Goblet cell carcinoid (GCC) or goblet cell carcinoma is a unique type of mixed endocrine-exocrine neoplasm that is almost exclusively seen in the appendix. It is found in 0.3% to 0.9% of appendectomies, accounting for 35% to 58% of all appendiceal neoplasms and ~14% of all malignant neoplasms of the appendix.1–3 In a study by Pahlavan and Kanthan,4 who reviewed nearly 600 cases published in 57 articles from 1966 to 2004, the mean age of the patients at time of diagnosis was 59 years (ranging from 18 to 89 y), which was about 20 years older than that of patients with well differentiated neuroendocrine tumor (WDNET; carcinoid) of the appendix. In a more recent study based on the Surveillance, Epidemiology, and End Results (SEER) database, the mean age at initial diagnosis was 52 years, which was ~10 years higher than that of appendiceal WDNET.5 Most studies showed no sex predilection. The most common clinical presentation is acute appendicitis. In patients with disseminated disease, abdominal pain or a lower abdominal palpable mass may be the initial presentation. Half of the female patients may present with ovarian metastasis.6
GCC is traditionally considered a low-grade malignancy with a biological behavior intermediate between that of classic WDNET and conventional adenocarcinoma of the appendix. At the time of diagnosis, over 50% of cases show tumor invasion through the serosa or into the mesoappendix. Approximately 15% to 30% of cases have regional lymph node metastasis. Trans-coelomic/peritoneal spread is the most common route of metastasis, which involves the peritoneal surface of the abdominal cavity, pelvis, and ovaries. Metastasis to solid organs such as the liver or lungs is uncommon. Five-year disease-specific survival varies from 58% to 84% among different studies.3,4,7,8 Peritoneal carcinomatosis is the most common cause of death.
The coexistence of high-grade adenocarcinoma with GCC has been increasingly recognized in recent years, which has been variably called adenocarcinoma ex GCC or mixed GCC-adenocarcinoma. The term “mixed carcinoid-adenocarcinoma” is less preferable because it does not distinguish GCC from classic WDNET. The 2010 World Health Organization (WHO) Classification of Tumors of the Digestive System uses the term “mixed adenoneuroendocrine carcinoma,” but this term is also used for adenocarcinoma with a component of poorly differentiated neuroendocrine carcinoma (small cell or large cell neuroendocrine carcinoma), and rarely with a component of WDNET.9 A number of studies have shown that it is the high-grade adenocarcinomatous component that dictates the prognosis of patients with GCC.10–16 This article will provide an update on the current understanding of GCC, with a focus on the diagnostic criteria for high-grade adenocarcinoma.
NOMENCLATURE AND HISTOGENESIS
The name of GCC was introduced by Subbuswamy and colleagues in 1974 to reflect the primary cell type that morphologically resembled intestinal goblet cells with an admixed population of argentaffin cells.17 Historically, it has been variably termed as adenocarcinoid, mucinous carcinoid, microglandular GCC, amphicrine neoplasm, mucin-producing neuroendocrine tumor or carcinoma, and crypt cell carcinoma. GCC has been the preferred term in the literature; however, the inclusion of the term “carcinoid” may lead to confusion with WDNET. The WHO 2010 tumor classification confused the issue further by introducing the term “mixed adenoneuroendocrine carcinoma,”9 implying that the tumor has components of adenocarcinoma and neuroendocrine carcinoma, the latter of which is typically used for poorly differentiated small or large cell neuroendocrine carcinoma. Wen et al18 carried out a survey showing that 43% of pathologists incorrectly indicated that WDNET staging system was applicable to GCC and 43% incorrectly responded that Ki67 proliferation index was necessary for GCC grading. Two cases of GCC and adenocarcinoma ex GCC were incorrectly interpreted as NETs by oncologists, who then considered an inappropriate adjuvant chemotherapeutic regimen. Thus, the authors proposed that the term “goblet cell carcinoid” be changed to “goblet cell carcinoma.” Nonaka et al19 conducted a retrospective study of 105 cases of GCC and adenocarcinoma ex GCC and found that the percentage of neuroendocrine component was insignificant in both low-grade and high-grade tumors, while the percentage of high-grade component correlated with cancer-related survival. The authors therefore proposed that GCC should be regarded as a variant of adenocarcinoma and advocated the name “crypt cell adenocarcinoma,” which might more appropriately reflect the nature and cell origin of the tumor. Similarly, Yozu et al20 believed that GCC is a form of adenocarcinoma of mucin-secreting cells and thus should be reclassified as “goblet cell adenocarcinoma.”
The histogenesis of GCC remains to be completely elucidated. It is generally believed, however, that it derives from the pluripotent intestinal stem cells at the base of crypts that are capable of undergoing dual mucinous and neuroendocrine differentiation (unitary intestinal stem cell theory).7 Earlier ultrastructural studies showed that neurosecretory granules were present within mucin-containing goblet cells, suggestive of an amphicrine nature,21,22 but other investigators failed to identify cells containing both structures.23 Other studies have shown that GCC shares some features with classic WDNET and conventional adenocarcinoma of the appendix at the immunophenotypical and molecular levels (Table 1).
Whether GCC should be considered as a special form of adenocarcinoma, a variant of NET, or a hybrid remains a subject of debate. It is known to us, however, that GCC is frequently associated with high-grade adenocarcinoma, which is believed to represent a progression from preexisting GCC. From that perspective, the diagnostic term “adenocarcinoma ex GCC” appears appropriate.
HISTOLOGIC, IMMUNOHISTOCHEMICAL, AND MOLECULAR CHARACTERISTICS
Unlike classic WDNET of the appendix, GCC rarely forms a well-defined mass lesion. Instead, it usually diffusely infiltrates the appendiceal wall circumferentially in a concentric pattern (Fig. 1A). The histologic hallmark of GCC is the presence of small tight clusters, nests, or cords of tumor cells that exhibit a goblet cell morphology with a small compressed nucleus and conspicuous intracytoplasmic mucin (Fig. 1B). Individual goblet cells can occasionally be seen, which may result from sectioning at the edge of tumor cell clusters. Most tumor clusters are solid and do not show luminal formation. Small extracellular mucin pools, which frequently contain clusters of tumor cells, are commonly seen (Fig. 1C). Nuclear atypia is typically minimal and mitoses are infrequent (Fig. 1D). Scattered Paneth cells may be present, as well as neuroendocrine cells. Characteristically, the appendiceal mucosa does not show adenomatous or dysplastic changes. In fact, the mucosa is typically spared, except for the areas where tumor nests are connected with the base of crypts (Fig. 1E). Extension into the muscle and serosa is common. Despite its infiltrative growth, desmoplasia is not a typical feature of GCC (Fig. 1F).
In contrast to classic WDNET that typically shows strong and diffuse immunoreactivity for neuroendocrine markers such as chromogranin and synaptophysin, GCC often shows only scattered positive cells (Fig. 2). Expression of neuroendocrine markers is thus not a requirement for the diagnosis. Studies have also shown that GCC shares some of the immunohistochemical and molecular features with both classic WDNET and conventional adenocarcinoma of the appendix (Table 1). In 3 studies that examined a total of 51 cases of GCC,24–26 the frequencies of cytokeratin 20 (CK20) and cytokeratin 7 (CK7) expression were 100% and 63%, respectively. A diffuse staining pattern was commonly seen for CK20, whereas focal immunoreactivity was more common for CK7. This CK7/CK20 expression profile is somewhat similar to that of appendiceal adenocarcinomas, in which CK20 and CK7 positivity is present in 100% and 40% of cases, respectively. In contrast, out of 58 cases of classic appendiceal WDNET, only 10 cases (17%) showed focal CK20 immunoreactivity and only 2 cases (3%) showed focal CK7 immunoreactivity. Mucicarmine and carcinoembryonic antigen are consistently positive in GCC. There is also frequent expression of CD19 and CD99; however, there is no correlation between expression level of these proteins and prognosis.43
There have been a few molecular studies on GCC, which mainly focused on the comparison with conventional adenocarcinoma and classic WDNET. Jesinghaus et al33 recently performed a next-generation sequencing analysis on 25 appendiceal tumors including 11 GCCs, 7 adenocarcinomas ex GCC, and 7 primary colorectal-type adenocarcinomas using a modified colorectal cancer-specific panel of 32 genes linked to colorectal and neuroendocrine tumorigenesis. GCCs and adenocarcinomas ex GCC were similar in their mutational profiles and lacked mutations in typical colorectal cancer-related genes (eg, KRAS, APC, and TP53), showing that they are genetically distinct from colorectal-type adenocarcinomas. GCCs and adenocarcinomas ex GCC were also found to have mutations in genes associated with Wnt-signalling pathway (eg, NOTCH1, CTNNA1, and CTNNB1). In a similar study by Johncilla et al,46 next-generation sequencing of a 282 gene panel performed on 18 GCCs and 16 adenocarcinomas ex GCC of the appendix found mutations that differed significantly from those found in typical intestinal WDNET and conventional colorectal adenocarcinoma. In addition, the mutational burden in adenocarcinomas ex GCC was significantly higher than that of GCCs, but the spectrum of mutations overlapped between the 2 groups. The most frequently mutated genes included ARID1A, ARID2, CDH1, RHPN2, and MLL2. Mutations in TP53, CDH1, and MLL2 genes were predominantly present in the adenocarcinoma ex GCC group, consistent with transformation to a higher-grade lesion.
In a study by Stancu et al,47 allelic loss of chromosomes 11q, 16q, and 18q was found in both GCCs and ileal WDNETs, suggesting that GCCs resemble neuroendocrine tumors at the molecular level. In contrast, in a study by Wen et al,48 next-generation sequencing of 479 cancer genes revealed a mutational profile of GCCs and adenocarcinomas ex GCC that was distinct from both appendiceal WDNETs and conventional adenocarcinomas. Somatic mutations were not detected in WDNETs in this study. Mutations in the APC and KRAS genes were not observed in GCCs or adenocarcinomas ex GCC.
Overall, mutations involving the APC, KRAS, BRAF, and TP53 genes, characteristic of colorectal tumorigenesis, are a rare occurrence in GCC. The reported low frequencies of detection are usually seen in cases of adenocarcinoma ex GCC.
ADENOCARCINOMA EX GOBLET CELL CARCINOID
At least half of GCC tumors contain a component of associated high-grade adenocarcinoma, often signet-ring cell type or poorly differentiated, which has been called “adenocarcinoma ex GCC” or “mixed GCC-adenocarcinoma.”11,12 The 2 recent independent next-generation sequencing studies suggest that GCC and adenocarcinoma ex GCC are a single tumor type with varying grades of differentiation.33,46 The distinction of adenocarcinoma ex GCC (or high-grade goblet cell carcinoma) from pure GCC (or low-grade goblet cell carcinoma) was initially defined by Burke et al10 in 1990 as the presence of carcinomatous growth patterns featuring fused or cribriform glands, single file structures, diffusely infiltrating signet-ring cells, or solid sheets of cells. This diagnosis (which the authors called “mixed carcinoid-adenocarcinoma”) required the carcinomatous growth patterns to comprise at least 50% of the tumor volume and was associated with a worse prognosis compared with that of pure GCC. A more recent study by Taggart et al12 further stratified GCC and mixed GCC-adenocarcinoma into 3 groups: (1) GCC or GCC with <25% adenocarcinoma, (2) GCC with 25% to 50% adenocarcinoma, and (3) GCC with >50% adenocarcinoma. The overall patient survival was 83.8±34.6, 60.6±30.3, and 45.6±39.7 months for groups 1, 2, and 3, respectively. These studies highlight the importance of quantifying the proportion of adenocarcinoma in GCC cases. In the study by Taggart et al,12 the carcinomatous growth patterns were defined as individual dyshesive cells, solid sheets of cells, infiltrative cords of cells (not within the muscularis propria) or larger cords incompatible with GCC, complex glandular architecture (irregular, angulated, cribriform, or tufting), clusters of cells simulating GCC but with increased cytologic or architectural atypia beyond typical GCC nests (enlarged or irregular nests, increased cytologic atypia, increased mitotic activity), and destructive invasion or desmoplasia.
Tang et al11 also subclassified GCC and mixed GCC-adenocarcinoma into 3 groups: (A) typical GCC, (B) adenocarcinoma ex GCC, signet-ring cell type, and (C) adenocarcinoma ex GCC, poorly differentiated carcinoma type (Table 2). The 3- and 5-year disease-specific survival rates were 100% and 100% for group A, 85% and 36% for group B, and 17% and 0% for group C. The mean survival time was close to 10 years for group A, but only 43±6 and 31±6 months for groups B and C, respectively. In the stage IV–matched survival analysis, the 3- and 5-year survivals were 100% for group A, in which only 1 patient deceased after 119 months. The 3- and 5-year survivals were 82% and 38% for group B. Group C patients had the worst outcome with 3- and 5-year survivals of 17% and 0%, similar to those of stage-matched conventional adenocarcinoma of the appendix.
Although the classification proposed by Tang and colleagues has been shown to be useful according to a few studies,8,14,16 there is questionable reproducibility in distinguishing signet-ring cells from goblet cells in order to separate group B from group A.56 Pathologists may even have some difficulty in separating group B from group C.8 The term “signet-ring cell” also usually connotes a poorly differentiated carcinoma, which can lead to confusion when using the nomenclature proposed by Tang and colleagues. In addition, Taggart et al12 showed contrasting data in their group 3 patients (GCC with >50% adenocarcinoma), in which patients with signet-ring cell adenocarcinoma had a worse prognosis when compared to patients with non–signet-ring cell adenocarcinoma.
Lee et al13 instead proposed a simplified 2-tier histologic grading system, which separated GCC cases into low-grade and high-grade categories based on the assessment of 3 histologic features: cytologic atypia, stromal desmoplasia, and solid growth pattern (Table 3). Follow-up data showed that patients with low-grade histology had a good prognosis with median survival of 51 months and 10-year overall survival of 80.5%. These are in marked contrast to those with high-grade histology, which had median and 10-year overall survivals of 16.5 months and 0%, respectively. Using this 2-tier system, nearly all (98%) of group A tumors (using the histologic criteria defined by Tang and colleagues) were classified as low grade. All group C tumors were classified as high grade. Group B tumors were classified as either low grade (40%) or high grade (60%). An advantage of this simplified system is that it does not rely on a clear distinction between goblet cells and signet-ring cells. However, histologic assessment of cytologic atypia can still be challenging, and some degree of subjectivity is unavoidable.13 Compared with Tang’s 3-tier system, Lee’s 2-tier system showed a similar interobserver agreement among gastrointestinal pathologists (κ=0.65 for both systems) but a better agreement among non–gastrointestinal-trained pathologists (κ=0.44 for the 2-tier system vs. 0.22 for the 3-tier system).57 The challenging areas mainly included distinguishing goblet cells from signet-ring cells, applying the 1 mm2 criterion to multifocal noncontiguous glandular and single infiltrating cell architecture, recognizing solid growth pattern in cases with abundant extracellular mucin, differentiating fibroinflammatory stroma from desmoplasia, and distinguishing reactive atypia from true cytologic atypia.57
More recently, Yozu et al20 proposed a new 3-tier grading system that emphasized quantification of the low-grade component by assessing the proportion of the tumor that showed tubular or clustered growth (Table 4). Tumors with >75% low-grade component were classified as low grade (grade 1), 50% to 75% as intermediate grade (grade 2), and <50% as high grade (grade 3). The overall patient survival was significantly different among the 3 grades independent of stage, with median overall survival of 204, 86, and 29 months for grade 1, 2, and 3 tumors, respectively. According to the authors, this system had a high concordance rate (94.4%) with the Tang’s classification. Of 126 tumors analyzed, only 7 cases were differently classified: all low grade using authors’ criteria but high grade (group B) by Tang’s system. Of the 6 cases with follow-up data (mean follow-up time: 123 mo), 5 were alive with no evidence of disease and 1 died of C. difficile colitis. The concordance rate with the Lee’s grading system was lower (75.4%). All 31 discordant cases were high grade using authors’ criteria but low grade by Lee’s system. Of the 30 cases with follow-up data, only 15 were alive (4 with disease). These data suggest that this new grading system is potentially superior to other systems in substratifying goblet cell tumors. As briefly mentioned earlier, the authors also proposed a name change to “goblet cell adenocarcinoma” to include both GCC and adenocarcinoma ex GCC as a spectrum of a single disease entity. Under this name, tumors can be graded using the methodology that mirrors the practice of grading colorectal adenocarcinoma by assessing the proportion of tumor with gland formation. Typical GCC would be classified as low grade, whereas adenocarcinoma ex GCC would be either intermediate or high grade.
Interestingly, none of the above classification/grading systems used the WHO criteria for mixed adenoneuroendocrine carcinoma that require >30% for both components.9 In a recent study on the SEER data by Brathwaite et al15 using the WHO criteria, appendiceal mixed adenoneuroendocrine carcinoma was shown to be more aggressive than GCC. Specifically, the study included 249 appendiceal mixed adenoneuroendocrine carcinomas, 944 GCCs, 950 classic WDNETs, and 579 signet-ring cell carcinomas. The median overall survivals for these tumors were 6.5, 13.8, 39.4, and 2.1 years, respectively. More patients with mixed adenoneuroendocrine carcinoma had stage III or IV disease at the time of diagnosis (46%) than those with GCC (16%).
On the basis of the above studies, it appears reasonable to conclude that any histologic feature that deviates from the clustered architecture and low-grade cytology of typical GCC should be considered high-grade adenocarcinomatous component. This mainly includes complex glandular structures (Fig. 3A), too many dyshesive individual cells (Fig. 3B), large confluent solid sheets (Fig. 3C), large irregular clusters (Fig. 3D), obvious nuclear atypia (Fig. 3E), lack of intracytoplasmic mucin (Fig. 3F), and desmoplasia (Fig. 3G). It is important to emphasize that the diagnosis and grading of adenocarcinoma ex GCC or mixed GCC-adenocarcinoma require not only the identification of adenocarcinomatous components but also quantification. Confusions exist given different quantification cut-offs used in different classification/grading systems such as 1 mm2,11,13 25%/50%/75%,10,12,20 40%/90%,19 and 30%.9 It should also be mentioned that Ki67 proliferation index, a very useful prognostic parameter for classic WDNET, has been shown to have no prognostic value for GCC,8,14,44 and is thus not required for GCC grading.18 However, the adenocarcinomatous component in a adenocarcinoma ex GCC case may show a higher Ki67 labeling index than pure GCC component,11 which may help increase the confidence level for the diagnosis.
In addition to high-grade histology, tumor stage is another important independent prognostic factor for GCC. In the study by Yozu et al,20 multivariate analysis showed that tumor stage was highly predictive of outcome. Other factors such as lymphovascular invasion, perineural invasion, perforation, acute appendicitis, and the type of surgical resection were not significantly associated with overall patient survival. In a recent study of 34 mixed adenoneuroendocrine carcinomas of the appendix by Brathwaite et al,27 the factors significantly associated with worse prognosis included pathologic T stage, number of metastatic sites, percentage of goblet cell clusters, percentage of single cell infiltration, and percentage of tumoral mucin. The poorest overall survival was associated with advanced stage (pT4), a prominent mucinous component, and lack of goblet cell clusters. According to the American Joint Committee on Cancer (AJCC) 8th Edition Cancer Staging Manual, GCC should be staged using the TNM system designed for appendiceal adenocarcinoma, and not using the one for appendiceal WDNET.58
Due to the rarity of GCC, there is a lack of high-level consensus regarding the optimal extent of surgical resection. In fact, the European Neuroendocrine Tumor Society (ENETS) 2012 guidelines were developed based on expert opinion after a retrospective review of the literature.5 Nonetheless, treatment options are usually based on tumor stage as well as the presence or absence of high-grade adenocarcinomatous component.7,8,11,59 Stage I (pT1 or pT2) tumors may be adequately managed with appendectomy with a negative margin alone, but lifelong surveillance for metastasis may be needed. Appendectomy may also be indicated for patients with comorbidities that do not allow further surgical intervention. For higher stage tumors (pT3 or pT4), right hemicolectomy is recommended with the aims of complete excision, adequate lymph node sampling, and appropriate disease staging, but this approach has been controversial and is not universally endorsed.7,60 Right hemicolectomy is also recommended for cases with positive appendectomy margin, perforated appendix, and the presence of high-grade adenocarcinomatous component. The 2-cm size criterion used for appendiceal WDNET to help decide if the patient needs further right hemicolectomy after appendectomy does not apply to GCC because it rarely forms a mass lesion. Prophylactic oophorectomy is advocated by some authors, particularly for postmenopausal women, due to the high risk of ovarian metastasis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy may be an option for patients with peritoneal carcinomatosis.1 Adjuvant chemotherapy with 5-fluorouracil-based regimens, similar to those for colorectal adenocarcinoma, is recommended for patients with stage III, stage IV, or recurrent disease.5
Thorough sampling of appendectomy specimen for histologic assessment is imperative, which require submission of the entire appendix. The goals of histologic examination mainly include assessment of T stage, evaluation of appendectomy margin, and identification of tumor components that may suggest a more aggressive behavior, which thus help decide whether further right hemicolectomy is necessary.
EXTRA-APPENDICEAL GOBLET CELL CARCINOID
True extra-appendiceal GCCs are exceedingly rare. GCCs found in locations other than the appendix are most likely extra-appendiceal presentations of an occult appendiceal primary (Fig. 4). Gui et al61 reported that among 65 cases of GCC, 16 (24.6%) were reported as extra-appendiceal, in which 5 cases (31.3%) presented with disseminated abdominopelvic disease but primary sites were unknown at the initial diagnosis. The other 11 cases presented with a mass or nodular lesion in the stomach, ileum, colon, and rectum, including 1 case incidentally found in an adenomatous polyp of the colon. Nine cases (56.3%) were initially diagnosed as poorly differentiated, mucinous, or signet-ring cell adenocarcinomas, but the diagnoses were questioned due to unusually slow disease progression and were ultimately revised 1 to 3 years later. Interestingly, of the 16 cases of putative extra-appendiceal GCC, a primary appendiceal GCC was demonstrated in 4 cases (25%) 1 week to 13 months later. In 10 cases, the appendix was surgically absent and resected specimens were not available for review. In only 2 cases (12.5%) was the appendix found to be negative for tumor, but one of the cases had only 1 tissue section sampled from the appendix for histologic examination. Therefore, only 1 case had the entire appendix examined histologically, which appeared to be the only case of true extra-appendiceal GCC in this study.61 The authors also reviewed the literature and found 10 putative extra-appendiceal GCCs, but only 1 case excluded an appendiceal primary by histology. Therefore, complete histologic examination of the appendix is required before an extra-appendiceal GCC is diagnosed.
GCC is a unique appendiceal neoplasm that is frequently associated with high-grade adenocarcinoma and that, despite having “carcinoid” in its name, should be staged as an adenocarcinoma. Several classification/grading systems have been proposed for this tumor in order to better stratify patients by prognosis and to guide clinical management. All these systems rely on careful histologic assessment to identify and quantify the percentage and grade of adenocarcinomatous component within the tumor, but vary in definitions. Additional data are needed to further evaluate the utility of the proposed classification/grading systems, and a consensus on nomenclature is also needed to better facilitate patient care and future investigations.
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