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Significance of Proximal Margin Involvement in Low-Grade Appendiceal Mucinous Neoplasms.

Low-grade appendiceal mucinous tumors include those that are confined to the mucosa and that are classified as adenomas and those that display pushing or expansile invasion and can disseminate in the peritoneal cavity as pseudomyxoma peritonei, for which the term low-grade appendiceal mucinous neoplasm (LAMN) was proposed (1) and adopted by the World Health Organization. (2) In the latter group, the risk of developing pseudomyxoma peritonei is most clearly related to extension of mucin or epithelial cells beyond the appendiceal serosa. The presence of acellular mucin in the right lower quadrant confers a low risk of recurrence, whereas mucin with mucinous epithelial cells in the right lower quadrant confers a high risk of recurrence. (3,4)

Assessment of surgical margins is an integral part of pathologic tumor evaluation, and the evaluation of an appendix with an adenoma or LAMN includes reporting on the status of the margin. An involved margin would be a rational basis for a cecectomy given the assumption that it indicates a possibility that residual disease remains in the appendiceal stump or cecum that can lead to disease recurrence or dissemination. In fact, several authors recommend additional surgery for patients with appendiceal mucinous neoplasia at the proximal margin, but these suggestions are based largely on assumptions of what an involved margin signifies. (4-6) In reality, the significance of proximal margin involvement by an appendiceal adenoma or a LAMN that is otherwise confined to the appendix is not clear and data to guide management of these patients are lacking. Therefore, we undertook this study to determine whether a positive margin in the setting of an appendiceal adenoma or LAMN confined to the appendix requires surgical resection of the cecum, or whether a conservative approach can be justified.


Identification of Cases

The pathology archives of 3 institutions were searched to identify appendectomy specimens containing LAMNs and appendiceal adenomas that were diagnosed between January 1990 and March 2014. The surgical pathology reports were reviewed to identify cases with either neoplastic epithelium at the resection margin or acellular mucin at the resection margin. Cases that showed only denuded mucosa at the margin or only scant acellular mucin in the lumen were excluded. Also excluded were cases with periappendiceal mucin, periappendiceal mucinous epithelium, or overtly malignant cytologic features (ie, invasive adenocarcinoma), as it is likely that these features would confound the impact of margin status on clinical outcome. The study protocol was approved by the institutional review board at the Massachusetts General Hospital, Boston.

Pathology Review

Hematoxylin and eosin-stained sections were available for review in 14 cases and these cases were evaluated by 3 study pathologists to confirm the diagnoses. The presence of high-grade dysplasia, if any, was noted. Subsequent materials were also reviewed when patients received further surgery, in order to confirm the presence or absence of residual disease. The slides could not be obtained for review in 2 cases, for which the status of resection margins was established based on review of prior surgical pathology reports.

Patient Outcomes

Medical records of all study patients were evaluated for clinical follow-up. All available clinical and imaging records were reviewed to determine whether any patient developed local recurrence or disseminated peritoneal disease (ie, pseudomyxoma peritonei). The follow-up period was calculated as the time from appendectomy to the time of the last available abdominal computed tomography, last colonoscopy, or last laparoscopic or open procedure, or the last available clinical note that documented the clinical history and physical examination. We included patients with at least 1 year follow-up or who underwent additional surgical resection.


The study group included 16 patients (14 women and 2 men) with a mean age of 55 years (range 28-85 years) at appendectomy (Table). The tumors were classified as LAMNs (Figure 1) in 15 cases and appendiceal adenoma in 1 case. Nine cases were classified as having a positive margin based on the presence of neoplastic epithelium lining the appendiceal lumen at the surgical resection margin (Figure 2). Seven of the LAMN cases showed no neoplastic epithelium at the margin, but had dissecting acellular mucin at the margin (Figure 3).

Six patients underwent a second surgical procedure, 4 of whom had mucinous epithelium at the margin and 2 with acellular mucin at the margin. None of these patients had residual neoplasia in the resection specimen. One patient (case 1) had a small pool of acellular mucin in the cecal cuff. The other 10 patients were followed nonsurgically. There was no significant difference between the 2 groups in terms of patient age or the type of involved margin. None of the patients experienced disease recurrence or developed pseudomyxoma peritonei. The follow-up interval ranged from less than a year in a single recent case to 11.7 years (mean 4.7 years; median 3.5 years).


Tumor involvement of a surgical resection margin is considered to be an indication for additional treatment or additional surgery in many organ systems. Certainly some appendiceal neoplasms, including endocrine tumors, goblet cell carcinoid tumors, conventional adenocarcinomas, and high-grade mucinous neoplasms, are managed in this fashion, as complete resection and pathologic staging of regional lymph nodes are important for tumor staging and subsequent management. (5) However, low-grade appendiceal mucinous tumors infrequently involve lymph nodes, even when they have spread to the peritoneum, and thus the role of right hemicolectomy in patients with disseminated peritoneal disease (ie, pseudomyxoma peritonei) is not clear. In fact, some studies have shown that right hemicolectomy can have a negative survival advantage in the setting of pseudomyxoma peritonei, and should only be carried out at the time of complete cytoreduction and intraperitoneal chemotherapy, as success of the latter may be impaired by adhesions created by prior colonic surgery. (6,7)

Low-grade appendiceal mucinous neoplasms with acellular or cellular mucin in the right lower quadrant are at low and high risk, respectively, for dissemination in the peritoneal cavity, and that risk is not clearly modified by the status of the surgical resection margin. (3,4) Pai et al (4) evaluated a series of 116 patients with appendiceal mucinous neoplasms, including 1 who had extra-appendi Appendectomy Margin Involvement in LAMNs--Arnason et al ceal mucin and neoplastic epithelial cells in the right lower quadrant as well as tumor present at the surgical resection margin. That patient subsequently underwent a colectomy procedure and the resection specimen did not contain residual tumor. However, the patient developed disseminated peritoneal disease 41 months later, indicating that additional surgery did not eliminate the risk for disease recurrence. However, the status of the margin may be one factor in the management of these patients, because patients with epithelial cells outside the appendix but confined to the right lower quadrant may undergo additional surgery and/or heated intraperitoneal chemotherapy, and at that time, the possibility of residual disease in the cecum can be addressed.

The benefit of further surgery to achieve a clear margin for appendiceal adenomas and LAMNs in patients who otherwise would not require surgery is less clear, although several groups recommend this practice. (4,8,9) Indeed, some authors base their classification of appendiceal mucinous neoplasms on the status of the proximal surgical margin. Pai et al (4) classified mucinous tumors that are cured by appendectomy as adenomas, provided they have a negative resection margin. Presumably, then, tumors with a positive margin should be classified in their system as low-grade mucinous neoplasms of low malignant potential (4) or, according to an earlier review on appendiceal neoplasia by the same authors, as mucinous tumors of uncertain malignant potential. (9) They caution that, given its prognostic implications, the surgical margin must be completely evaluated, even though those implications are assumed rather than proved.

There are no clear guidelines regarding appropriate management of patients with appendiceal adenomas or LAMNs who have positive surgical margins on their appendectomy specimens, particularly when the tumors are confined within the serosa. None of the 10 patients in this series who underwent appendectomy alone developed recurrent disease, despite the presence of a positive surgical resection margin. Six of our patients underwent additional surgery, 4 of whom had neoplastic epithelium at the margin. None of these patients had residual neoplastic epithelium in subsequent surgical material. One of these patients did have acellular mucin in the subsequent cecal cuff resection specimen, but interestingly, this individual's appendectomy margin was involved by neoplastic epithelium in the lumen, without dissecting mucin. One possible explanation is that the cecal mucin originated from surgical manipulation during appendectomy that resulted in mechanical extrusion of mucin into the cecal wall. However, it may also represent discontinuous mucin extrusion from the neoplasm. There are at least 4 other reports in the literature describing cases of low-grade appendiceal neoplasms with positive appendectomy margins with no additional tumor in resection specimens. (4,10) A possible explanation for this consistent finding is that many appendectomies have a stapled resection margin, and the tissue designated as the margin is in fact not the true surgical margin. Although very rarely villous adenomas extend into the cecum from the appendix, (11) this unlikely possibility can be excluded with colonoscopic examination, as has been suggested by others. (12)

We conclude that in patients with LAMNs confined to the appendix, without extrusion of mucin or mucinous neoplasia beyond the appendiceal serosa, involvement of the appendectomy margin by either neoplastic epithelium or acellular mucin is not associated with disease recurrence or peritoneal dissemination. These observations suggest that nonsurgical modalities, including colonoscopy and radiographic studies, are a reasonable option for the management of these patients. We recognize that, given the assumption that an involved margin denotes the presence of residual tumor and its attendant risk for recurrence or dissemination, some might find it unacceptable to recommend conservative follow-up rather than cecectomy. However, in our series, most patients did not have additional surgery, evidence that conservative follow-up is already an option for some patients. Our data provide justification for that approach. Furthermore, none of the cecal resection specimens in our series or in the literature had residual neoplasia, refuting the assumption that a positive margin necessarily indicates disease left behind in the patient. Although we understand that a limitation of this study is the small number of cases, we encourage others to report their experience with this patient group in order to accumulate data upon which to base reasonable treatment recommendations.

Please Note: Illustration(s) are not available due to copyright restrictions.

Dr Arnason's fellowship funding was provided through scholarships from the Royal College of Physicians and Surgeons of Canada (Detweiler Traveling Fellowship) and Dalhousie University (McLoughlin Scholarship).


(1.) Misdraji J, Yantiss RK, Graeme-Cook FM, Balis UJ, Young RH. Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases. Am J Surg Pathol. 2003; 27(8):1089-1103.

(2.) Carr NJ, Sobin LH. Adenocarcinoma of the appendix. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of Tumors of the Digestive System. 4th ed. Lyon, France: International Agency for Research on Cancer; 2010:122-125.

(3.) Yantiss RK, Shia J, Klimstra DS, Hahn HP, Odze RD, Misdraji J. Prognostic significance of localized extra-appendiceal mucin deposition in appendiceal mucinous neoplasms. Am J Surg Pathol. 2009; 33(2):248-255.

(4.) Pai RK, Beck AH, Norton JA, Longacre TA. Appendiceal mucinous neoplasms: clinicopathologic study of 116 cases with analysis of factors predicting recurrence. Am J Surg Pathol. 2009; 33(10):1425-1439.

(5.) Nitecki SS, Wolff BG, Schlinkert R, Sarr MG. The natural history of surgically treated primary adenocarcinoma of the appendix. Ann Surg. 1994; 219(1):51-57.

(6.) Gonzalez-Moreno S, Sugarbaker PH. Right hemicolectomy does not confer a survival advantage in patients with mucinous carcinoma of the appendix and peritoneal seeding. Br J Surg. 2004; 91(3):304-311.

(7.) Foster JM, Gupta PK, Carreau JH, et al. Right hemicolectomy is not routinely indicated in pseudomyxoma peritonei. Am Surg. 2012; 78(2):171-177.

(8.) Hameed K. Epithelial polyps of the vermiform appendix--a review. Am J Gastroenterol. 1966; 46(4):339-346.

(9.) Pai RK, Longacre TA. Appendiceal mucinous tumors and pseudomyxoma peritonei: histologic features, diagnostic problems, and proposed classification. Adv Anat Pathol. 2005; 12(6):291-311.

(10.) Hameed K. Villous adenoma of the vermiform appendix: a review with report of a case. Arch Pathol. 1966; 81(5):465-468.

(11.) Higa E, Rosai J, Pizzimbono CA, Wise L. Mucosal hyperplasia, mucinous cystadenoma, and mucinous cystadenocarcinoma of the appendix: a reevaluation of appendiceal "mucocele." Cancer. 1973; 32(6):1525-1541.

(12.) Wolff M, Ahmed N. Epithelial neoplasms of the vermiform appendix (exclusive of carcinoid), II: cystadenomas, papillary adenomas, and adenomatous polyps of the appendix. Cancer. 1976; 37(5):2511-2522.

Thomas Arnason, MD; Michal Kamionek, MD; Michelle Yang, MD; Rhonda K. Yantiss, MD; Joseph Misdraji, MD

Accepted for publication May 21, 2014.

Published as an Early Online Release June 27, 2014.

From the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston (Drs Arnason, Kamionek, and Misdraji); the Division of Anatomical Pathology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada (Dr Arnason); the Department of Pathology, University of Massachusetts Memorial Medical Center, Worcester (Dr Yang); and the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York (Dr Yantiss). Dr Kamionek is now located at the Carolinas Pathology Group, Carolinas Medical Center, Charlotte, North Carolina.

The authors have no relevant financial interest in the products or companies described in this article.

An abstract with preliminary results of this study was presented as a platform presentation at the United States and Canadian Academy of Pathology meeting; March 2014;San Diego, California.

Reprints: Joseph Misdraji, MD, Department of Pathology, Warren 105, Massachusetts General Hospital, 55 Fruit St, Boston, Ma 02114 (e-mail:

Caption: Figure 1. Low-grade appendiceal mucinous neoplasm. The appendiceal lumen is lined by a villous proliferation of mildly atypical mucinous epithelial cells (hematoxylin-eosin, original magnification X200).

Caption: Figure 2. Margin involvement by low-grade appendiceal mucinous neoplasm (LAMN). At the resection margin, the appendiceal lumen is lined by a single layer of mucinous epithelial cells with mildly atypical, pseudostratified, and hyperchromatic nuclei, consistent with involvement by LAMN (hematoxylin-eosin, original magnification X100).

Caption: Figure 3. Dissecting mucin at the margin. At the resection margin, the mucosa lining the appendiceal lumen (left) is hyperplastic with crypts showing superficial serration and lymphoid tissue, but does not show features of low-grade appendiceal mucinous neoplasm. Rather, a pool of acellular mucin with dystrophic calcifications is present in the submucosa (right) (hematoxylin-eosin, original magnification X10).
Summary of Pathologic Findings and Clinical Follow-up for
Cases With Margin Involvement by Low-Grade Appendiceal
Mucinous Neoplasm (LAMN) or Appendiceal Adenoma

        Age                Pattern of Margin            Subsequent
Case   y/Sex   Diagnosis   Involvement                  Resection

1      36/F    LAMN        Neoplastic epithelium        Cecum
2      64/F    LAMN        Neoplastic epithelium        Cecum
3      51/F    LAMN        Neoplastic epithelium        Cecum
4      43/F    LAMN        Neoplastic epithelium        Cecum
5      80/F    LAMN        Neoplastic epithelium        None
6      60/M    LAMN        Neoplastic epithelium        None
7      48/F    LAMN        Neoplastic epithelium        None
8      43/M    LAMN        Neoplastic epithelium        None
9      85/F    Adenoma     Neoplastic epithelium        None
10     66/F    LAMN        Dissecting acellular mucin   Ileocecum
11     38/F    LAMN        Dissecting acellular mucin   Ileocecum
12     51/F    LAMN        Dissecting acellular mucin   None
13     71/F    LAMN        Dissecting acellular mucin   None
14     48/F    LAMN        Dissecting acellular mucin   None
15     28/F    LAMN        Dissecting acellular mucin   None

16     64/F    LAMN        Dissecting acellular mucin   None

Case   Interval, y   Method of Follow-up

1          3.5       Abdominal CT and colonoscopy
2          2.3       Abdominal CT
3          2.2       Abdominal CT
4         11.7       Abdominal CT and colonoscopy
5          7.4       Abdominal CT
6          5.0       Abdominal CT
7          1.0       Abdominal CT
8          2.1       Abdominal CT and colonoscopy
9          3.0       Abdominal CT and colonoscopy
10      Recent       Recent case
11         2.5       Pelvic ultrasound
12         8.8       Abdominal CT and colonoscopy
13         8.6       Abdominal CT and colonoscopy
14         3.5       Physical examination
15         4.7       Laparoscopy (ovarian fibroma) and
                     pelvic ultrasound
16         8.6       Abdominal CT and colonoscopy

Abbreviation: CT, computed tomography.
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Author:Arnason, Thomas; Kamionek, Michal; Yang, Michelle; Yantiss, Rhonda K.; Misdraji, Joseph
Publication:Archives of Pathology & Laboratory Medicine
Date:Apr 1, 2015
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