A case of diffuse goblet cell adenocarcinoma of the appendix showing carcinoid-like expansion.

To the Editor, Goblet cell adenocarcinoma (GCA) arises exclusively in the appendix and is a very rare tumor (0.3%–0.9% of appendectomies and 35%–58% of all appendiceal neoplasms). Consequently, the clinicopathological characteristics of GCA have rarely been reported. Historically, GCA has been confused with (typical) carcinoid tumor of the appendix. GCA was first reported as “goblet cell carcinoid (GCC)” by Subbuswamy et al. in 1974 and considered an amphicrine tumor with histopathologic and immunohistochemical features that overlap between typical carcinoid and adenocarcinoma. As a result of historical ambiguity, GCA has been referred to under various names, such as GCC, mucinous carcinoid, adenocarcinoid, and crypt cell carcinoma. Currently, GCA is considered to develop from multipotential crypt stem cells, and is treated as a distinct tumor with a histogenesis different from (typical) carcinoid tumor, which is thought to develop from subepithelial neuroendocrine cells of neural crest derivation. Recently, it was finally classified as GCA and is now an independent epithelial tumor of the appendix (World Health Organization (WHO) classification, 5th Ed). Although few papers have examined multiple cases of GCA, Tang et al. examined 63 cases of GCA and signet ring cell carcinoma in 2008 and classified GCC on the basis of histologic characteristics including the arrangement of the goblet cells, the degree of atypia, and the degree of desmoplasia. GCC is classified into three categories: typical GCC (group A), adenocarcinoma ex‐GCC, signet ring cell (group B), and adenocarcinoma ex‐GCC (group C). Clinicopathologically, the mean overall survival for the three categories has been reported to be 199, 43, and 31 months, with 5‐year overall survival rates of 100%, 36%, and 0%, respectively. According to the classification, typical GCC (group A) has an extremely favorable prognosis compared with the adenocarcinoma groups (groups B and C), and typical GCC (Group A) can be dealt with as a benign counterpart of GCA. Therefore, GCC seems to clinicopathologically mimic (typical) carcinoid tumor. However, the WHO have classified GCA using a consecutive grading system (Grades 1, 2, and 3) and have not set a benign counterpart of GCA. Here we describe a case of GCA (Grade 1) without any mucosal element and showing subepithelial diffuse proliferation. The patient was a 48‐year‐old Japanese woman who presented with pain in the right lower abdomen. Laboratory examinations revealed no abnormalities except for an elevated C‐reactive protein level. Abdominal CT showed no masses or urinary stones. She was diagnosed clinically as having acute appendicitis and underwent appendectomy. Macroscopically, the resected appendix was 10 cm in length with a wall thickness of 6mm. No palpable mass or tumorous lesion was evident in the specimen. The mucosal surface was flat with no evident tumorous lesion, stones, ulcer or perforation, but mild erosion was evident (Figure 1a). After fixation with 10% neutral formalin, the entire appendix specimen submitted to the pathology division was cut vertically and total tissue sections were embedded in paraffin and histologically examined. Mild inflammatory cell infiltration was evident, extending from the mucosal surface to the subserosal layer. In the lamina propria, the density of acinar glands was decreased and mild erosion was detected. Surprisingly, small nests of tumor cells or single cells were found to diffusely infiltrate the submucosal region and muscle layer without any lesion in the lamina propria (Figure 1b,c). Diffuse tumor cell infiltration was detected in half the area of the submucosal layer and in the muscular layer of the appendix (50 × 26mm). The tumor cells had small nuclei compressed by abundant cytoplasmic mucin, showing a signet ring appearance and forming small nests of several cells (Figure 1d). Immunohistochemically, the tumor cells were positive for CK7, CK20 and E‐cadherin (Figure 1e). The tumor cells were also partly positive for synaptophysin and chromogranin A (Figure 1f). The Ki67 labeling index was less than 5%, and the cells were negative for p53 protein (immunohistochemistry). Finally, the tumor was diagnosed as “GCA, Grade 1.” Recently, most pathologists have assumed that typical carcinoid tumor of the appendix and GCA are different disease entities, and independent tumors. GCA arises from multipotent stem cells of the mucosal crypt. However, the present case showed diffuse