Adenocarcinoma Ex Goblet Cell Carcinoid in a Renal Transplant Patient: A Case Report and Review of the Literature

Discussion

Carcinoid tumors are the most common neoplasm of the appendix, with appendiceal carcinoids found in 1 out of every 300 appendectomies. Goblet cell carcinoid (GCC) is a rare subtype that comprises 6% of carcinoids (1) and fewer than 5% of primary appendiceal tumors overall (2). GCC is characterized by neoplastic cells with features of both neuroendocrine and mucinous cells (3). In a SEER-based population study, the incidence of GCC was equal in men and women (4). The age at presentation for GCC was intermediate between that for classical carcinoid and for adenocarcinoma of the appendix; the average age at presentation for carcinoid was 38 years, for GCC 52 years, and for adenocarcinoma 60 years (4). The biological behavior and prognosis of GCC is worse than that of carcinoids; while appendiceal carcinoids metastasize in 2-5% of cases, GCCs have a rate of metastasis of 15-30% (2, 4). These differential features between appendiceal carcinoids and GCCs support the concept that GCC is a tumor type that is biologically distinct from classical carcinoids (5).

Patients with GCC most commonly present with either an acute appendicitis, or abdominal symptoms such as pain and bloating with a palpable abdominal mass (Table I). GCC often presents at an advanced stage with transmural invasion of the appendiceal wall on pathology; studies have estimated that 65-97% of tumors are T3 or T4 at the time of diagnosis (4, 6). The most frequent metastatic sites include local extension into the right colon or ileum, and peritoneal or omental spread. Women can present with Krukenberg tumor, and among women the ovary is the most common site of metastasis site (6, 7). In our case, no abnormalities in the appendix were noted at the time of surgery. This is not unusual, however, as in a review of 30 cases of Krukenberg tumor of appendiceal origin, 16 were due to GCC of the appendix, and four out of the 16 required a second laparotomy to identify the primary site in the appendix (8). Because GCC's are typically infiltrative and do not present as well-defined macroscopically evident masses or discrete tumors, they can be clinically occult at the time of laparotomy for the ovarian lesions (9-11).

Immunohistochemistry in GCC frequently demonstrates the presence of the neuroendocrine markers synaptophysin and chromogranin (5). Serum chromogranin-A levels are also often elevated. In our patient, all cells, including the signet-ring cells, stained with synaptophysin, indicating that the tumor was not likely to be a collision tumor consisting of adenocarcinoma and neuroendocrine tumor originating from two separate primaries. GCC also stains positively for CK20, CK7 (less commonly than CK20), and neuron-specific enolase (5). Although our patient had no signs or symptoms of a primary tumor in the gastrointestinal tract, lack of PAX-8- and CDX2-positive staining suggested that the tumor originated from a gastrointestinal, rather than an ovarian, site.

A retrospective study of 63 cases of appendiceal GCC sub-classified the tumors by histology into three types: A:) Typical GCC; B:) adenocarcinoma EX GCC, signet-ring type; C) Adenocarcinoma exGCC, poorly-differentiated type (6) The histological subtype of GCC as defined by this group was found to be predictive of survival at advanced stage, with a 5-year survival in stage IV disease of 100%, 38%, and 0%, respectively. However it has been noted that the distinction between types B and C is not always clear, and can be difficult to accomplish prospectively (12). In our case, signet ring features were suggestive of type B disease, however the patient had a high mitotic index in the tumor (>20 mitoses per hpf), which in this series was more common among type C tumors, although not used as a criterion for classification as a type C tumor (12). The authors of this retrospective study also found p53 staining to be more common in type C than in type B tumors, and in future this could be evaluated as a way to distinguish between the two prospectively.

Due to the rarity of adenocarcinoma ex GCC, the management of this tumor is extrapolated from case series of metastatic GCCs. In a series of four patients with diffuse peritoneal involvement from GCC, debulking surgery alone resulted in a median survival of seven (range 5-24) months (13). In a series of 22 patients with peritoneal disease and mucinous ascites from GCC of the appendix, a comparatively longer median overall survival of 18.5 (range 3.2-95.1) months was seen with debulking surgery and intraperitoneal chemotherapy (14). The patients in this series that did not receive intraperitoneal chemotherapy (n=2) had a shorter survival of 4.1 and 6 months. The extent of intraperitoneal disease preoperatively (measured by the peritoneal cancer index) was negatively-correlated with survival, while the degree of cytoreduction achieved (measured by the completeness of cytoreduction score), was positively-correlated with survival.

Case series of ovarian and peritoneal metastasis from GCC have also described the use of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin, with minimal effect (15, 16). In another case, cisplatin-based chemotherapy given both intraperitoneally and i.v. resulted in survival for 24 months after surgery (8). One case report of adjuvant oxaliplatin, 5-FU and leucovorin (FOLFOX4) in a woman with diffuse peritoneal and lymph node metastastases reported a complete remission of the cancer for up to three years after diagnosis (17). The rarity of this tumor makes prospective studies using FOLFOX in appendiceal GCC unlikely, however the more aggressive adenocarcinomatous component likely drives the prognosis in this tumor and FOLFOX has been used more for appendiceal carcinomas with some success in the adjuvant setting (18).

One unique aspect of this case is that the patient's cancer arose two years after renal transplant. It has been well-documented that the incidence of malignancy is increased in the post-transplant setting, and this has been ascribed to the effects of chronic immunosuppression. Although the most common types of cancers in the post-transplant setting are squamous cell carcinomas and lymphoproliferative disorders, it is increasingly recognized that the incidence of other types of cancers is also slightly higher (19).

No prior cases of adenocarcinoma ex goblet cell carcinoid appear to have been published, although two cases of mixed tumors consisting of mucinous cystadenoma and goblet cell carcinoid have been published in the same report (20). In one of these cases the patient presented with ovarian metastasis and had radical surgery with no recurrence, although the period of follow-up after surgery was not reported. In the second case, the tumor was suspected at the time of second renal transplant when the appendix appeared enlarged, and appendectomy was performed, revealing mucinous cystadenoma and GCC. It is unclear in our case whether an occult appendiceal GCC predated the patient's transplant and evolved into adenocarcinoma after immunosuppression was started, or whether this was a tumor that arose de novo in the setting of immunosuppressive therapy. With the increasing rate of solid-organ transplantation, we expect that more rare tumors will be diagnosed in post-transplant patients. It remains to be seen whether immunosuppression contributes to the risk of transformation of more benign entities such as typical GCC to more aggressive histologies such as signet ring or poorly differentiated GCC.