Cervical and endometrial metastases of appendiceal goblet cell carcinoid.
Abstract: * Appendiceal goblet cell carcinoid (GCC) is a rare tumor with histologic features of both adenocarcinoma and neuroendocrine tumor (carcinoid). Clinically, it behaves more aggressively than classic appendiceal carcinoid and commonly presents with peritoneal carcinomatosis. We report 2 cases of appendiceal GCC, one with uterine cervical involvement and the other with endometrial involvement as the initial presentations. The first patient's invasive cervical signet ring cell carcinoma was diagnosed on routine screening. The second patient presented with abnormal uterine bleeding, and endometrial curettage showed an adenocarcinoma with signet ring cell features. Primary appendiceal GCC was demonstrated in both cases after systematic clinical investigations. Metastatic appendiceal GCC to uterine cervix and endometrium can potentially be misinterpreted as primary cervical or endometrial signet ring cell carcinoma. Therefore, for any uterine cervical/endometrial signet ring cell carcinoma, a metastatic appendiceal GCC should be considered in the differential diagnosis, especially after excluding other primary sites.

(Arch Pathol Lab Med. 2010;134:776-780)
Article Type: Case study
Subject: Metastasis (Development and progression)
Metastasis (Diagnosis)
Metastasis (Care and treatment)
Metastasis (Case studies)
Carcinoid (Development and progression)
Carcinoid (Diagnosis)
Carcinoid (Care and treatment)
Carcinoid (Case studies)
Authors: Pan, Zenggang
Repertinger, Susan
Leonard, Ronald
Bewtra, Chhanda
Gatalica, Zoran
Sharma, Poonam
Pub Date: 05/01/2010
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 College of American Pathologists ISSN: 1543-2165
Issue: Date: May, 2010 Source Volume: 134 Source Issue: 5
Topic: Canadian Subject Form: Carcinoid tumours; Carcinoid tumours; Carcinoid tumours; Carcinoid tumours
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230246566
Full Text: Appendiceal goblet cell carcinoid (GCC) is rare, with a significantly higher metastatic rate than the conventional appendiceal carcinoid. It is frequently misinterpreted as signet ring cell carcinoma (SRCC), but recent literature outlined its morphologic and immunophenotypic characteristics. (1-3) The tumor is characteristically composed of 2 types of cells arranged in small nests: neuroendocrine cells with eosinophilic granular cytoplasm and goblet cells of gastrointestinal type. It often extensively disseminates into the peritoneal and pelvic cavities without much tissue destruction or formation of tumor masses. Therefore, the primary appendiceal tumor may be difficult to discover, even after comprehensive clinical workups. Primary SRCC of cervix/endometrium is extremely rare, (4,5) although focal signet ring cell differentiation may be noted occasionally in primary endocervical/endometrial adenocarcinoma and squamous cell carcinoma. (6,7) To our knowledge, primary appendiceal GCC with metastasis to the endometrium or uterine cervix has not been reported in the medical literature. We present 2 such cases and contrast our findings with rare primary SRCC of the uterine cervix and endometrium.


Case 1

A 49-year-old white woman had a past medical history of papillary thyroid carcinoma with a total thyroidectomy performed when she was 36 years old. At the time of the current presentation, she was otherwise healthy and asymptomatic. However, a recent screening with cervical Papanicolaou smear revealed a few atypical squamous cells of undetermined significance. Follow-up endocervical curettage showed a small focus of signet ring cells of uncertain origin. A repeated endocervical curettage was reported as "suspicious for invasive squamous cell carcinoma," whereas a diagnosis of "reactive squamous epithelium and benign endocervical glandular epithelium, no definite dysplasia or carcinoma" was rendered for the same specimen sent for consultation. Cervical conization was performed to resolve this discrepancy.

Microscopic evaluation of the conization specimen demonstrated reactive squamous hyperplasia without atypia. The submucosal connective tissue contained scattered mucinous cells with signet ring features (Figure 1, A) focally forming small clusters without distinct glandular lumens (data not shown). Lymphovascular invasion was identified. In addition, several small clusters of similar neoplastic cells were identified in the endometrial and endocervical curettage specimens taken at the same time as the cone (Figure 1, B). These neoplastic cells contained abundant intracytoplasmic mucin (mucicarmine positive; Figure 1, C). Additionally, these cells showed diffuse and strong reactivity for cytokeratin 20 (CK20; Figure 1, D) and CDX2 but were negative for CK7, gross cystic disease fluid protein-15, cancer antigen 125, and human papilloma virus (in situ hybridization). The proliferative index was relatively high, with 20% to 30% of the tumor cells staining with Ki-67.

Because the histology and immunoprofile of the cervical lesion were highly suggestive of a primary tumor of gastrointestinal origin, a systemic clinical investigation was performed. Computed tomographic scans demonstrated omental thickening, soft tissue stranding, and thickening of the pelvic base in the region of the cervix; the chest, abdomen, and remaining pelvis, including bilateral ovaries, were unremarkable. Upper endoscopy showed a normal esophagus, stomach, and duodenum. However, colonoscopy revealed an ulcer with submucosal thickening of the cecum near the appendiceal orifice. A biopsy of this site demonstrated an adenocarcinoma with prominent signet ring cell features. A right hemicolectomy was performed, which included removal of the appendix. At surgery, diffuse peritoneal carcinomatosis of the cecum, transverse colon, small intestine, and omentum was found. Extensive implants were also noted in the cul-de-sac, base of the uterus, and uterine cervix. Examination of the right hemicolectomy specimen revealed a primary appendiceal GCC with full-thickness involvement of the appendix (Figure 1, E), mesoappendiceal tissue, adjacent cecum, and mesenteric adipose tissue. Microscopically, the tumor in the appendix demonstrated extensive intramucosal and submucosal infiltration, with desmoplastic reaction. The neoplastic cells appeared singly or as small, irregular nests without visible lumens (Figure 1, E); the cells were similar histologically to those neoplastic cells seen in the cervical conization specimen. Importantly, 2 types of tumor cells composed the nests: neuroendocrine cells with moderate eosinophilic granular cytoplasm and a round or oval nucleus with a centrally located nucleolus, and admixed goblet cells (data not shown). In the cecum, the tumor showed diffuse mucosal and submucosal infiltration of predominantly mucin-containing goblet (signet ring) cells. The tumor cells revealed strong positivity for the neuroendocrine markers CD56 and synaptophysin (Figure 1, F), confirming the GCC histologic type of the primary tumor. (2) On follow-up, the patient's disease was stable 12 months after the initial diagnosis.


Case 2

A 40-year-old, previously healthy woman reported to her physician for recent onset of abnormal uterine bleeding. A physical examination revealed an enlarged uterus of approximately 16-week gestational size. A histologic evaluation of endometrial curettage showed a poorly differentiated adenocarcinoma with signet ring cell features. The tumor cells were strongly and diffusely positive for CK20 but were negative for CK7, CD10, estrogen receptor, and Wilms tumor 1 protein, suggesting a metastatic carcinoma arising from the gastrointestinal tract (hematoxylin-eosin and immunostains not shown). Surgical exploration with removal of appendix, bowel, and hysterectomy was performed. Pathology exam revealed a primary appendiceal tumor with extensive involvement of the ileum, cecum, omentum, and uterus, including the cervix (Figure 2, A through C). Microscopically, the tumor displayed similar histologic features to those described in case 1, with full-thickness involvement of the appendiceal wall and the periappendiceal tissue. The tumor cells appeared singly and in small clusters. Dual populations of cells were seen within the clusters: well-differentiated neuroendocrine cells with pale, eosinophilic, and granular cytoplasm, and mucin-containing goblet cells (signet ring cell). Immunostains were performed on the appendiceal specimen. The tumor cells were strongly and diffusely positive for CK20 and CDX2 (Figure 2, D and E) but were negative for CK7. The tumor cells also showed strong reactivity with CD56, synaptophysin, and chromogranin A immunostains (Figure 2, F), supporting the diagnosis of GCC.


Here, we report 2 cases of appendiceal GCC: one with metastases to the uterine endocervix, and the other with metastasis to the endometrium. To our knowledge, these are the only cases of metastatic appendiceal GCC reported in the medical literature with initial presentations as endocervical or endometrial involvement. Although focal signet ring cell differentiation may be noted occasionally in primary endocervical adenocarcinoma and squamous cell carcinoma, (6,7) primary cervical adenocarcinoma with prominent signet ring cell differentiation is extremely unusual, with fewer than 10 cases reported in the medical literature. (5) Rare cases of cervical adenocarcinoma with signet ring cell features metastatic from gastrointestinal tract, ovary, and breast have been reported. (8) Our findings suggest that metastatic appendiceal GCCs should also be considered in the differential diagnosis in such cases.

Appendiceal GCC, also called mucinous carcinoid, adenocarcinoid, and crypt cell carcinoma, is rare and demonstrates characteristic histologic features of both adenocarcinoma and carcinoid tumor. It is proposed to arise from crypt pluripotent cells with divergent neuroendocrine and mucinous differentiation. This tumor comprises approximately 6% of all appendiceal carcinoids. Appendiceal GCC occurs equally in both sexes, with higher occurrence in whites, and a mean age of 58.8 years. (9)

Characteristically, appendiceal GCC does not have a luminal in situ adenomatous phase and often diffusely infiltrates the mucosa and submucosa, with penetration into the subserosa. Tumor can subsequently spread into the peritoneal and pelvic cavities, often without causing significant gastrointestinal symptoms. With extensive infiltration, the appendiceal wall is indurated, and the lumen can become stenotic because of diffuse fibrosis. Because appendiceal GCC arises within the lower lamina propria and typically infiltrates extensively through the appendiceal wall without much tissue destruction or formation of tumor masses, imaging studies may reveal only slight thickening of the appendiceal wall or focal omental caking, even in patients with extensive intra-abdominal spread.

Histologically, the tumor cells are arranged in intestinal cryptlike patterns, nests, rosettes, or groups without distinct lumens. A dual differentiation of tumor cell type is seen within the nests: neuroendocrine cells with eosinophilic, granular cytoplasm, and mucinous goblet cells of gastrointestinal type. Argyrophil cells, argentaffin cells, and Paneth cells are the major nonmucinous components in GCC. Focally, especially in extra-appendiceal sites, the tumor may consist purely of individual signet ring cells and/or small clusters of mucinous cells, which might lead to a diagnosis of classic SRCC. Appendiceal GCC exhibits strong and diffuse positivity for CK20, whereas CK7 is usually negative. The tumor shows variable expressions of the neuroendocrine markers chromogranin A, synaptophysin, and CD56. Carcinoembryonic antigen usually shows diffuse membranous staining. Periodic acid-Schiff-diastase and mucicarmine stains highlight abundant intracellular mucin within the goblet cells.

Appendiceal GCC with endocervical involvement should be distinguished from rare primary cervical SRCC. Helpful in this regard is the finding in primary SRCC of other adjacent cervical lesions, including high-grade dysplasia, adenocarcinoma in situ, and squamous and adenosquamous carcinomas. (10) In addition, immunohistochemical analysis may be very helpful in this differentiation. According to some studies, the primary cervical adenocarcinomas, including the intestinal type, are typically diffusely positive for CK7 and p16, whereas CK20 is usually negative or only focally positive in a few cases. (6,11) CDX2 is negative in most primary cervical intestinal-type adenocarcinomas. (11) Two cervical adenocarcinomas in one study had focal signet ring cell features, which were [CK7.sup.+], [p16.sup.+], [CK20.sup.-], and [CDX2.sup.-]. (6) Therefore, these immunohistochemical markers may be useful in distinguishing the primary SRCC from intestinal metastases to the uterine cervix. Finally, in contrast to metastatic adenocarcinomas from the gastrointestinal tract, primary cervical SRCC has a strong association with human papilloma virus infection, particularly with types 16 and 18. (10,12)


Clinically, patients with appendiceal GCC commonly present with signs and symptoms of acute appendicitis due to luminal obstruction or of acute peritonitis resulting from appendiceal rupture. Extensive intraperitoneal seeding may occur in such cases. Only in rare instances is appendiceal GCC identified incidentally during procedures for unrelated clinical indications, as occurred in our cases. Compared with classic appendiceal carcinoids that metastasize in 2% to 5% of cases, appendiceal GCCs metastasize at a rate of 15% to 30%. In most reports of metastasizing appendiceal GCCs, the patients presented with spread beyond the appendix at initial diagnosis. (2) Other manifestations include intussusception, a palpable mass, gastrointestinal bleeding, increasing abdominal girth, chronic intermittent lower abdominal pain, and secondary genitourinary complications. In the largest series of appendiceal GCCs presenting with metastases to the ovaries, nearly all cases presented with diffuse peritoneal involvement with high mortality. (13) The authors of this article discourage the use of the term goblet cell carcinoid because the term does not accurately reflect the malignant behavior of this tumor. In this series of cases, the authors suggest that the term goblet cell carcinoid may be misleading and should be replaced by an alternative term, appendiceal tumors with goblet cell carcinoid-like and signet ring patterns. These tumors show a limited expression of the neuroendocrine markers chromogranin and synaptophysin, leading some authors to suggest terminology such as crypt cell carcinoma and mixed crypt cell carcinoma for these tumors. (14)

Therapy for widely disseminated appendiceal GCC, presenting as peritoneal carcinomatosis, is still being debated. Some authors recommend against radical surgery, whereas others recommend an aggressive cytoreduction procedure, including appendectomy, right hemicolectomy, and extensive peritoneal and pelvic debulking, combined with intraoperative and postoperative chemotherapy. (15) The efficiency of such protocol is under assessment.

In summary, appendiceal GCC is a rare and unique tumor with characteristic histologic features of both mucin-producing adenocarcinoma and neuroendocrine carcinoma. Appendiceal GCC shows more aggressive behavior than the conventional appendiceal carcinoid tumor. In the cases of unusual adenocarcinomas of the cervix and endometrium with prominent signet ring cells, metastatic GCC from the appendix should be considered in the differential diagnosis, especially after excluding the more common gastrointestinal and ovarian primary sites.


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Zenggang Pan, MD, PhD; Susan Repertinger, MD; Ronald Leonard, DO; Chhanda Bewtra, MD; Zoran Gatalica, MD, DSc; Poonam Sharma, MBBS

Accepted for publication June 10, 2010.

From the Department of Pathology, Creighton University Medical Center, Omaha, Nebraska (Drs Pan, Repertinger, Bewtra, Gatalica, and Sharma); and Cytocheck Laboratory, LLC, Parsons, Kansas (Dr Leonard).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Poonam Sharma, MBBS, Department of Pathology, Creighton University Medical Center, Omaha, NE 68131 (e-mail: poonamsharma@creighton.edu).
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