Primary Epithelial Tumors of the Appendix and a Reappraisal of the Appendiceal "Mucocele"*
G r~r tD V. ArtANHA, M.D.F.R.C.S.(C), CrSAR V. Rrvrs, M.D.
UIHLEIN AND McDoNALD 1 in 1943 wrote, "Much has been written concerning epithelial neoplasms of the appendix, but there is still considerable confusion with regard to the classification of these tumors." T h ey went on to suggest that a simple and workable classification for these tumors would be to divide them into three types: 1) carcinomas of the carcinoid type; 2) carcinomas of the cystic type p r o d u c i n g pseudomyoma peritonei; 3) carcinomas which resemble, both grossly and microscopically, carcinoma of the colon. In time, the-carcinomas of the cystic type came to be known as malignant mucoceles. T h e term mucocele refers to a lesion of the appendix with a dilated lumen filled with mucus? In a review, Higa and co-workers a r e c o m m e n d e d elimination of the term "mucocele" since it referred only to the presence and effects of accumulation of mucus in the lumen of the appendix and gave no information about the primary disease that caused it. T hey were able to reclassify all 73 "mucoceles" in their series into 1) focal or diffuse mucosal hyperplasia, 2) mucinous cystadenoma, or 3) mucinous cystadenocarcinoma. T h e confusion Uihlein and McDonald ~ referred to, obviously remains, but much of it is due to the so-called "mucocele." This study was undertaken with three objectives in mind: first, review all primary epithelial tumors of the appendix seen at V.A. Medical Center, Hines, Illinois, between the years 1950 and 1978; second, to reclassify all the o b s e r v e d mucoceles along the lines suggested by Higa, a Wolff, and Ahmed4'S; and third, suggest a classification for primary epithelial tumors o f the a p p e n d i x that takes into account definite pathologic entities. Material a n d M e t h o d s
Those charts carrying the diagnosis of neoplasm of the appendix of all patients between the years 1950 * Received for publication May 18. 1979. Address reprint requests to Dr. Aranha: P.O. Box 1044, Hines, Illinois 60141.
From the Department of Surgery and the Department of Pathology, Hines V.A. Hospital, Hines, Illinois and the Department of Surgery, Loyola University Medical Center, Ma~wood, Illinois
and 1978 at Hines V.A. Medical Center, were reviewed. All pathologic slides pertaining to these patients were reviewed by the same pathologist (C.R.) for the purpose of the study. A total of 19 primary neoplasms of the appendix had been seen between the years 1950-1978 at Hines, V.A. Medical Center. Four of the lesions were designated "mucocele." A review of these lesions by the surgical pathologist led to two of the four mucoceles being reclassified as diffuse mucosal hyperplasia; of the remaining two, one was assigned the diagnosis of mucinous cystadenoma and the other, the diagnosis of mucinous cystadenocarcinoma. Since this is a discussion of primary epithelial neoplasms of the appendix, the patients with focal or diffuse mucosal hyperplasia were excluded from analysis. O f the remaining 17 primary tumors, five were b e n i g n and 1'2 malignant (Table 1). Further analysis of the malignant tumors revealed six adenocarcinomas (of which three were mucin producing and three, the usual colonic type) and six careinoids. No adenocant hom as were seen. All six p a t i e n t s with a d e n o c a r c i n o m a h a d symptoms of acute appendicitis, namely periumbilical or right lower quadrant pain, associated with nausea and occasional vomiting. Physical examination revealed definite evidence of generalized peritonitis in one and evidence of small-intestinal obstruction in another. All others had right lower quadrant tenderness and rebound. While plain x-rays of the abdomen were useful in delineating associated ileus or smallintestinal obstruction, no barium-contrast studies were used to make a diagnosis. One patient died before surgery could be done. At autopsy, he was found to have a mucinous adenocarcinoma of the appendix,
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with p s e u d o m y x o m a peritonei. T h e five o t h e r patients with a d e n o c a r c i n o m a had a p p e n d e c t o m y as the initial p r o c e d u r e , followed by right hemicolectomy as a definitive p r o c e d u r e 2 - 4 weeks after the pathologic diagnosis of a d e n o c a r c i n o m a was made on the appendix, O f the five patients, one was lost to follow up, one survived six months, two survived two years, and one, five years. T h e patient who survived five years died o f carcinoma o f the pancreas, a diagnosis m a d e at autopsy. O f the six patients with carcinoid tumors o f the appendix, three had symptoms and signs o f acute appendicitis; in two patients, the t u m o r was discovered after incidental a p p e n d e c t o m y ; and in one, exploration following an abnormal liver scan revealed a carcinoid o f the a p p e n d i x greater than 2 cm in diameter, with metastases to the ileocolic lympth nodes and liver. All six patients had an a p p e n d e c t o m y as their initial p r o c e d u r e . T w o patients n e e d e d right hemicolectomy because o f cecal involvement. T h e patient with metastasis to the liver survived nine months. One patient died, 12 months after the diagnosis o f carcinoid, f r o m a new primary carcinoma o f the colon. T h e f o u r others are alive seven years, 15 years, 95 years, and 25 years since diagnosis. T w o patients had p s e u d o m y x o m a peritonei, one associated with a m u c i n o u s a d e n o c a r c i n o m a and a n o t h e r with a benign cystadenoma of the appendix. Discussion Incidence: T u m o r s of the a p p e n d i x are rare and no definite statement can be m a d e with respect to the percentage they make up o f all tumors. T h e incidence of a d e n o c a r c i n o m a of the a p p e n d i x is r e p o r t e d to be a r o u n d 0.089 per cent o f resected appendices. 6 T h e incidence o f carcinoids of the a p p e n d i x is many times that o f a d e n o c a r c i n o m a and t h o u g h t to vary f r o m 0.3 per cent to 0.7 per cent o f all surgically r e m o v e d appendices. 7.8 Previously, it was t h o u g h t that 89 per cent o f all p r i m a r y epithelial tumors of the a p p e n d i x were carcinoids, and mucoceles and a d e n o c a r c i n o m a accounted for 8 per cent and 3 per cent, respectively? With the reclassification o f mucoceles it is m o r e likely that carcinoids will account for about 90 per cent of all primary epithelial tumors o f the a p p e n d i x and a d e n o c a r c i n o m a for a b o u t 10 per cent. B e g e r 9 is c r e d i t e d with r e p o r t i n g t h e first two cases o f a d e n o c a r c i n o m a o f the appendix. These, however, are now t h o u g h t to have been actually carcinoids. In o u r series, the ages o f the p a t i e n t s with a d e n o c a r c i n o m a r a n g e d f r o m 37 to 65 years, and those with carcinoids f r o m 28 to 69 years. All o u r patients were men. T h e literature does favor a slight
TABLE 1. Primary Epithelial Tumors of the Appendix Seen at Hines V.A. Medical Center 1950 -1978
Number Benign Mucinous cystadenoma Papillary adenoma Adenomatous polyp Malignant Adenocarcinoma Mucin producing Colonic type Carcinoid TOTAL
3 3 6 17
p r e p o n d e r a n c e for m e n over women in patients having a d e n o c a r c i n o m a , 8 whereas, for carcinoids o f the appendix, w o m e n p r e d o m i n a t e slightly over men. r T h o u g h m e n and w o m e n have similar incidence rates for carcinoids detected by a p p e n d e c t o m y , m o r e appendectomies were p e r f o r m e d in women (incidental to pelvic or gallbladder surgery), so m o r e carcinoids are d e t e c t e d ? P a t h o l o g i c Classification: Any new classification for p r i m a r y epithelial tumors o f the a p p e n d i x must take into consideration benign or malignant tumors. Benign epithelial tumors are likely to be m u c i n o u s cystadenomas, single a d e n o m a s , and a d e n o m a t o u s p o l y p s o f t h e a p p e n d i x , a'5 P a t h o l o g i c a l l y , cyst a d e n o m a s resemble villous a d e n o m a s seen in the colon and are t h o u g h t to be their c o u n t e r p a r t in the a p p e n d i x . 2 In several publications, mucoceles are c l a s s i f i e d as b e n i g n o r m a l i g n a n t o r j u s t mucoceles. 10-14 A c c o r d i n g to H i g a a n d c o - w o r k e r s , a the t e r m "mucocele" has usually been applied to a g r o u p o f appendiceal lesions, characterized by one to two o f the following: 1) dilatation of the lumen; 2) alteration o f the mucosal lining; 3) hypersecretion o f mucus; 4) occasional extension outside the appendix, either as p s e u d o m y x o m a peritonei or, unusually, as distant metastasis. T h e i r review o f 73 lesions d e s i g n a t e d "mucocele" resulted in all these lesions being reclassified into three distinctive clincopathologic entities: focal or d i f f u s e m u c o s a l h y p e r p l a s i a , m u c i n o u s cystadenoma, or mucinous cystadenocarcinoma. Further, they f o u n d the views on the pathogenesis o f these lesions, very controversial. Some authors considered a "mucocele" a cystic dilatation of the l u m e n secondary to obstruction; some considered it a true neoplasm; others considered "mucocele" as a single
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T.~.BLE 2- Classificationof Primary Epithelial Tumors of the Appendix Benign Mucinous cystadenoma Papillary adenoma Adenomatous polyp Malignant Adenocarcinoma--rnucin producing --colonic type Carcinoid Adenoacanthoma entity, and still others divided them into benign and malignant types. Since the term "mucocele" failed to d e n o t e the pathogenic mechanism causing dilatation o f the a p p e n d i c e a l l u m e n , with a c c u m u l a t i o n o f mucus, it was r e c o m m e n d e d that the term be elimin a t e d . S u p p o r t f o r this position has c o m e f r o m others. 2,5 F o u r l e s i o n s in o u r s t u d y w e r e d e s i g n a t e d "mucoceles"; all f o u r could be reclassified, two as d i f f u s e mucosal h y p e r p l a s i a , one as a m u c i n o u s c y s t a d e n o m a a n d one" as a m u c i n o u s c y s t a d e n o carcinoma. Because o f this experience, t h o u g h small, we also feel that mucoceles can be assigned definite pathologic entities and favor elimination o f the term. Mucinous cystadenocarcinoma o f the a p p e n d i x may well be an a d e n o c a r c i n o m a showing excessive mucin production? Carcinoids o f the a p p e n d i x are ten times m o r e c o m m o n t h a n a d e n o c a r c i n o m a s . * T h e y o c c u r in about 0.3 to 0.10 per cent o f all appendectomies. 7,s,15 No controversy s u r r o u n d s the pathologic features o f carcinoid t u m o r s o f the appendix. Carcinoids o f the a p p e n d i x t y p i c a l l y o c c u r as small, f i r m , circumscribed, yellow-tan nodules usually seen in the distal appendix. Less than 10 per cent occur at the base o f the a p p e n d i x . While all carcinoids have a malignant potential, only 2 per cent o f appendiceal carcinoids metastasize to the liver. 7 A third p r i m a r y malignant t u m o r o f the appendix, o f which there has been only one case r e p o r t is the a d e n o a c a n t h o m a . '6 T h e s e tumors are usually seen in areas that have contiguous squamous and glandular surfaces, e.g., the cardioesophageal junction, the uterus, and the rectum. Symptomatic tumors usually cause symptoms like those o f a d e n o c a r c i n o m a s . T h e a d e n o a c a n thomas also behave like adenocarcinomas and their surgical m a n a g e m e n t must be the same. ~6 With the above considerations, and with elimination o f the term "mucocele" in mind; we suggest a new classification for p r i m a r y epithelial tumors o f the a p p e n d i x as shown in T a b l e 2. Symptoms, Signs and Diagnosis: T h e majority o f cases o f a d e n o c a r c i n o m a o f the a p p e n d i x a p p e a r to
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have s y m p t o m s and signs o f appendicitis. 1~ One case o f a d e n o c a r c i n o m a o f the a p p e n d i x occurring in an appendiceal s t u m p and a p p e a r i n g to be a right colonic obstruction has been r e p o r t e d . 's T h e reason stated for the high p e r c e n t a g e o f symptomatic patients with a d e n o c a r c i n o m a is that the t u m o r occurs at the base o f the a p p e n d i x and causes obstruction early. Most carcinoids o f the a p p e n d i x are discovered incidentally at o p e r a t i o n for a n o t h e r process, or after a p p e n d e c t o m y , s T h e lesion is usually seen as a yellow n o d u l e at the tip o f the a p p e n d i x , and only rarely involves the base o f that organ. This lesion, t h o u g h highly malignant locally, s rarely metastasizes to distant sites, r O n e fact stands out; the majority o f carcinoids o f the a p p e n d i x m o r e than 2 cm in size will have distant metastases, s F o u r o f the five b e n i g n lesions in o u r series were discovered at l a p a r o t o m y for a n o t h e r problem. T h e fifth patient had an a b n o r m a l barium e n e m a showing a filling defect in the cecum. At o p e r a t i o n this filling defect was f o u n d to be mucin. Primary t u m o r s o f the a p p e n d i x are rarely diagnosed before operation. A t u m o r o f the a p p e n d i x was strongly s u s p e c t e d in two patients a f t e r b a r i u m e n e m a e x a m i n a t i o n ? 9 In both patients the a p p e n d i x was partially filled, revealing a n o d u l a r defect in the base o f the a p p e n d i x or in the adjacent caput cecum. O t h e r suggested diagnostic tests for early diagnosis are selective a n g i o g r a p h y , electronic r a d i o g r a p h y , fiberoptic colonoscopy, and abdominal ultrasonography. 2~ It is quite a p p a r e n t , though, that with the present state o f o u r knowledge, the diagnosis of primary t u m o r o f the a p p e n d i x will be m a d e only after incidental a p p e n d e c t o m y , or after a p p e n d e c t o m y for acute appendicitis. Treatment and Prognosis: T h e t r e a t m e n t f o r p r i m a r y epithelial tumors o f the a p p e n d i x is surgical. T h e p r o c e d u r e s involved are 1) a p p e n d e c t o m y alone or 2) appendectomy followed by right hemicolectomy. Appendectomy Alone: This p r o c e d u r e is a p p r o p r i a t e for all benign p r i m a r y epithelial tumors o f the app e n d i x , n a m e l y m u c i n o u s c y s t a d e n o m a s (villous adenoma), a d e n o m a , and a d e n o m a t o u s polyps o f the appendix. A p p e n d e c t o m y is also sufficient for carcinoid o f the a p p e n d i x w h e r e there is no gross evidence o f local metastasis and when the t u m o r does not involve the cecal wall a n d is less than 2 cm in size. 7'8 Using such criteria, simple a p p e n d e c t o m y would be a d e q u a t e t r e a t m e n t for the majority o f carcinoid tumors o f the a p p e n d i x . Some have suggested that simple a p p e n d e c t o m y a l o n e is s u f f i c i e n t f o r mucinous c y s t a d e n o c a r c i n o m a o f the a p p e n d i x which is confined to the mucosa or tip o f the a p p e n d i x ? 2
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Others feel that this is not an adequate operation for this lesion. 2~ Appendectomy Plus Right Hemicolectomy: These procedures, in our opinion, are indicated for all adenocarcinomas of the appendix, whether they are o f the mucinous or colonic type; all adenoacanthomas; and for all carcinoids of the appendix that are 2 cm or greater in size, or have evidence of gross local metastasis. T h e rationale for this is twofold: 1) lymphatic drainage of the appendix goes to the lower ileocolic nodes and then to the upper ileocolic nodes; and 2) the longitudinal and circular muscular fibers of the muscularis propria are deficient in certain areas of the appendix, thus causing the submucosa and serosa in these areas to lie in proximity. A tumor o f the epithelium, especially an a d e n o c a r c i n o m a which has a propensity to spread by lymph channels, becomes potentially aggressive in this circumstance. We do not make a difference between mucinous adenocarcinoma and the colonic type of adenocarcinoma of the appendix. We believe, as do others, that the former is most like!y an example of the latter with excessive mucin production? T h e five-year survivals of patients with carcinoid tumors of the appendix approaches 100 per cent. 22 This, of course, applies to carcinoid tumors confined to the appendix, or with local metastasis. Only 2 per cent of all cases of carcinoid of the appendix are associated with distant metastasis. In these patients, the five-year survival is 0 per cent. z2 In our series, one patient had distant metastases to the liver. He died nine months after diagnosis. T h e f i v e - y e a r survival rate f or p a t i e n t s with adenocarcinoma of the appendix varies from 46 per cent for those having appendectomy alone, to 60 per cent for those subjected to additional right hemicolectomy? = These statistics are in relation to 51 cases of the colonic type of adenocarcinoma of the appendix, gleaned flom literature by the authors. T h e treatment and survival data of all patients with primary malignant epithelial tumors in our series is shown in Table 3.
TABLE 3.
Pseudomyxoma Peritonei: Mucinous implants in the peritoneal cavity are designated pseudomyxoma peritonei. This condition usually is of ovarian or app e n d i c e a l o r i g i n . 3'13"2a W h e n p s e u d o m y x o m a peritonei is secondary to appendicular disease, it is most often seen when cystic neoplasms r u p t u r e , whether mucinous cystadenoma or mucinous cystade n o c a r c i n o m a . In o u r series, two p a t i e n t s h a d p s e u d o m y x o m a peritonei, one associated with a mucinous cystadenoma and the other associated with a mucinous cystadenocarcinoma. T h e surgical importance of pseudomyxoma peritonei is that these patients can have r e c u r r e n t episodes of intestinal obstruction. Pseudomyxoma peritonei is associated with mucinous cystadenoma of the appendix and will subside after appendectomy. 23 Those associated with m u c i n o u s c y s t a d e n o c a r c i n o m a will persist a f t e r treatment of the primary tumor.4At operation, as far as possible, all mucinous material must be evacuated from the peritoneal cavity, and a search for tumors of the ovary must be made if the patient is a woman. 2a T h e use of intraperitoneal instillation of radioactive gold and hyaluronidase la and external radiation 2a has not been known to alter the course of repeated intestinal obstruction seen in patients who have the condition in association with mucinous adenocarcinoma of the appendix. T h e greatest salvage can be gained by repeated laparotomy with evacuation of ascites, lysis of adhesions, and intestinal resection. 2a Sum m ary A 28-year review of the records at Hines V.A. Medical Center revealed 17 primary epithelial tumors of the appendix. Five of these tumors were benign and 12 malignant. It is suggested that the term mucocele be abandoned, because it represents the end resuh, rather than a definite pathologic entity. T h e majority of benign tumors and carcinoid tumors of the appendix are discovered incidentally to other procedures. T h e majority of adenocarcinomas cause symptoms and signs of appendicitis. Simple appendectomy is sufficient treatment o f all
Treatment and Surznval of 12 Patients with Malignant Epithelial Tumors of the Appendix Treatment
Tumor Type Adenocarcinoma Carcinoid TOTAL
Survival
Number
Appendectomy Only
Appendectomy Plus Right Hemicolectomy
Biospy Only
2-Year
5-Year
10-Year
6 6 12
0 4 4
5 2 7
1 0 1
3 5 8
1 4 5
0 3 3
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b e n i g n t u m o r s o f the a p p e n d i x , a n d f o r all c a r c i n o i d s t h a t show n o gross local m e t a s t a s e s a n d are less t h a n 2 cm in diameter. S i m p l e a p p e n d e c t o m y f o l l o w e d by r i g h t h e m i c o l e c t o m y o r initial r i g h t h e m i c o l e c t o m y is the t r e a t m e n t o f choice for all c a r c i n o i d s o f the a p p e n d i x t h a t show gross local m e t a s t a s e s a n d a r e 2 c m o r m o r e in d i a m e t e r a n d for all a d e n o c a r c i n o m a s o f the a p p e n d i x , w h e t h e r m u c i n o u s o r colonic, in the a b s e n c e o f dist a n t metastasis. A n e w classification f o r p r i m a r y e p i t h e l i a l t u m o r s o f the a p p e n d i x is s u g g e s t e d .
References 1. Uihlein A, McDonald JR: Primary carcinoma of the appendix resembling carcinoma of the colon. Surg Gynecol Obstet 76: 711, 1943 2. Qizilbash AH: Mucoceles of the appendix: Their relationship to hyperplastic polyps, mucinous cystadenomas, and cystadenocarcinomas. Arch Pathol 99: 548, 1975 3. Higa E, Rosai J, Pizzimbono CA, et al: Mucosal hyperplasia, mucinous cystadenoma, and mucinous cystadenocarcinoma of the appendix: A re-e~aluation of appendiceal "mucocele." Cancer 32: 1525, 1973 4. Wolff M, Ahmed N: Epithelial neoplasms of the vermiform appendix (exclusive of carcinoid). I. Adenocarcinoma of the appendix. Cancer 37: 2493, 1976 5. Wolff M, Ahmed N: Epithelial neoplasms of the vermiform appendix (exclusive of carcinoid). II. Cystadenomas, papillary adenomas, and adenomatous polyps of the appendix. Cancer 37: 2511, 1976 6. Collins DC: A study of 50,000 specimens of the human vermiform appendix. Surg Gynecol Obstet 101: 437, 1955
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Dis.October Col. & Rect. I979
7. Cheek RC, Wilson H: Carcinoid tumors. Curr Probl Surg (Nov) 1970, p 4 8. Moertel CG~ Dockerty MB, Judd ES: Carcinoid tumors of the vermiform appendix. Cancer 21: 270, 1968 9. Beger A: Quoted by Cheek RC, Wilson H 7 10. Aburahma AF: Primary adenocarcinoma of the vermiform appendix: Report of five new cases and review of the literature. W Va MedJ 73: 296, 1977 11. Aho AJ, Heinonen R, Laur&n P: Benign and malignant mucocele of the appendix. Histological types and prognosis. Acta Chit Scand 139: 392, 1973 12. Andersson A, Bergdahl L, Boquist L: Primary carcinoma of the appendix. Ann Snrg 183: 53, 1976 13. Bernhardt H, Young JM: Mucocele and pseudomyxoma peritonei of appendiceal origin. Clinicopathologic aspects. Am J Surg 109: 235, 1965 14. Cohen SE, Wolfman EF Jr: Primary adenocarcinoma of the vermiform appendix. Am J Surg 127: 704, 1974 15. Schmutzer KJ, Bayar M, Zaki AE, et al: Tumors of the appendix. Dis Colon Rectum 18: 324, 1975 16. Schulte WJ, Pintar K, Schmahl T: Adenoacanthoma of the appendix. J Surg Oncol 6: 93, 1974 17. Qizilbash AH: Primary adenocarcinoma of the appendix: A clinicopathological study of 11 cases. Arch Pathol 99: 556, 1975 18. Gamble HA II: Adenocarcinoma of the appendix: An unusual case and review. Dis colon Rectum 19: 621, 1976 19. Ger R, Buch J, Held BT, et al: Carcinoma of the appendix: Report of two cases. Disc Colon Rectum 17: 370, 1974 20. Dross VP, Hipsley RW: The problem of carcinoma of the vermiform appendix: Review of literature proposals for use of new diagnostic techniques (case report). W Va MedJ 70: 80, 1974 21. Herczeg E, Winter S, Weissberg D: Primary carcinoma of the appendix. JAMA 238: 51, 1977 22. Godwin JD II: Carcinoid tumors: An analysis of 2837 cases. Cancer 36: 560, 1975 23. Parsons J, Gray GF, Thorbjarnarson B: Pseudomyxoma peritonei. Arch Surg 101: 545, 1970
Memoir jVDD, JOSEPH HARRY, McKeesport, Pennsylvania; born July 4, 1907, blcKeesport, Pennsylvania. Dr. J u d d graduated from Temple University School of Medicine in 1931, received his postgraduate surgical training at McKeesport Hospital, and his colon and rectal training with Dr. C. C. Mechling of Pittsburgh. He served with the U.S. A r m e d Forces d u r i n g World War II. Dr. J u d d was elected to membership in the American Society of Colon and Rectal Surgeons in 1949 and elevated to Associate Fellowship in 1950. He was a Fellow, American College of Surgeons, and a member of the American Medical Association, Pennsylvania State Medical Society, Allegheny County Medical Society, and Pittsburgh Proctologic Society. He was on the staff of the McKeesport Hospital. Dr. J u d d died J u n e 26, 1979.
G r~r tD V. ArtANHA, M.D.F.R.C.S.(C), CrSAR V. Rrvrs, M.D.
UIHLEIN AND McDoNALD 1 in 1943 wrote, "Much has been written concerning epithelial neoplasms of the appendix, but there is still considerable confusion with regard to the classification of these tumors." T h ey went on to suggest that a simple and workable classification for these tumors would be to divide them into three types: 1) carcinomas of the carcinoid type; 2) carcinomas of the cystic type p r o d u c i n g pseudomyoma peritonei; 3) carcinomas which resemble, both grossly and microscopically, carcinoma of the colon. In time, the-carcinomas of the cystic type came to be known as malignant mucoceles. T h e term mucocele refers to a lesion of the appendix with a dilated lumen filled with mucus? In a review, Higa and co-workers a r e c o m m e n d e d elimination of the term "mucocele" since it referred only to the presence and effects of accumulation of mucus in the lumen of the appendix and gave no information about the primary disease that caused it. T hey were able to reclassify all 73 "mucoceles" in their series into 1) focal or diffuse mucosal hyperplasia, 2) mucinous cystadenoma, or 3) mucinous cystadenocarcinoma. T h e confusion Uihlein and McDonald ~ referred to, obviously remains, but much of it is due to the so-called "mucocele." This study was undertaken with three objectives in mind: first, review all primary epithelial tumors of the appendix seen at V.A. Medical Center, Hines, Illinois, between the years 1950 and 1978; second, to reclassify all the o b s e r v e d mucoceles along the lines suggested by Higa, a Wolff, and Ahmed4'S; and third, suggest a classification for primary epithelial tumors o f the a p p e n d i x that takes into account definite pathologic entities. Material a n d M e t h o d s
Those charts carrying the diagnosis of neoplasm of the appendix of all patients between the years 1950 * Received for publication May 18. 1979. Address reprint requests to Dr. Aranha: P.O. Box 1044, Hines, Illinois 60141.
From the Department of Surgery and the Department of Pathology, Hines V.A. Hospital, Hines, Illinois and the Department of Surgery, Loyola University Medical Center, Ma~wood, Illinois
and 1978 at Hines V.A. Medical Center, were reviewed. All pathologic slides pertaining to these patients were reviewed by the same pathologist (C.R.) for the purpose of the study. A total of 19 primary neoplasms of the appendix had been seen between the years 1950-1978 at Hines, V.A. Medical Center. Four of the lesions were designated "mucocele." A review of these lesions by the surgical pathologist led to two of the four mucoceles being reclassified as diffuse mucosal hyperplasia; of the remaining two, one was assigned the diagnosis of mucinous cystadenoma and the other, the diagnosis of mucinous cystadenocarcinoma. Since this is a discussion of primary epithelial neoplasms of the appendix, the patients with focal or diffuse mucosal hyperplasia were excluded from analysis. O f the remaining 17 primary tumors, five were b e n i g n and 1'2 malignant (Table 1). Further analysis of the malignant tumors revealed six adenocarcinomas (of which three were mucin producing and three, the usual colonic type) and six careinoids. No adenocant hom as were seen. All six p a t i e n t s with a d e n o c a r c i n o m a h a d symptoms of acute appendicitis, namely periumbilical or right lower quadrant pain, associated with nausea and occasional vomiting. Physical examination revealed definite evidence of generalized peritonitis in one and evidence of small-intestinal obstruction in another. All others had right lower quadrant tenderness and rebound. While plain x-rays of the abdomen were useful in delineating associated ileus or smallintestinal obstruction, no barium-contrast studies were used to make a diagnosis. One patient died before surgery could be done. At autopsy, he was found to have a mucinous adenocarcinoma of the appendix,
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with p s e u d o m y x o m a peritonei. T h e five o t h e r patients with a d e n o c a r c i n o m a had a p p e n d e c t o m y as the initial p r o c e d u r e , followed by right hemicolectomy as a definitive p r o c e d u r e 2 - 4 weeks after the pathologic diagnosis of a d e n o c a r c i n o m a was made on the appendix, O f the five patients, one was lost to follow up, one survived six months, two survived two years, and one, five years. T h e patient who survived five years died o f carcinoma o f the pancreas, a diagnosis m a d e at autopsy. O f the six patients with carcinoid tumors o f the appendix, three had symptoms and signs o f acute appendicitis; in two patients, the t u m o r was discovered after incidental a p p e n d e c t o m y ; and in one, exploration following an abnormal liver scan revealed a carcinoid o f the a p p e n d i x greater than 2 cm in diameter, with metastases to the ileocolic lympth nodes and liver. All six patients had an a p p e n d e c t o m y as their initial p r o c e d u r e . T w o patients n e e d e d right hemicolectomy because o f cecal involvement. T h e patient with metastasis to the liver survived nine months. One patient died, 12 months after the diagnosis o f carcinoid, f r o m a new primary carcinoma o f the colon. T h e f o u r others are alive seven years, 15 years, 95 years, and 25 years since diagnosis. T w o patients had p s e u d o m y x o m a peritonei, one associated with a m u c i n o u s a d e n o c a r c i n o m a and a n o t h e r with a benign cystadenoma of the appendix. Discussion Incidence: T u m o r s of the a p p e n d i x are rare and no definite statement can be m a d e with respect to the percentage they make up o f all tumors. T h e incidence of a d e n o c a r c i n o m a of the a p p e n d i x is r e p o r t e d to be a r o u n d 0.089 per cent o f resected appendices. 6 T h e incidence o f carcinoids of the a p p e n d i x is many times that o f a d e n o c a r c i n o m a and t h o u g h t to vary f r o m 0.3 per cent to 0.7 per cent o f all surgically r e m o v e d appendices. 7.8 Previously, it was t h o u g h t that 89 per cent o f all p r i m a r y epithelial tumors of the a p p e n d i x were carcinoids, and mucoceles and a d e n o c a r c i n o m a accounted for 8 per cent and 3 per cent, respectively? With the reclassification o f mucoceles it is m o r e likely that carcinoids will account for about 90 per cent of all primary epithelial tumors o f the a p p e n d i x and a d e n o c a r c i n o m a for a b o u t 10 per cent. B e g e r 9 is c r e d i t e d with r e p o r t i n g t h e first two cases o f a d e n o c a r c i n o m a o f the appendix. These, however, are now t h o u g h t to have been actually carcinoids. In o u r series, the ages o f the p a t i e n t s with a d e n o c a r c i n o m a r a n g e d f r o m 37 to 65 years, and those with carcinoids f r o m 28 to 69 years. All o u r patients were men. T h e literature does favor a slight
TABLE 1. Primary Epithelial Tumors of the Appendix Seen at Hines V.A. Medical Center 1950 -1978
Number Benign Mucinous cystadenoma Papillary adenoma Adenomatous polyp Malignant Adenocarcinoma Mucin producing Colonic type Carcinoid TOTAL
3 3 6 17
p r e p o n d e r a n c e for m e n over women in patients having a d e n o c a r c i n o m a , 8 whereas, for carcinoids o f the appendix, w o m e n p r e d o m i n a t e slightly over men. r T h o u g h m e n and w o m e n have similar incidence rates for carcinoids detected by a p p e n d e c t o m y , m o r e appendectomies were p e r f o r m e d in women (incidental to pelvic or gallbladder surgery), so m o r e carcinoids are d e t e c t e d ? P a t h o l o g i c Classification: Any new classification for p r i m a r y epithelial tumors o f the a p p e n d i x must take into consideration benign or malignant tumors. Benign epithelial tumors are likely to be m u c i n o u s cystadenomas, single a d e n o m a s , and a d e n o m a t o u s p o l y p s o f t h e a p p e n d i x , a'5 P a t h o l o g i c a l l y , cyst a d e n o m a s resemble villous a d e n o m a s seen in the colon and are t h o u g h t to be their c o u n t e r p a r t in the a p p e n d i x . 2 In several publications, mucoceles are c l a s s i f i e d as b e n i g n o r m a l i g n a n t o r j u s t mucoceles. 10-14 A c c o r d i n g to H i g a a n d c o - w o r k e r s , a the t e r m "mucocele" has usually been applied to a g r o u p o f appendiceal lesions, characterized by one to two o f the following: 1) dilatation of the lumen; 2) alteration o f the mucosal lining; 3) hypersecretion o f mucus; 4) occasional extension outside the appendix, either as p s e u d o m y x o m a peritonei or, unusually, as distant metastasis. T h e i r review o f 73 lesions d e s i g n a t e d "mucocele" resulted in all these lesions being reclassified into three distinctive clincopathologic entities: focal or d i f f u s e m u c o s a l h y p e r p l a s i a , m u c i n o u s cystadenoma, or mucinous cystadenocarcinoma. Further, they f o u n d the views on the pathogenesis o f these lesions, very controversial. Some authors considered a "mucocele" a cystic dilatation of the l u m e n secondary to obstruction; some considered it a true neoplasm; others considered "mucocele" as a single
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T.~.BLE 2- Classificationof Primary Epithelial Tumors of the Appendix Benign Mucinous cystadenoma Papillary adenoma Adenomatous polyp Malignant Adenocarcinoma--rnucin producing --colonic type Carcinoid Adenoacanthoma entity, and still others divided them into benign and malignant types. Since the term "mucocele" failed to d e n o t e the pathogenic mechanism causing dilatation o f the a p p e n d i c e a l l u m e n , with a c c u m u l a t i o n o f mucus, it was r e c o m m e n d e d that the term be elimin a t e d . S u p p o r t f o r this position has c o m e f r o m others. 2,5 F o u r l e s i o n s in o u r s t u d y w e r e d e s i g n a t e d "mucoceles"; all f o u r could be reclassified, two as d i f f u s e mucosal h y p e r p l a s i a , one as a m u c i n o u s c y s t a d e n o m a a n d one" as a m u c i n o u s c y s t a d e n o carcinoma. Because o f this experience, t h o u g h small, we also feel that mucoceles can be assigned definite pathologic entities and favor elimination o f the term. Mucinous cystadenocarcinoma o f the a p p e n d i x may well be an a d e n o c a r c i n o m a showing excessive mucin production? Carcinoids o f the a p p e n d i x are ten times m o r e c o m m o n t h a n a d e n o c a r c i n o m a s . * T h e y o c c u r in about 0.3 to 0.10 per cent o f all appendectomies. 7,s,15 No controversy s u r r o u n d s the pathologic features o f carcinoid t u m o r s o f the appendix. Carcinoids o f the a p p e n d i x t y p i c a l l y o c c u r as small, f i r m , circumscribed, yellow-tan nodules usually seen in the distal appendix. Less than 10 per cent occur at the base o f the a p p e n d i x . While all carcinoids have a malignant potential, only 2 per cent o f appendiceal carcinoids metastasize to the liver. 7 A third p r i m a r y malignant t u m o r o f the appendix, o f which there has been only one case r e p o r t is the a d e n o a c a n t h o m a . '6 T h e s e tumors are usually seen in areas that have contiguous squamous and glandular surfaces, e.g., the cardioesophageal junction, the uterus, and the rectum. Symptomatic tumors usually cause symptoms like those o f a d e n o c a r c i n o m a s . T h e a d e n o a c a n thomas also behave like adenocarcinomas and their surgical m a n a g e m e n t must be the same. ~6 With the above considerations, and with elimination o f the term "mucocele" in mind; we suggest a new classification for p r i m a r y epithelial tumors o f the a p p e n d i x as shown in T a b l e 2. Symptoms, Signs and Diagnosis: T h e majority o f cases o f a d e n o c a r c i n o m a o f the a p p e n d i x a p p e a r to
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have s y m p t o m s and signs o f appendicitis. 1~ One case o f a d e n o c a r c i n o m a o f the a p p e n d i x occurring in an appendiceal s t u m p and a p p e a r i n g to be a right colonic obstruction has been r e p o r t e d . 's T h e reason stated for the high p e r c e n t a g e o f symptomatic patients with a d e n o c a r c i n o m a is that the t u m o r occurs at the base o f the a p p e n d i x and causes obstruction early. Most carcinoids o f the a p p e n d i x are discovered incidentally at o p e r a t i o n for a n o t h e r process, or after a p p e n d e c t o m y , s T h e lesion is usually seen as a yellow n o d u l e at the tip o f the a p p e n d i x , and only rarely involves the base o f that organ. This lesion, t h o u g h highly malignant locally, s rarely metastasizes to distant sites, r O n e fact stands out; the majority o f carcinoids o f the a p p e n d i x m o r e than 2 cm in size will have distant metastases, s F o u r o f the five b e n i g n lesions in o u r series were discovered at l a p a r o t o m y for a n o t h e r problem. T h e fifth patient had an a b n o r m a l barium e n e m a showing a filling defect in the cecum. At o p e r a t i o n this filling defect was f o u n d to be mucin. Primary t u m o r s o f the a p p e n d i x are rarely diagnosed before operation. A t u m o r o f the a p p e n d i x was strongly s u s p e c t e d in two patients a f t e r b a r i u m e n e m a e x a m i n a t i o n ? 9 In both patients the a p p e n d i x was partially filled, revealing a n o d u l a r defect in the base o f the a p p e n d i x or in the adjacent caput cecum. O t h e r suggested diagnostic tests for early diagnosis are selective a n g i o g r a p h y , electronic r a d i o g r a p h y , fiberoptic colonoscopy, and abdominal ultrasonography. 2~ It is quite a p p a r e n t , though, that with the present state o f o u r knowledge, the diagnosis of primary t u m o r o f the a p p e n d i x will be m a d e only after incidental a p p e n d e c t o m y , or after a p p e n d e c t o m y for acute appendicitis. Treatment and Prognosis: T h e t r e a t m e n t f o r p r i m a r y epithelial tumors o f the a p p e n d i x is surgical. T h e p r o c e d u r e s involved are 1) a p p e n d e c t o m y alone or 2) appendectomy followed by right hemicolectomy. Appendectomy Alone: This p r o c e d u r e is a p p r o p r i a t e for all benign p r i m a r y epithelial tumors o f the app e n d i x , n a m e l y m u c i n o u s c y s t a d e n o m a s (villous adenoma), a d e n o m a , and a d e n o m a t o u s polyps o f the appendix. A p p e n d e c t o m y is also sufficient for carcinoid o f the a p p e n d i x w h e r e there is no gross evidence o f local metastasis and when the t u m o r does not involve the cecal wall a n d is less than 2 cm in size. 7'8 Using such criteria, simple a p p e n d e c t o m y would be a d e q u a t e t r e a t m e n t for the majority o f carcinoid tumors o f the a p p e n d i x . Some have suggested that simple a p p e n d e c t o m y a l o n e is s u f f i c i e n t f o r mucinous c y s t a d e n o c a r c i n o m a o f the a p p e n d i x which is confined to the mucosa or tip o f the a p p e n d i x ? 2
V o l u m e 22
Number 7
475
EPITHELIAL TUMORS OF' THE APPENDIX
Others feel that this is not an adequate operation for this lesion. 2~ Appendectomy Plus Right Hemicolectomy: These procedures, in our opinion, are indicated for all adenocarcinomas of the appendix, whether they are o f the mucinous or colonic type; all adenoacanthomas; and for all carcinoids of the appendix that are 2 cm or greater in size, or have evidence of gross local metastasis. T h e rationale for this is twofold: 1) lymphatic drainage of the appendix goes to the lower ileocolic nodes and then to the upper ileocolic nodes; and 2) the longitudinal and circular muscular fibers of the muscularis propria are deficient in certain areas of the appendix, thus causing the submucosa and serosa in these areas to lie in proximity. A tumor o f the epithelium, especially an a d e n o c a r c i n o m a which has a propensity to spread by lymph channels, becomes potentially aggressive in this circumstance. We do not make a difference between mucinous adenocarcinoma and the colonic type of adenocarcinoma of the appendix. We believe, as do others, that the former is most like!y an example of the latter with excessive mucin production? T h e five-year survivals of patients with carcinoid tumors of the appendix approaches 100 per cent. 22 This, of course, applies to carcinoid tumors confined to the appendix, or with local metastasis. Only 2 per cent of all cases of carcinoid of the appendix are associated with distant metastasis. In these patients, the five-year survival is 0 per cent. z2 In our series, one patient had distant metastases to the liver. He died nine months after diagnosis. T h e f i v e - y e a r survival rate f or p a t i e n t s with adenocarcinoma of the appendix varies from 46 per cent for those having appendectomy alone, to 60 per cent for those subjected to additional right hemicolectomy? = These statistics are in relation to 51 cases of the colonic type of adenocarcinoma of the appendix, gleaned flom literature by the authors. T h e treatment and survival data of all patients with primary malignant epithelial tumors in our series is shown in Table 3.
TABLE 3.
Pseudomyxoma Peritonei: Mucinous implants in the peritoneal cavity are designated pseudomyxoma peritonei. This condition usually is of ovarian or app e n d i c e a l o r i g i n . 3'13"2a W h e n p s e u d o m y x o m a peritonei is secondary to appendicular disease, it is most often seen when cystic neoplasms r u p t u r e , whether mucinous cystadenoma or mucinous cystade n o c a r c i n o m a . In o u r series, two p a t i e n t s h a d p s e u d o m y x o m a peritonei, one associated with a mucinous cystadenoma and the other associated with a mucinous cystadenocarcinoma. T h e surgical importance of pseudomyxoma peritonei is that these patients can have r e c u r r e n t episodes of intestinal obstruction. Pseudomyxoma peritonei is associated with mucinous cystadenoma of the appendix and will subside after appendectomy. 23 Those associated with m u c i n o u s c y s t a d e n o c a r c i n o m a will persist a f t e r treatment of the primary tumor.4At operation, as far as possible, all mucinous material must be evacuated from the peritoneal cavity, and a search for tumors of the ovary must be made if the patient is a woman. 2a T h e use of intraperitoneal instillation of radioactive gold and hyaluronidase la and external radiation 2a has not been known to alter the course of repeated intestinal obstruction seen in patients who have the condition in association with mucinous adenocarcinoma of the appendix. T h e greatest salvage can be gained by repeated laparotomy with evacuation of ascites, lysis of adhesions, and intestinal resection. 2a Sum m ary A 28-year review of the records at Hines V.A. Medical Center revealed 17 primary epithelial tumors of the appendix. Five of these tumors were benign and 12 malignant. It is suggested that the term mucocele be abandoned, because it represents the end resuh, rather than a definite pathologic entity. T h e majority of benign tumors and carcinoid tumors of the appendix are discovered incidentally to other procedures. T h e majority of adenocarcinomas cause symptoms and signs of appendicitis. Simple appendectomy is sufficient treatment o f all
Treatment and Surznval of 12 Patients with Malignant Epithelial Tumors of the Appendix Treatment
Tumor Type Adenocarcinoma Carcinoid TOTAL
Survival
Number
Appendectomy Only
Appendectomy Plus Right Hemicolectomy
Biospy Only
2-Year
5-Year
10-Year
6 6 12
0 4 4
5 2 7
1 0 1
3 5 8
1 4 5
0 3 3
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b e n i g n t u m o r s o f the a p p e n d i x , a n d f o r all c a r c i n o i d s t h a t show n o gross local m e t a s t a s e s a n d are less t h a n 2 cm in diameter. S i m p l e a p p e n d e c t o m y f o l l o w e d by r i g h t h e m i c o l e c t o m y o r initial r i g h t h e m i c o l e c t o m y is the t r e a t m e n t o f choice for all c a r c i n o i d s o f the a p p e n d i x t h a t show gross local m e t a s t a s e s a n d a r e 2 c m o r m o r e in d i a m e t e r a n d for all a d e n o c a r c i n o m a s o f the a p p e n d i x , w h e t h e r m u c i n o u s o r colonic, in the a b s e n c e o f dist a n t metastasis. A n e w classification f o r p r i m a r y e p i t h e l i a l t u m o r s o f the a p p e n d i x is s u g g e s t e d .
References 1. Uihlein A, McDonald JR: Primary carcinoma of the appendix resembling carcinoma of the colon. Surg Gynecol Obstet 76: 711, 1943 2. Qizilbash AH: Mucoceles of the appendix: Their relationship to hyperplastic polyps, mucinous cystadenomas, and cystadenocarcinomas. Arch Pathol 99: 548, 1975 3. Higa E, Rosai J, Pizzimbono CA, et al: Mucosal hyperplasia, mucinous cystadenoma, and mucinous cystadenocarcinoma of the appendix: A re-e~aluation of appendiceal "mucocele." Cancer 32: 1525, 1973 4. Wolff M, Ahmed N: Epithelial neoplasms of the vermiform appendix (exclusive of carcinoid). I. Adenocarcinoma of the appendix. Cancer 37: 2493, 1976 5. Wolff M, Ahmed N: Epithelial neoplasms of the vermiform appendix (exclusive of carcinoid). II. Cystadenomas, papillary adenomas, and adenomatous polyps of the appendix. Cancer 37: 2511, 1976 6. Collins DC: A study of 50,000 specimens of the human vermiform appendix. Surg Gynecol Obstet 101: 437, 1955
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Dis.October Col. & Rect. I979
7. Cheek RC, Wilson H: Carcinoid tumors. Curr Probl Surg (Nov) 1970, p 4 8. Moertel CG~ Dockerty MB, Judd ES: Carcinoid tumors of the vermiform appendix. Cancer 21: 270, 1968 9. Beger A: Quoted by Cheek RC, Wilson H 7 10. Aburahma AF: Primary adenocarcinoma of the vermiform appendix: Report of five new cases and review of the literature. W Va MedJ 73: 296, 1977 11. Aho AJ, Heinonen R, Laur&n P: Benign and malignant mucocele of the appendix. Histological types and prognosis. Acta Chit Scand 139: 392, 1973 12. Andersson A, Bergdahl L, Boquist L: Primary carcinoma of the appendix. Ann Snrg 183: 53, 1976 13. Bernhardt H, Young JM: Mucocele and pseudomyxoma peritonei of appendiceal origin. Clinicopathologic aspects. Am J Surg 109: 235, 1965 14. Cohen SE, Wolfman EF Jr: Primary adenocarcinoma of the vermiform appendix. Am J Surg 127: 704, 1974 15. Schmutzer KJ, Bayar M, Zaki AE, et al: Tumors of the appendix. Dis Colon Rectum 18: 324, 1975 16. Schulte WJ, Pintar K, Schmahl T: Adenoacanthoma of the appendix. J Surg Oncol 6: 93, 1974 17. Qizilbash AH: Primary adenocarcinoma of the appendix: A clinicopathological study of 11 cases. Arch Pathol 99: 556, 1975 18. Gamble HA II: Adenocarcinoma of the appendix: An unusual case and review. Dis colon Rectum 19: 621, 1976 19. Ger R, Buch J, Held BT, et al: Carcinoma of the appendix: Report of two cases. Disc Colon Rectum 17: 370, 1974 20. Dross VP, Hipsley RW: The problem of carcinoma of the vermiform appendix: Review of literature proposals for use of new diagnostic techniques (case report). W Va MedJ 70: 80, 1974 21. Herczeg E, Winter S, Weissberg D: Primary carcinoma of the appendix. JAMA 238: 51, 1977 22. Godwin JD II: Carcinoid tumors: An analysis of 2837 cases. Cancer 36: 560, 1975 23. Parsons J, Gray GF, Thorbjarnarson B: Pseudomyxoma peritonei. Arch Surg 101: 545, 1970
Memoir jVDD, JOSEPH HARRY, McKeesport, Pennsylvania; born July 4, 1907, blcKeesport, Pennsylvania. Dr. J u d d graduated from Temple University School of Medicine in 1931, received his postgraduate surgical training at McKeesport Hospital, and his colon and rectal training with Dr. C. C. Mechling of Pittsburgh. He served with the U.S. A r m e d Forces d u r i n g World War II. Dr. J u d d was elected to membership in the American Society of Colon and Rectal Surgeons in 1949 and elevated to Associate Fellowship in 1950. He was a Fellow, American College of Surgeons, and a member of the American Medical Association, Pennsylvania State Medical Society, Allegheny County Medical Society, and Pittsburgh Proctologic Society. He was on the staff of the McKeesport Hospital. Dr. J u d d died J u n e 26, 1979.
