10.1245/ASO.2006.02.016
Annals of Surgical Oncology 13:370-376 (2006)
© 2006 Society of Surgical Oncology
Surgical and Chemotherapy Treatment Outcomes of Goblet Cell Carcinoid: A Tertiary Cancer Center Experience
Tuan H. Pham, MD, PhD1,
Bruce Wolff, MD1,
Susan C. Abraham, MD2 and
Ernesto Drelichman, MD3
1 Department of Colorectal Surgery, Mayo Clinic, 200 First Street S. W., Rochester, Minnesota 55905
2 Department of Pathology, Mayo Clinic, 200 First Street S. W., Rochester, Minnesota 55905
3 Department of Surgery, University of Alabama at Birmingham, KB417, 1530 3rd Avenue South, Birmingham, Alabama 35294
Correspondence: Address correspondence and reprint requests to: Bruce Wolff, MD; E-mail: wolff.bruce{at}mayo.edu.
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ABSTRACT
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Background: Goblet cell carcinoid (GCC) is a rare malignant tumor with distinct histological and clinical features. Our goals were to review the surgical and chemotherapy outcomes of patients with GCC.
Methods: We performed a retrospective review of the Mayo Clinic database from 1984 to 2004 with a prospective follow-up of 57 patients with GCC.
Results: The age at diagnosis (mean ± SE) was 55 ± 13 years. The most common presentations were right lower quadrant pain mimicking appendicitis (70%) and right lower quadrant or pelvic mass (25%). Only patients with T4 lesions had positive mesenteric nodes, with a frequency of 28%. Fifty percent of female patients had metastasis to the ovaries. The disease-specific 5-year survivals for stages I, II, III, and IV were 100%,76 %,22 %, and 14%, respectively; the overall mean survival was 47 ± 3 months. All stage I patients had simple appendectomy. The overall 5-year survival rates for patients with combined stages II to IV who underwent appendectomy versus right hemicolectomy were 43% and 34%, respectively (P = .604). The corresponding survival rates for adjuvant chemotherapy versus no chemotherapy were 32% and 27%, respectively (P = .151).
Conclusions: The prognosis for patients with GCC tumors correlates well with the American Joint Committee on Cancer stage at initial presentation. Appendectomy alone seems adequate for stage I disease. For staging purposes, right hemicolectomy is appropriate for T4 tumors or stage II to III disease provided that it can be performed with minimal risk. Surgical debulking is a consideration but is controversial. Adjuvant chemotherapy with 5-fluorouracil and leucovorin regimen is minimally effective against GCC.
Key Words: Goblet cell carcinoid • Adenocarcinoid • Small-bowel neoplasms • Appendix
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INTRODUCTION
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Primary appendiceal neoplasms include carcinoid, adenocarcinoma, cystadenocarcinoma, and goblet cell carcinoid (GCC). GCC, also variably known as adenocarcinoid, mucinous carcinoid, and crypt cell carcinoma, is a rare neoplasm with distinct histological and clinical features. It has histological features of carcinoid as well as adenocarcinoma and was initially described in a large series by Subbuswamy et al.1 in 1974. It is believed to arise from crypt base stem cells.2 Generally, it stains positive for synaptophysin, neuron-specific enolase, cytokeratin, chromogranin, and bioamines, which are characteristic of carcinoid lineage.3,4 However, it does not secrete the active hormones, i.e., serotonin and its byproducts, typically seen in carcinoid, at least not to the extent detectable in systemic circulation or enough to produce carcinoid symptoms. GCC produces mucin, a feature consistent with adenocarcinoma cell line.3,5 Figure 1
shows representative histological features of GCC.
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FIG. 1. (A) Goblet cell carcinoid at high magnification shows an admixture of small, uniform glands and single infiltrating tumor cells that resemble goblet cells (stain, hematoxylin and eosin; original magnification, x20). (B) Neuroendocrine differentiation is demonstrated by chromogranin labeling (brown staining) in scattered tumor cells (chromogranin immunohistochemistry; original magnification, x40).
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Reports from the medical literature on GCC are sparse; however, the general consensus is that the clinical behavior of GCC is intermediate between carcinoid and adenocarcinoma.6–8 It is a more aggressive neoplasm compared with appendiceal carcinoid but is more indolent compared with adenocarcinoma.9
Surgical resection is the primary treatment for local control and possible cure for early-stage disease. Chemotherapy is frequently recommended, especially for patients with advanced peritoneal disease. Given the rarity of the disease, consensus on the surgical approach—i.e., appendectomy versus right hemicolectomy (RH), as well as chemotherapeutic treatment—is lacking. The rationale for performing RH includes the goals of achieving a wide surgical margin, resecting involved nodes, and staging the disease. There is no convincing evidence to suggest that hemicolectomy will decrease recurrence or improve survival,8,10 nor is there a clear guideline as to when to perform a RH. A similar dilemma is encountered for female patients as to whether the ovaries should be removed prophylactically, given the high incidence of ovarian metastasis. An even less defined but reasonable consideration is the role of tumor cytoreduction; this consideration has a practical basis because patients often present with extensive peritoneal metastasis, and GCC seems to be an indolent neoplasm. Debulking of GCC peritoneal metastasis is an aggressive surgical approach but has a precedent in other neoplasms: specifically, ovarian cancer11,12 and appendiceal pseudomyxoma.13,14 Tumor debulking has been shown to prolong survival in these neoplasms.14–18
The aims of this study were to (1) review the epidemiology and clinical presentation of GCC, (2) evaluate survival outcome with respect to surgical interventions (specifically, append ectomy vs. RH or more extensive resection), and (3) assess the efficacy of chemotherapy.
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METHODS
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The Mayo Clinic Institutional Review Board approved this study, and it was conducted in accordance with Institutional Review Board guidelines. We reviewed the Mayo Clinic databases, specifically the Tumor Registry and Medical Index, for the diagnoses of "adenocarcinoid" and "goblet cell carcinoid" tumor in the time period from 1984 to 2004. A total of 60 patients were found, but 2 patients did not consent to a review of their medical records for research purposes. Histological results from one patient showed that the tumor was actually adenocarcinoma of the appendix. Therefore, data from 57 patients were available for analysis. Our pathologist (S.C.A.) reviewed hematoxylin and eosin as well as immunohistochemical staining to confirm the diagnosis of GCC.
A chart review was performed to retrieve epidemiology data and clinical information. Living status was confirmed through clinical records, direct communication with patients or family, or the national death registry. Staging of GCC was based on American Joint Committee on Cancer criteria.19 July 2004 was the end point for time-related analysis. The Kaplan-Meier method was used for survival analysis. For treatment outcome analysis, patients in stage II and III were combined to improve statistical power. Standard error is used to report uncertainty. The log-rank test was used to evaluate statistical difference between groups, and a P value <.05 was considered statistically significant.
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RESULTS
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The age (mean ± SE) at presentation of GCC was 55 ± 13 years. GCC occurred more frequently in women, with a female:male ratio of 1.7:1 in this series. Patients most frequently presented with symptoms of appendicitis, followed by lower abdominal mass and bowel obstruction. Table 1 summarizes the frequency of the main presenting signs and symptoms, as well as the stage at initial presentation. None of the patients was positive for carcinoid tumor markers, such as 5-hydroxyindoleacetic acid and dopamine. Most patients had stage II and IV disease at the time of initial presentation. With regard to anatomical distribution, GC C occurred most commonly in the appendix, but one patient developed GCC in the ileum. Half of the female patients had metastasis to the ovaries at the time of initial presentation. It is interesting to note that 10% of the patients with GCC had other primary malignancies. Tumor size information was incomplete. For example, pathology reports often mentioned the gross appendiceal dimensions instead of the tumor size. Consequently, we could not accurately assess their effect on survival.
The mean survival was 47 ± 3 months, the overall 5-year survival was 45%, and the disease-specific 5-year survival was 47% from the time of presentation. Survival was significantly correlated with the stage at presentation. In particular, the 5-year disease-specific survivals for each stage were as follows: stage I, 100%; stage II, 76 %; stage III, 22 %; and stage IV, 14%. Figure 2 shows the Kaplan-Meier overall survival curves for the four stages. Four patients in stage I underwent appendectomy for symptoms of appendicitis. The other four patients in stage I had incidental appendectomy while they underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometrial bleeding (n = 2) and presumed ovarian cancer (n = 2). One of the two patients with presumed ovarian cancer had in reality a metastasis from a primary pancreatic adenocarcinoma. She was also found to have GCC in the appendix. She died 2 months after the abdominal procedure during the same hospitalization.
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FIG 2. Kaplan-Meier plots of survival versus stage at initial presentation: stage I (diamonds), II (asterisks), III (squares), and IV (pluses). P values from comparison of stages II, III, and IV versus stage I were statistically significant for stage III versus I and stage IV versus I.
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The overall probabilities of recurrence after surgical resection for each of the tumor stages were as follows: T1/2, 0 %; T3, 33 %; and T4, 71 %. Patients initially presenting with stage IV disease were excluded from this analysis because they already had disseminated intra-abdominal disease at initial presentation and continued to have disease burden afterward. Ideally, we would like to calculate the probability of recurrence for each tumor stage for each type of surgical intervention (i.e., append ectomy vs. RH or more extensive resection), as well as the type of adjuvant chemotherapy. There was an inadequate number of patients in the initial stages (I to III) for this kind of detailed subgroup analysis. Consequently, the probability of recurrence for tumor stage was calculated irrespective of the type of intervention.
Peritoneal carcinomatosis is the most common disease-specific cause of death for GCC patients. Virtually all patients who died of GCC had peritoneal carcinomatosis, as diagnosed by imaging or abdominal exploration. None of the cases in this series had extra-abdominal metastases. A few patients did have malignant pleural effusions that led to respiratory failure, but metastases to the lung parenchyma were not observed. GCC spreads by direct peritoneal seeding; thus, even with advanced stages, it is a local-regional disease confined to the abdominal cavity.
The effect of surgical and chemotherapeutic intervention on survival was examined. Stage I patients were cured with an appendectomy, except for one patient, who had an incidental finding of GCC while undergoing exploration for pancreatic primary tumor. Patients with stage II and III disease were combined to improve statistical power when the data were analyzed for the effect of surgical and chemotherapeutic intervention on survival. Surgical interventions were grouped into patients who underwent appendectomy versus those who had RH or more extensive surgery. The 5-year survival rates for combined stages II/III were not statistically different between treatment groups (appendectomy vs. RH). Similarly, RH did not improve the survival rate for stage IV patients. The effect of surgical intervention on survival is summarized in Table 2 and depicted as Kaplan-Meier survival plots in Figure 3.
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FIG. 3. Effect of surgical intervention on survival of patients with (a) combined stages II to III and (b) stage IV. Appendectomy (circles), right hemicolectomy, or more extensive procedures (squares).
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Twenty-seven patients received chemotherapy, and multiple chemotherapy regimens were tried. Most of the regimens contained 5-fluorouracil (5-FU) and leucovorin (70%). Table 3 summarizes the effect of chemotherapy on survival for stage II to IV patients. There was a trend toward improved mean survival, but it was not statistically significant. The mean survival for combined stage II to III patients who received chemotherapy versus no chemotherapy was 47 and 32 months, respectively (P = .383). For stage IV patients, the corresponding mean survival was 39 and 29 months, respectively (P = .281).
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DISCUSSION
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We acknowledge the biases and limitations of a retrospective study, but this large case series provides important insight into the clinical presentation and management of the rare GCC neoplasm. GCC was more common in women in this series but was reported to be equal in a large census study9; there may be a bias toward a higher female prevalence in this study because of higher incidental appendectomy during gynecological procedures in the surgical population. Patients with GCC have a prognosis intermediate between carcinoid and adenocarcinoma of the appendix, with an overall mean survival of 47 months. Even with advanced stages (III to IV), the mean survival is approximately 32 months. An epidemiological study by McCusker et al.9 showed a 5-year survival of approximately 75%, although it was significantly lower, at 45%, in this study. The differences in overall survival may be due to the fact that a much greater fraction (51%) of our patients presented with advanced stages.
Appendectomy is curative for stage I cancer, but patients rarely present at this stage other than as a chance discovery after an incidental appendectomy. Symptomatic patients frequently presented at a later stage and often had symptoms that mimicked appendicitis. A common dilemma for the surgeon is a situation in which GCC is diagnosed after a routine appendectomy for presumed appendicitis. Most surgical textbooks recommend RH on the basis of various criteria,20,21 such as tumor size, grade, invasion, and stage, but admittedly there is insufficient evidence to support this recommendation. A recent meta-analysis by Varisco et al.10 suggested that RH is not necessary for localized tumors (i.e., tumor stage less than T2) unless there is direct cecal involvement. Our data show that RH does not change survival outcomes for patients with stage II to IV disease, nor does it decrease recurrence.
Metastasis to the liver parenchyma or extra-abdominal organs was not observed in this series, and no patient died from extra-abdominal metastasis, with the exception that some patients developed malignant pleural effusions that led to respiratory failure. Mesenteric nodal metastasis was seen only in patients with T4 tumors. These data suggest that GCC has a propensity for peritoneal seeding and that patients who die from GCC already have microscopic peritoneal disease at the time of presentation. It makes sense that an RH would not eliminate microscopic disease and thus would not alter the course of GCC. However, RH and attendant mesenteric nodal resection are recommended for (1) T3/4 disease, for which there is a high frequency of recurrence (30% for T3 and 70% for T4) or nodal involvement,(2) direct cecal extension, and (3) clinically positive mesenteric nodes. Obviously, the intent of mesenteric nodal resection is to stage and debulk nodal disease. Similarly, bilateral oophorectomy is a reasonable consideration for postmenopausal women or those past childbearing age because of the high rate of metastasis to the ovaries.
GCC has a propensity for peritoneal seeding with the end point of peritoneal carcinomatosis. Most patients with GCC unfortunately present at later stages of the disease: >51% are in stage III or IV at the time of diagnosis. It is interesting to note that it is an indolent disease with similar modes of dissemination and survival outcomes as compared to ovarian neoplasms and mucinous cystadenocarcinoma of the appendix. Aggressive surgical debulking to decrease tumor burden has been shown to improve survival in ovarian neoplasms and appendiceal mucinous cystadenocarcinoma. 22,23 It is thus reasonable to ask whether we should take a more aggressive surgical approach and debulk peritoneal metastasis for GCC. A notable difference between GCC and ovarian neoplasms is that chemotherapy is much more effective in the latter. The response to the current chemotherapy regimens for GCC is minimal, as was demonstrated in this study. New regimens, such as FOLFOX (5-FU, oxaliplatin, and leucovorin) and FOLFORI (5-FU, folic acid, and irinotecan), may provide more effective responses and should be tried on GCC. Intraperitoneal chemotherapy is a reasonable consideration for GCC, because it has been used for other indolent neoplasms with a propensity for peritoneal seeding. Aggressive cytoreduction, combined with more effective chemotherapy, may significantly extend survival and be a worthwhile endeavor. Of course, this endeavor requires individual surgical assessment of the risks and benefits.
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CONCLUSIONS
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GCC is a rare malignancy that arises mostly from the appendix but can also occur in other parts of the small bowel. Its prognosis is intermediate between classic carcinoid and adenocarcinoma of the appendix, with mean survival of 47 months and an overall 5-year survival of 45%. GCC has a propensity for peritoneal seeding that leads to peritoneal carcinomatosis. Because most patients present in the later stages of this disease, it is logical that RH did not significantly improve survival, especially because it was performed without attempts at cytoreduction. Aggressive surgical cytoreduction and chemotherapy may be a viable option to manage peritoneal seeding, as has been done with other indolent neoplasms such as ovarian and mucinous cystadenocarcinoma. However, this approach remains controversial for GCC.
Received for publication February 14, 2005.
Accepted for publication August 31, 2005.
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ABSTRACT
INTRODUCTION
