Answer 1: C - High-grade appendiceal mucinous neoplasm

This is a case of High-Grade Appendiceal Mucinos Neoplasm (HAMN) characterized by non-invasive mucinous epithelium with increased epithelial atypia. The newly-introduced term, HAMN, was proposed following the international modified Delphi consensus process called to address contentious terminology and definitions for appendiceal and peritoneal mucinous tumors (1). In a recent case series by Gonzalez et. al., most patients with HAMN were middle-age and presented with abdominal/pelvic pain. Histologically, about half of their tumors had widespread high-grade features, with the remaining being more focal (2).

Appendiceal mucinous neoplasms (AMNs) are typically composed of circumferential, flat or villiform architecture with low-grade or high-grade epithelial features (LAMN or HAMN, respectively). High-grade cytological atypia encompasses enlarged, hyperchromatic, and/or pleomorphic nuclei, while high-grade architectural patterns include cribriform or micropapillary complexities and/or epithelial tufting. Although AMNs by definition lack infiltrative or destructive invasion, they may exhibit a “pushing” border of neoplastic epithelium. A basic criterion for diagnosis of AMN is (at least focal) obliteration of the lamina propria and muscularis mucosa, associated with fibrosis and lack of usual lymphoid follicles (3). 

When limited to the appendix at presentation, HAMN is suggested to behave similar to LAMN. According to a recent study, cases of HAMN, when confined to the appendix, did not recur (2). HAMN and LAMN are staged differently however. While the Tis system is used for LAMN, the invasive appendiceal adenocarcinoma scheme is utilized for HAMN. Appendiceal mucinous neoplasms have a propensity for peritoneal dissemination, resulting in clinical presentation of so-called "pseudomyxoma peritonei". HAMNs that spread to the peritoneum typically produce grade 2 pseudomyxoma peritonei, which has been associated with a worse prognosis than classical grade 1 pseudomyxoma peritonei. LAMN is typically treated surgically with resection of the primary site in early-stage, or peritoneal debulking and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in advanced-stage. Patients with HAMN may receive preoperative chemotherapy in addition to debulking surgery and HIPEC. Understanding optimal treatment for HAMN is still in its infancy (3,4).

Option A is incorrect as there is no evidence of destructive invasion into the sub-epithelium, but rather there are pushing fronds of neoplastic epithelium into the wall. Option B is incorrect since, at least focally, there is increased cytologic and architectural atypia, beyond what is expected for LAMN. Option D is incorrect as mucocele is a clinical term and not per se a pathologic entity. Mucocele describes a dilated appendix which can result from a multitude of etiologies (e.g., diverticulitis, mucinous adenocarcinoma, mucinous neoplasm, etc.). Option E is incorrect as there would be retention of the lamina propria and reactive, rather than dysplastic epithelial features, in diverticulosis.

Answer 2: B - CK20+, SATB2+, PAX8- ; KRAS and/ or GNAS mutated

HAMN is most commonly CK20 +, PAX8-, SATB2+ and CDX2 +; Although not entirely specific or sensitive, this staining pattern may occasionally offer utility in differentiating HAMN from ovarian mucinous tumors (5). Molecular studies indicate AMNs frequently harbor KRAS mutations and have loss of chromosome 5q (6). Microsatellite instability and BRAF mutations have not been demonstrated. Similar to LAMNs, HAMNs frequently harbor mutations in KRAS, GNAS, and RNF43. Compared to LAMNs, HAMNs are more likely to have mutations in TP53, ATM, and APC; and these additional alterations may be responsible for the more aggressive phenotype (6, 7). 

References

1. Carr NJ, Cecil TD, Mohamed F, et al. A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated Appendiceal Neoplasia: The Results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process. Am J Surg Pathol. 2016;40(1):14-26.

2. Gonzalez RS, Carr NJ, Liao H, Pai RK, Agostini-Vulaj D, Misdraji J. High-Grade Appendiceal Mucinous Neoplasm [published online ahead of print, 2022 Apr 26]. Arch Pathol Lab Med. 2022;10.5858/arpa.2021-0430-OA. 

3. Umetsu SE, Kakar S. Staging of appendiceal mucinous neoplasms: challenges and recent updates [published online ahead of print, 2022 Jul 16]. Hum Pathol. 2022;S0046-8177(22)00177-0. 

4. Shaib WL, Assi R, Shamseddine A, et al. Appendiceal Mucinous Neoplasms: Diagnosis and Management. Oncologist. 2018;23(1):137.

5. Strickland S, Parra-Herran C. Immunohistochemical characterization of appendiceal mucinous neoplasms and the value of special AT-rich sequence-binding protein 2 in their distinction from primary ovarian mucinous tumours. Histopathology. 2016;68(7):977-987

6. Szych C, Staebler A, Connolly DC, Wu R, Cho KR, Ronnett BM. Molecular genetic evidence supporting the clonality and appendiceal origin of Pseudomyxoma peritonei in women. Am J Pathol. 1999;154(6):1849-1855.

7. Liao X, Vavinskaya V, Sun K, et al. Mutation profile of high-grade appendiceal mucinous neoplasm. Histopathology. 2020;76(3):461-469.