Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases

Abstract

High-grade versions of appendiceal goblet cell carcinoids ('adenocarcinoma ex-goblet cell carcinoids') are poorly characterized. We herein document 77 examples. Tumors occurred predominantly in females (74%), mean age 55 years (29-84), most with disseminated abdominal (77% peritoneal, 58% gynecologic tract involvement) and stage IV (65%) disease. Many presented to gynecologic oncologists, and nine had a working diagnosis of ovarian carcinoma. Metastases to liver (n=3) and lung (n=1) were uncommon and none arose in adenomatous lesions. Tumors had various histologic patterns, in variable combinations, most of which were fairly specific, making them recognizable as appendiceal in origin, even at metastatic sites: I: Ordinary goblet cell carcinoid/crypt pattern (rounded, non-luminal acini with well-oriented goblet cells), in variable amounts in all cases. II: Poorly cohesive goblet cell pattern (diffusely infiltrative cords/single files of signet ring-like/goblet cells). III: Poorly cohesive non-mucinous cell (diffuse-infiltrative growth of non-mucinous cells). IV: Microglandular (rosette-like glandular) pattern without goblet cells. V: Mixed 'other' carcinoma foci (including ordinary intestinal/mucinous). VI: goblet cell carcinoid pattern with high-grade morphology (marked nuclear atypia). VII: Solid sheet-like pattern punctuated by goblet cells/microglandular units. Ordinary nested/trabecular ('carcinoid pattern') was very uncommon. In total, 33(52%) died of disease, with median overall survival 38 months and 5-year survival 32%. On multivariate analysis perineural invasion and younger age (<55) were independently associated with worse outcome while lymph-vascular invasion, stage, and nodal status trended toward, but failed to reach, statistical significance. Worse behavior in younger patients combined with female predilection and ovarian-affinity raise the possibility of hormone-assisted tumor progression. In conclusion, 'adenocarcinoma ex-goblet cell carcinoid' is an appendix-specific, high-grade malignant neoplasm with distinctive morphology that is recognizable at metastatic sites and recapitulates crypt cells (appendiceal crypt cell adenocarcinoma). Unlike intestinal-type adenocarcinoma, it occurs predominantly in women, is disguised as gynecologic malignancy, and spreads along peritoneal surfaces with only rare hematogenous metastasis. It appears to be significantly more aggressive than appendiceal mucinous neoplasms.

Figure 1

(a) Cross-section of appendix showing concentric mural infiltration by tumor with preservation of the layers of the appendiceal wall. (b) ‘Conventional goblet cell carcinoid/crypt cell pattern’ is characterized by small round collections of goblet cells with acinar configuration, closely resembling colonic crypts, but lacking distinct lumina.

Figure 2

Images are from two patients (a–c (one patient) and d–f (another patient]), each with multiple tumor patterns. (a) ‘Poorly cohesive goblet cell pattern’ with non-gland forming, diffusely infiltrative pattern of stromal invasion by goblet-type cells in a manner akin to ‘poorly cohesive cell’ carcinoma. (b) These tumor cells have voluminous cytoplasm containing more basophilic mucin unlike the pale, acidophilic (foveolar-like) mucin more frequently seen in gastric signet ring cell carcinoma. (c) Within the same patient tumor cells showed a ‘Goblet cell carcinoid pattern with high-grade morphology’ characterized by ill-defined acini with marked nuclear enlargement, pleomorphism and hyperchromasia. (d) ‘Poorly cohesive non-mucinous cell pattern’ is composed of small, non-mucinous cells distributed as thin, diffusely infiltrative cords. (e) Note the focus of ‘ordinary carcinoid-like pattern (well-differentiated neuroendocrine tumor)’ with nested/trabecular growth on the right and the more solid goblet cell carcinoid tumor clusters with isolated goblet cells on the left. (f) The same tumor (shown in d and e) also showed a ‘microglandular pattern’ composed of polarized cuboidal-columnar cells forming small, punched-out, rosette-like tubules with interspersed goblet-type cells.

Figure 3

(a) ‘Microglandular pattern’ composed of tumor cells dispersed as punched-out rosette-like tubules with rigid luminal borders and lined by polarized cuboidal-columnar cells. Single goblet-type tumor cells are interspersed between tubules. (b) Mixed mucinous type carcinoma pattern’ with abundant stromal mucin containing small clusters of floating goblet cell carcinoid-type crypts within it.

Figure 4

(a) ‘Solid sheet-like growth pattern’ is characterized by islands and cords of mitotically active tumor cells with high nuclear to cytoplasmic ratio, scant mucin, and interspersed singly distributed signet ring-like goblet cells. (b) Metastatic tumor deposits were seen in ovarian stroma and lymphatic spaces adjacent to a corpus albicans within the same patient.

Figure 5

Kaplan–Meier survival curves show that patients <55 years of age (a) and women (b) had lower survival than their respective counterparts. However, the gender difference was no longer statistically significant after controlling for other variables, and the age difference was no longer evident by 70 months of follow-up.