Simplified 2-tier histologic grading system accurately predicts outcomes in goblet cell carcinoid of the appendix

doi:10.1016/j.humpath.2015.08.005

Human Pathology

Volume 46, Issue 12, December 2015, Pages 1881-1889

https://doi.org/10.1016/j.humpath.2015.08.005 Get rights and content

Summary

Goblet cell carcinoid (GCC) is a rare appendiceal malignancy with both neuroendocrine and glandular features. Clinical outcomes of patients with GCC vary widely and a histology-based 3-tiered prognostic scheme has been previously suggested; however, this scheme is subjective and challenging to apply in day-to-day practice. We sought to construct a simplified and prognostic grading system based on objective histologic features with specific criteria. A continuous population-based cohort of GCC with clinical outcome data and archival tissue available for review was extracted from regional databases. For the 78 patients with confirmed appendiceal GCC, specific histologic features, including cytologic atypia, peritumoral stromal desmoplasia, and solid growth pattern, were recorded, and a scoring system was devised, which separates patients with GCC into low-grade (n = 55; 71%) or high-grade (n = 23; 29%) histology. Correspondingly, clinical follow-up data show good prognosis in those with low-grade histology with median and 10-year overall survival of 51.0 months and 80.5%, respectively, whereas those with high-grade histology have a poor prognosis with median and 10-year overall survival of 16.5 months (P = .006) and 0% (P < .001), respectively. Multivariate Cox proportional hazard modeling demonstrates that this 2-tier histologic system remains predictive of overall survival when controlled for TNM clinicopathological stage. These data show that a simple and objective histologic scoring system separates GCC into low- and high-grade histology with divergent clinical outcomes.

Introduction

Goblet cell carcinoids (GCCs) are rare malignancies that arise almost exclusively in the vermiform appendix and have both neuroendocrine and glandular histologic features [1], [2], [3]. When initially described, they were thought to be slow growing and clinically indolent—akin to classic appendiceal carcinoid tumors [4]. However, adenocarcinomas have been reported to arise from GCC [5], and several multicenter cohorts have shown GCC to have a prognosis similar to that of appendiceal adenocarcinoma [1], [6], [7]. GCCs are, therefore, generally considered to behave more similarly to adenocarcinomas and are staged using the TNM system for appendiceal carcinoma [8].

Similar to adenocarcinoma, outcomes for patients with GCC cover a wide range and are closely related to TNM stage at time of diagnosis [9]. However, TNM staging does not fully predict outcome, and a histologic grading system that is reproducible and provides additional prognostic information would be very useful. Unlike typical neuroendocrine tumors, the Ki-67 proliferative index is not prognostic in GCC [10]. Moreover, the standard colonic adenocarcinoma grading system based on gland formation [11] is not readily applicable to GCCs given their inherently nonglandular architecture.

To address this deficit, Tang et al [5], [12] suggested classifying GCCs of the appendix into 3 histologic subtypes: typical GCC (group A); adenocarcinoma ex-GCC, signet ring cell type (group B); and adenocarcinoma ex-GCC, poorly differentiated carcinoma type (group C). However, the “Tang classification” poses several difficulties in day-to-day practice: First, in GCC, the clear delineation of signet ring cells from goblet cells can be challenging and is prone to significant interobserver variation [12]. Second, the classification relies on the holistic evaluation of several morphologic criteria. If some but not all the criteria are met, the correct classification is unclear. In addition, the classification scheme was based on a case series collected in a specialty referral center and may not represent the true spectrum of GCC. Finally, the 3 proposed histologic subgroups contained patients with markedly different TNM stage, and this factor was not accounted for in the survival analysis.

In this study, we present a histopathologic analysis of a population-based cohort of patients with GCC, controlling for TNM stage, with full treatment and outcome data. We propose an alternative histologic grading system that stratifies GCC into low- and high-grade subtypes and predicts clinical outcome.

Section snippets

Patient selection

A continuous population-based cohort of patients with GCC of the vermiform appendix was identified from the British Columbia Cancer Agency's Gastrointestinal Cancers Outcome Unit (GICOU) database and the Vancouver Lower Mainland pathology archive. The GICOU database was searched for the years 1986 to 2012, based on the availability of data. International Classification of Diseases for Oncology-3 (ICD-O-3) site identifier 18.1 with histology codes 82433, 82443, 82453, and 82463 was included. The

Results

From the identified cohort of 108 potential patients, 20 were excluded on review of pathology reports (13 clearly had a non-GCC malignancy, and 1 had no surgery performed), and 1 had no pathology report available. Archival specimens were sought for the remaining 87 potential GCC patients. Archival material was either lost or destroyed in 2 cases, a non-GCC primary was found on histopathologic review in a further 6 cases, and 1 case had no clinical outcome data available. A diagnosis of primary

Discussion

We sought to derive a histologic grading system for goblet cell carcinoids of the appendix that not only predicts clinical outcomes independent of clinicopathological stage but also is objective and easily applicable by nonsubspecialized pathologists in day-to-day practice. In our cohort, GCCs of the vermiform appendix most commonly presented with symptoms related to acute appendicitis. In such patients, the disease was typically localized to the appendix without metastatic disease, which

Conclusion

The clinical spectrum of goblet cell carcinoid of the vermiform appendix varies widely, and a reproducible and accurate means of predicting outcomes would be of great clinical utility. We present an objective, readily applicable histologic grading system that predicts OS independent of TNM staging. The proposed histologic grading system separates GCC into low- versus high-grade histology using 3 histologic criteria that can be assessed without use of special tests and does not rely on the

References (19)

J.A. Butler et al.
Goblet cell carcinoid of the appendix
Am J Surg
(1994)
E. Liu et al.
The role of Ki-67 in predicting biological behavior of goblet cell carcinoid tumor in appendix
Am J Surg
(2011)
K. Kadota et al.
A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma
Mod Pathol
(2012)
N. Holt et al.
Goblet cell carcinoids of the appendix
TheScientificWorldJournal
(2013)
P. Roy et al.
Goblet cell carcinoid tumors of the appendix: an overview
World J Gastrointest Oncol
(2010)
S.G. Subbuswamy et al.
Goblet cell carcinoid of the appendix
Cancer
(1974)
L.H. Tang et al.
Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix
Am J Surg Pathol
(2008)
Y.J. McConnell et al.
Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: an emerging treatment option for advanced goblet cell tumors of the appendix
Ann Surg Oncol
(2014)
M.E. McCusker et al.
Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998
Cancer
(2002)

There are more references available in the full text version of this article.

Cited by (28)

Goblet cell adenocarcinoma of the appendix: an update and practical approach to diagnosis and grading
2023, Human Pathology
Citation Excerpt :
Patients with high-grade goblet cell adenocarcinoma more commonly present with symptoms related to metastases, including abdominal pain and fullness and bowel obstruction [6,14]. The mean age of patients with goblet cell adenocarcinoma is between 50 and 60 years, although tumors can be identified in patients as young as 25–30 years [6,10,15,16]. Some literature reports have identified a predominance in women (greater than a 2:1 ratio of women to men) [6,10].
Goblet cell adenocarcinoma is a rare appendiceal tumour with amphicrine differentiation that has distinct morphologic and clinical features compared to carcinomas seen elsewhere in the gastrointestinal tract. These tumors have engendered considerable confusion in the literature regarding their classification, and they have been described under several different names including goblet cell carcinoid, adenocarcinoid, and adenocarcinoma, among others. In the recent fifth edition of the World Health Organization Classification of Digestive System Tumors, goblet cell adenocarcinoma is the preferred diagnosis because of the increasing recognition of a frequent co-existing high-grade adenocarcinoma component. This review will present the clinicopathologic, molecular, and immunohistochemical features of goblet cell adenocarcinoma and discuss the current challenges in diagnosis, grading, and clinical management.
The 2019 World Health Organization Classification of appendiceal, colorectal and anal canal tumours: an update and critical assessment
2021, Pathology
Citation Excerpt :
Unusually, for a system that had not been independently validated by another study at the time of writing, the three tier system proposed by Yozu et al.46 was endorsed to grade the spectrum of tumours in the unified category of GCAs. This system is an evolution from two previous grading systems,47,48 and is based on the proportion of goblet-like mucinous cells with tubular/nested architecture (low grade component) to complex cribriform sheet-like growth pattern and/or single mucinous or non-mucinous cells (high grade component). Presence of at least 75% low grade pattern is required for qualification of a tumour as grade 1, while grade 3 tumours should contain greater than 50% high grade pattern.
The recently published 5th edition 2019 World Health Organization (WHO) Classification of Tumours of the Digestive System brings significant changes from the 2010 4th edition. An emphasis on uniformity in nomenclature and grading for tumours across all organ systems is a particular feature of the 5th edition blue book series that is reflected in the gastrointestinal tract (GIT) classification. For example, simplified two tiered grading is reinforced for preinvasive lesions throughout the GIT, with dysplasia at all sites now being considered either low or high grade. Similarly, a uniform approach to classification and grading of GIT neuroendocrine neoplasms has been consolidated, with an emphasis on distinguishing grade 3 neuroendocrine tumours from neuroendocrine carcinomas.
In this review, we discuss and critically assess the important and sometimes controversial changes made to the classification of tumours of the lower GIT, comprising the colorectum, vermiform appendix and anal canal. The particularly controversial decision to endorse the term ‘sessile serrated lesion’ for lesions previously termed ‘sessile serrated polyp/adenoma’ is explored. The morphological, molecular, and clinical insights behind the substitution of the term ‘goblet cell adenocarcinoma’ for ‘goblet cell carcinoid’ are assessed. The evolution of the classification of appendiceal mucinous neoplasms is considered. Inflammatory bowel disease related dysplasia and its evolving subtypes, with major implications for pathologists in routine practice, is explained.
Goblet cell adenocarcinoma: concepts and updates
2021, Diagnostic Histopathology
Appendiceal goblet cell adenocarcinoma, previously called goblet cell carcinoid and adenocarcinoma ex goblet cell carcinoid, is a rare neoplasm that occurs almost exclusively in the appendix. Several classification and grading systems have been proposed that can separate patients into prognostic groups. This review will provide an update on various classification systems with emphasis on the newly published 2019 World Health Organization Classification of Tumors, which proposed a 3-tiered grading system for appendiceal goblet cell adenocarcinoma based on the extent of low and high-grade patterns.
Updates in Appendix Pathology: The Precarious Cutting Edge
2020, Surgical Pathology Clinics
Citation Excerpt :
However, some lesions are more aggressive and this behavior is associated with adverse histologic features (Box 4, Fig. 14). These features have been incorporated into a variety of grading systems, but a discussion of their relative merits is beyond the scope of this article.65,67,75,80,81 Data regarding appropriate management of GCAs are lacking owing to their overall rarity.65
Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas
2019, Surgical Pathology Clinics
Goblet cell tumors of the appendix: A review
2019, Annals of Diagnostic Pathology
Citation Excerpt :
The ovary is a common metastatic site in women [7]. Lymph node metastases have been detected in 22–38% of cases [7,9]. Metastasis to solid organs, such as the liver, bone, and brain, is uncommon [5].
Goblet cell tumors are rare tumors of the appendix that exhibit both neuroendocrine and mucinous differentiation. This dual differentiation has led to a controversy regarding the proper classification of these neoplasms as to whether they should be considered neuroendocrine tumors or adenocarcinomas. Multiple grading systems have been proposed that were able to segregate these tumors into prognostically significant groups. Many of these grading systems rely on identifying and/or quantifying the carcinomatous growth pattern. Goblet cell tumors show patchy and focal expression of neuroendocrine markers and are characterized by a mutational profile that is different from both appendiceal adenocarcinomas and neuroendocrine tumors. They exhibit a more aggressive behavior than neuroendocrine tumors, and as such, many authors recommend that they be approached and treated as adenocarcinomas.

View all citing articles on Scopus

^☆: Competing interests: None.

^☆☆: Funding/Support: Funding for this work was provided in part by the BC Cancer Foundation (Vancouver, British Columbia, Canada).

View full text

Original contributionSimplified 2-tier histologic grading system accurately predicts outcomes in goblet cell carcinoid of the appendix☆,☆☆

Summary

Introduction

Section snippets

Patient selection

Results

Discussion

Conclusion

Am J Surg

Am J Surg

Mod Pathol

Goblet cell carcinoids of the appendix

TheScientificWorldJournal

Goblet cell carcinoid tumors of the appendix: an overview

World J Gastrointest Oncol

Goblet cell carcinoid of the appendix

Cancer

Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix

Am J Surg Pathol

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: an emerging treatment option for advanced goblet cell tumors of the appendix

Ann Surg Oncol

Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998

Cancer

Original contribution
Simplified 2-tier histologic grading system accurately predicts outcomes in goblet cell carcinoid of the appendix☆,☆☆