there is evidence that antiangiogenic strategies can be efficacious (1, 10). Although clinical course and management of EHE is poorly-understood, retrospective analysis of SEER database has indicated that surgical intervention is associated with improved survival rate (11).

References

1.      Rosenberg A, Agulnik M. Epithelioid Hemangioendothelioma: Update on Diagnosis and Treatment. Curr Treat Options Oncol. 2018;19(4):19. Published 2018 Mar 15. doi:10.1007/s11864-018-0536-y

2.      Rosenbaum E, Jadeja B, Xu B, et al. Prognostic stratification of clinical and molecular epithelioid hemangioendothelioma subsets. Mod Pathol. 2020;33(4):591-602. doi:10.1038/s41379-019-0368-8

3.      Sardaro A, Bardoscia L, Petruzzelli MF, Portaluri M. Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor. Oncol Rev. 2014;8(2):259. Published 2014 Oct 13. doi:10.4081/oncol.2014.259

4.      Celikel C, Yumuk PF, Basaran G, Yildizeli B, Kodalli N, Ahiskali R. Epithelioid hemangioendothelioma with multiple organ involvement. APMIS. 2007;115(7):881-888. doi:10.1111/j.1600-0463.2007.apm_727.x

5.      Deyrup AT, Tighiouart M, Montag AG, Weiss SW. Epithelioid hemangioendothelioma of soft tissue: a proposal for risk stratification based on 49 cases. Am J Surg Pathol. 2008;32(6):924-927. doi:10.1097/pas.0b013e31815bf8e6

6.      Panzini L, Homer RJ. Duodenal hemangioendothelioma: a case report. Am J Gastroenterol. 1998;93(5):832-833. doi:10.1111/j.1572-0241.1998.236_a.x

7.      Yoshida R, Takada H, Iwamoto S, et al. Malignant hemangioendothelioma of the small intestine: report of a case. Surg Today. 1999;29(5):439-442. doi:10.1007/BF02483036

8.      Fraser SA, Deschênes J, Bloom C, Gordon PH. Ileocecal hobnail hemangioendothelioma: report of a case and review of the literature. Dis Colon Rectum. 2006;49(2):276-279. doi:10.1007/s10350-005-0254-y

9.      Iwaya Y, Streutker CJ, Coneys JG, Marcon N. Hemangiolymphangioma of the small bowel: A rare cause of chronic anemia. Dig Liver Dis. 2018;50(11):1248. doi:10.1016/j.dld.2018.05.008

10.   Smrke AM, Huang PH, Jones RL. Sirolimus for patients with progressive epithelioid hemangioendothelioma. Cancer. 2021;127(4):504-506. doi:10.1002/cncr.33246

11.   Chahrour MA, Khachfe HH, Habib JR, El-Asmar R, Saifi O, Jamali FR. Treatment and Prognosis of Hepatic Epithelioid Hemangioendothelioma: A SEER Database Analysis. World J Surg. 2021;45(9):2886-2894. doi:10.1007/s00268-021-06165-6