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Case 273 - Discussion

Uploaded: 2008-11-26, Updated: 2008-11-26

 

 

CK20

CK7

 

CDX2

 

CD56

Chromogranin A

NSE

Synaptophysin

   

Appendiceal goblet cell carcinoid with involvement of uterine cervix and endometrium

The endometrial curettage showed poorly differentiated adenocarcinoma with signet-ring cell features. The tumor cells were strongly positive for CK20 and CDX2, but were negative for CK7, CD10, estrogen receptor (ER) and Wilms tumor 1 (WT1), suggesting the presence of a metastatic tumor arising from the gastrointestinal tract. A systemic workup revealed a primary appendiceal tumor with extensive involvement of the ileum, cecum, omentum, and uterus, including the cervix. Microscopically, the tumor displayed similar histological features as described in Case 1, with full-thickness involvement of the appendiceal wall and the peri-appendiceal 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, granular cytoplasm and others with signet ring cell morphology.  The tumor cells showed strong reactivity with neuron specific enolase (NSE), CD56, synaptophysin, and chromogranin A, supporting a tumor of neuroendocrine origin.

Although focal signet-ring cell differentiation may be occasionally noted in primary endocervical adenocarcinoma and squamous cell carcinoma, primary cervical adenocarcinoma with prominent signet-ring cell differentiation is extremely unusual, with less than 10 cases reported in the medical literature. Usually cervical adenocarcinoma with signet-ring cell features represents metastatic disease, most often from the gastrointestinal tract and less frequently from the ovary and breast. However, our findings suggest that GCC of the appendix should also be considered in the differential diagnosis as a primary tumor site in such cases.

Appendiceal GCC, also called mucinous carcinoid, adenocarcinoid and crypt cell carcinoma, is rare and demonstrates histological 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 appendiceal carcinoid. Appendiceal GCC occurs equally in both genders with higher occurrence in the white race and a mean age of 58.8 years.

Grossly, appendiceal GCC often diffusely infiltrates the 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 as a result of diffuse fibrous thickening. Since appendiceal GCC tends to arise within the lower lamina propria and to infiltrate 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 intestinal crypt-like patterns, nests, rosettes, or groups without distinct lumens. A dual differentiation of tumor cell type is seen within nests: neuroendocrine cells with eosinophilic, granular cytoplasm and goblet cells of gastrointestinal type. Argyrophil cells, argentaffin cells and Paneth cells are the major non-mucinous components in GCC. Focally, especially in extra-appendiceal locations, the tumor may consist purely of individual signet-ring cells and/or of small clusters of cells, which might lead to a misinterpretation as classic signet-ring cell carcinoma. Appendiceal GCC exhibits strong and diffuse positivity for CK20, while CK7 is usually negative. The tumor shows variable expressions of the neuroendocrine markers NSE, chromogranin A, synaptophysin and CD56. Carcinoembryonic antigen (CEA) 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 carcincinoma. In addition, immunohistochemical analysis may be very helpful in this differentiation. In a study using a limited panel of immunohistochemical markers, including CK7, CK20, and CDX2,  primary cervical adenocarcinoma (CK7+, CK20- and CDX2-) was reported to be readily distinguished from intestinal metastases to the uterine cervix (CK7-, CK20+ and CDX2+). Finally, in contrast to metastatic adenocarcinomas from the gastrointestinal tract, primary cervical SRCC has an association with the human papilloma virus (HPV), particularly types 16 and 18.

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. 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. Other manifestations include intussusception, a palpable mass, gastrointestinal bleeding, increasing abdominal girth, chronic intermittent lower abdominal pain, and secondary genitourinary complications. In women, GCC may present as a Krukenberg tumor of the ovary. In rare instances, the tumor is identified incidentally during procedures for unrelated clinical indications.

Therapy of widely disseminated appendiceal GCC, also designated as peritoneal mucinous carcinomatosis, is still under debate. Some authors recommend against radical surgery, since whether the course of the disease following such surgery is altered remains contoversial. An aggressive cytoreduction procedure, including appendectomy, right hemicolectomy, and extensive peritoneal and pelvic debulking, may be considered when combined with intra- and post-operative chemotherapy. The efficiency of this protocol is under assessment.

In summary, appendiceal GCC is a rare and unique tumor with characteristic histological features of both adenocarcinoma and carcinoid tumor. However, appendiceal GCC shows more aggressive behavior when contrasted with the conventional appendiceal carcinoid tumor. Given our findings, we propose that GCC of the appendix be considered in the differential diagnosis of tumors metastatic to sites within the female genital tract, especially after gastric, intestinal and ovarian primary sites have been excluded.

 

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