Primary carcinoma of the appendix vs. carcinoid

PRIMARY

CARCINOMA OF THE APPENDIX VS. CARCINOID* RICHARD A. LEONARDO, M.D. ROCHESTER, N. Y.

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HERE is considerabIe confusion in the mind of the average surgeon on this subject. He has heard of carcinoid tumor, aIs of metastasizing carcinoid tumor, and, possibIy, even of a. true carcinoma of the appendix; but not, as a ruIe, ever having seen any such cases, he has no definite or cIear-cut conception about any of them other than that they might possibIy be much aIike, perhaps onIy different stages of the same disease. Such was the author’s misconception, unti1 a recent experience with a case of primary carcinoma of the appendix aroused his interest and caused him to investigate the Iiterature on this subject; with what resuIt? ActuaIIy he became more confused than ever, because most past authorities grouped a11 such cases together and made no distinction between carcinoid tumor and carcinoma. Not onIy is there confusion in the actua1 identification or separation of carcinoid tumor from a true carcinoma, but even eminent pathoIogists differ considerabIy on the question of whether carcinoid tumors are maIignant or not. One of our most prominent pathoIogists states positiveIy that carcinoid tumors of the appendix are practicaIIy aIways benign,3 whereas others5 are equaIIy certain that a11 carcinoid tumors, be they singIe or muItipIe, in the appendix or in the smaI1 or Iarge bowe1, are potentiaIIy maIignant because they a11 invade the surrounding tissues even though such invasion occurs very sIowIy. They fee1 that eventuaIIy a11 wouId metastasize and therefore these authorities definitely cIassify the carcinoid tumors among the carcinomata. Besides the author’s case onIy one other case has been recentIy encountered at our hospita1. Both of these cases of primary

carcinoma of the appendix were operated upon and I fee1 that they shouId both be reported if onIy because of their extreme rarity, but, in view of the widespread confusion amongst surgeons on this whoIe subject, it might not be amiss at this time to brieffy sketch the story of carcinoid tumor and try to show wherein it is definiteIy distinguishabIe from carcinoma, and to bring out the saIient facts in outIine form. “Carcinoid” tumors were first so named by Obendorfer (1907) because, though they morphoIogicaIIy resembIe basaI-ceIIed epitheIioma yet cIinicaIIy they act in the gross Iike benign growths; metastasis, in Obendorfer’s experience, never occurred, and recurrence after operation seIdom happened, or at Ieast onIy IocaIIy. Obendorfer is not onIy responsibIe for the name “carcinoid” but he aIso found and described the chromafhn granuIes and Iipoids contained in these carcinoid ceIIs. In 1912, SaItykow tried to demonstrate that these ceIIs represented aberrant isIands of Langerhans of the pancreas, which they resembIe. This is one theory of the origin of carcinoid tumors, but Iater work showed this theory to be in error by demonstrating that the carcinoid ceIIs granuIes” contain specia1 “siIver-reducing which the Langerhans ceIIs do not have. Beginning in 19 14, Masson is primariIy responsibIe for our present conception of the origin and deveIopment of carcinoid tumors. He showed that the KuItschitzky ce1I.s in the bases of Lieberkiihn’s gIands have silver-reducing granuIes identica1 with those found in carcinoid ceIIs and besides he was abIe to trace directIy the structura1 deveIopment of carcinoid tumors from these KuItschitzky ceIIs. Further,

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Masson (I 928) found evidence of a chronic inff ammation in a11of the cases of appendiceaI disease having carcinoid tumor, manifested not onIy microscopicaIIy but even grossIy by a compIete or partia1 obhteration of the appendicea1 Iumen. He found, further, definite microscopic evidences of a “neuroma” in 86 per cent of these cases; i.e., a hyperpIasia of argentaffrn ceIIs (ceIIs with silver-reducing granuIes) and nonmyeIinated nerves. He thus eIaborates the now most commonIy accepted, theory, that carcinoid tumor arises directIy from the KuItschitzky ceIIs in Lieberktihn’s crypts as a resuIt of chronic inflammation and passes through the “neuroma” stage prior to actua1 deveIopment of the carcinoid tumor itseIf. Thus, according to Masson, the carcinoids of the appendix are reIated to the sympathetic nervous system. Other theories on the origin of these tumors, viz: that they represent aberrant isIands of Langerhans (of the pancreas); that they represent heterotopic intestina1 that they represent true carmucosa; cinomata from the epitheIium of the gastrointestina1 mucosa; that they represent aberrant Brunner’s gIands (of the duodenum) ; are no Ionger heId by most authorities. WhiIe it is true that the intestina1 carcinoidsl fairIy cIoseIy resembIe pancreatic tissue or Brunner’s gIands or heterotopic intestina1 mucosa, the anaIogy ends there. There is no definite proof that the carcinoid tumors arise directIy from any such anIage. AI1 avaiIabIe proof, on confirms Masson’s work the contrary, that carcinoids arise directIy from the argentaffin ceIIs (KuItschitzky’s) in the Lieberkiihn gIands. Other authorities accepting Masson’s theory are Forbus, Ortynsky, Bonnard, Michot, Ewing and Gaspar. Carcinoids, single or muItipIe, are the most frequentIy found neopIasms of the appendix, and they occur principaIIy in the third decade; whereas true carcinomata (as in the 2 cases reported herewith) occur primariIy in the fifth or sixth decade, which is the average age for other gastrointestinal carcinomata. The incidence of

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carcinoid tumor varies, but its occurrence in 0.46 per cent of a11 appendices studied is the average figure given by most OnIy 6 per cent of these authorities. carcinoid cases ever show any cIinica1 signs of maIignancy such as extension, metastasis, recurrence after operation, etc. Sixty-seven per cent (Norment) to 73 per cent (Warren and Warren) of a11 reported cases of carcinoid tumor of the appendix occur in femaIes. The cIinica1 course is simpIy that of appendicitis, acute or chronic, aIthough cases without any symptoms aIso occur. The Ia tter are discovered accidentIy or onIy at autopsy. In a series of 96 cases reviewed by McWiIIiams, 83 per cent had symptoms of appendicitis. Diagnosis is d&uIt because symptoms are practicaIIy aIways identica1 with those of ordinary appendicitis. LCorat feeIs that pain in the right Iower quadrant in the absence of fever and with the tenderness persisting between the attacks, is characteristic of new growths of the appendix. The absence of fever and the presence of tenderness over McBurney’s point are common signs; whereas nausea, vomiting, generaIized abdomina1 cramps and rigidity were much Iess frequentIy found. The prognosis is good. These cases run a reIati\reIy benign course, cIinicaIIy. In fact Ewing says that carcinoids of the intestine are frequentIy maIignant in charcarcinoids are acter but “the appendix practicaIIy aIways benign. ” Metastasis usuaIIy does not occur and operation compIeteIy relieves the condition except possibIy in a very small percentage of cases where a IocaI recurrence may deveIop. PathoIogicaIIy, carcinoid tumors occur singIy or in muItipIes in the mucosa and submucosa, and on section are vellowish or orange in coIor and firm in consistency. OccasionaIIy they are brownish opaque noduIes that have a smooth outIine. They occur especiaIIy in the distal haIf (in 92 per cent of cases it was in the dista1 one-third, Norment) of an appendix, the seat of chronic inflammation. The ap-

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pendic’ea1 Iumen is aImost invariabIy obIiterated in whoIe or in part but the mucosa over the noduIe is smooth and never uIcerated. The average Iength of such a nodule is 8.1 mm., the average width 5.2 mm. In about 6 per cent of a11 carcinoid cases (in&ding intestina1 carcinoids) invoIvement of mesenteric and retroperitonea1 Iymph nodes occurs. According to Lkorat (1925) onIy 2 per cent of the strictIy appendicea1 carcinoids recur or actuaIIy metastasize. As earIy as 1924 Masson showed that these carcinoid ceIIs have defmite morphoIogica1 characteristics which distinguish them from the true carcinomata. MicroscopicaIIy, they are composed of soIid strands or cords of argentaffIn ceIIs having uniform, deep-staining nucIei with onIy a few mitotic figures. They are ova1 or round in shape and have a definite aIveoIar configuration but never an adenoid (gIanduIar) structure, such as is found with the true carcinomata. The report of our 2 cases of true primary appendicea1 carcinomata foIIows : J. R., aged seventy-seven, maIe, was admitted September I, and died September 4, 1929. Present Illness: The chief compIaint was no CASE

I.

white, married,

bowe1 movement for one week, and vomiting for the past four days. He was we11 unti1 one week ago, the boweIs normaI unti1 then, but no movement since. He never had any pain. The abdomen is distended but he denies Ioss of weight. Enemas were unsuccessfu1. He was hospitalized at once but refused operation for two days. When the bIood chemistry and cIinica1 findings became much worse (Sept. 3, 1929) he consented to operation. Laboratory Findings: BIood chemistry: September 2, 1929, N.P.N. 46; sugar 148; chIorides 460. September 3, 1929, N.P.N. 74; sugar 148; chIorides 390. X-rays: September 2, 1929, flat fiIm faiIs to show any evidence of intestina1 obstruction. Preoperative Diagnosis: IntestinaI obstruction. Operation (Dr. Prince): Through a right rectus muscIe-spIitting incision (exploratory) ; jejunostomy (through left upper rectus) was

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done. Exploration in the region of the cecum reveaIed a hard mass. The intestines were distended and coIor changes characteristic of obstruction were present. Because of the patient’s poor condition a simpIe jejunostomy was done and the abdomen cIosed without drainage. Progress Notes: There was good drainage

through the enterostomy tube but the patient became progressiveIy weaker with a rising temperature, p&e and respiratory rate and died on the day foIIowing operation. Autopsy Report: “The appendix is not to be found, but in its exact place there are adhesions between the cecum and the upper Ioop of the sigmoid. A Ioop of Iower iIeum I meter from the cecum is aIso adherent to this region. On cut section there is a tumor which has grown into and perforated through the sigmoid from the site of the appendix causing a stenosis of the sigmoid at this point. The tumor in the sigmoid does not invoIve the whoIe circumference, but onIy two-thirds of it. The perforation admits the index finger and passes into the cecum through the dilated appendiceal opening. The tumor is uIcerated and shows geIatinous, transparent areas. GeIatinous smaI1 tumor masses may aIso be seen on the serous surface near the main tumor mass; however metastases are nowhere found. The perforation in the waI1 of the sigmoid is funneI-Iike and shows an obIique course.” Anatomical Findings: “ I. Primary geIatinous carcinoma of the appendix with extension and perforation into the sigmoid.” CASE II. HospitaI No. 93234. R. J. H., aged seventy-four, white maIe, married, was admitted to the hospita1 ApriI 13 and died ApriI 26, 1933. He was admitted with a diagnosis of right femora1 hernia. Present Illness: His chief compIaint was a mass in right groin past four months, which appears to get larger in the daytime, smaIIer at night. The mass does not seem to increase in size when having a bowe1 movement, or when straining in any manner. He was constipated, occasionaIIy had nausea requiring Iaxatives; and vomiting, and had Iost 35 Ib. in weight during the past few months. Physical examination showed an emaciated oId man, weak and restIess. Abdominal Examination: The abdomen was tender a11 over especiaIIy in the right lower No masses or viscera were felt. quadrant.

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There was a large, soft, semi-fI uctuating mass in the femoraI region, beneath and IateraI to Poupart’s Iigament. It was the size of a smaI1, ffattened-out grapefruit, and feIt defrniteIy cystic. It couId not be reduced, did not transluminate; no impuIse was feIt on coughing; no visibIe or paIpabIe peristaIsis was present. Laboratory Findings: W.B.C. 14, IOO. UrinaIysis was negative except for a trace of aIbumin. BIood chemistry: N.P.N. 34; chIorides 437. Surgical Tissue Report: “ Several moderatesized pieces of yeIIowish tumor tissue and mucoid tissue were received from the operating room. YelIow pieces, formed of ceIIs containing abundant dust-Iike yeHow pigment and arranged in masses, resembIe adrena ceIIs, etc. The smaI1 mucoid tissue shows diIated structures fiIIed with abundant mucus. Such a picture may be seen in mucoid cancer of the Iarge intestine, but on account of the smaI1 specimen a correct diagnosis cannot be made. ” (Dr. Gaspar.) Operative Findings: Through an expIoratory incision of the femora1 region a waIIed-off mass containing geIatinous materia1 was found and opened. The tumor cavity extencled through the femora1 ring and into the peritonea1 cavity. The wound was cIosed with one gauze drain. Discussion: FemoraI hernia, Iipoma in the femoral cana and gastrointestinal malignancy with partia1 intestinal obstruction were considered. bye especiaIIy advised operation because of the cIinica1 symptoms of partia1 intestina1 obstruction and the preoperative diagnosis was “cystic maIignant tumor” in the femora1 region, possibIy in the gastrointestina1 tract. Pott’s disease with a coId abscess (psoas abscess) was ruIed out by spina x-rays. Intestina obstruction was not demonstrated in a preoperative flat fiIm of the abdomen. Progress Notes: The patient is coughing considerably since operation; expectorating puruIent sputum; getting weaker. He died ApriI 26, ‘933. Autopsy Report: “Abdomen : The omentum was roIIed up and matted together with a geIatinous tumor mass. The intestines were adherent with thin, smaI1, pear1 gray tumors in the serosa. The duodenum was acIherent to the Iiver with a hen’s egg sized tumor simiIar in character to that described above. Surrounding the end of the cecum and apparentIS arising from the base of the appendix which was compIeteIy destroyed was a fist-sized tumor mass. This was thick, white, noduIar mucoid in

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character and was adherent to the abdomina1 waI1 just above Poupart’s Iigament and continuous with a simiIar mass in the right groin. The center of the Iatter contained a Iight brown cheesy center present in copious amounts. The Iiver weighed 1260 gm. and was adherent to the diaphragm which was infiItratec1 with tumor mass simiIar to that described. The Iiver on section was yeIIow and showed a typica nutmeg appearance. The spIeen was adherent to the retroperitonea1 structures and surrounding tissues and was infiItrated with the metastatic tumor. It was somewhat Iarger than norma and on section was flabby. It weighed 210 gm. The kidneys presented a normal apthe capsuIes stripping easiIy. The pearance, right weighed 150 gm., Ieft 170 gm. Adrenals: there was some thickening of the cortex with thinning of the meduIIa. The pancreas was not remarkabIe. It weighed 60 gm. The bIacIder was distended haIfway to the umbiIicus with cIear urine. The waI1 and mucosa were norma in appearance. The prostate was sIightIy Iarger than normal, but was of normal consistency. Posterior to the rectum and infiItrating the waI1 and mucosa was a flattened hen’s egg sizec1 tumor mass extending to within 5 cm. of the Iomer Iimit of the rectum. The Iumen was somewhat constricted, bareIy aIlowing the passage of the index finger. On section, the tumor presented the appearance similar to that described for the other tumors.” “Anatomical Findings: (I) About two-fistsized primary mucoid adenocarcinoma of the appendicea1 region very probabIy originating from the appendix. (2) InfiItration of the psoas muscIe and the right inguinal region. (3) Generalized carcinomatosis: abundant cancerous noduIes of the peritoneum, serosa of the intestines, omentum and pIeura1 surfaces. (4) Moderate chronic fibrous endocarditis of the tricuspid vaIve and moderate arterioscIerosis throughout. (5) Brown atrophy of the heart and moderate anemia. (6) PartiaI intestina1 obstruction of the Iowest ileum due to the tumor mass in the vicinitv and moderate dilatation of’ the smaI1 intestines. (7) Moderate emphysema and edema of the lungs. Generalized osteoporosis.” “Cause of Death: (I) Large primary mucoid adenocarcinoma of appendicea1 region. (2) Generalized carcinomatosis and anemia.” “Tissue Report No. 576. AppendiceaI area: primary mucoid carcinoma. Widespread metastasis. Sections taken from heart, Iungs, liver,

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spIeen, kidney, pancreas, adrena1, prostate and the findings correspond with those indicated in anatomica diagnosis.” (Gaspar.) SUMMARY I. Two rare cases of primary carcinoma of the appendix are reported. 2. The essentia1 characteristics of carcinoid tumor are given to enabIe the surgeon to more readiIy understand the differences between these two easiIy confused tumors. REFERENCES I. DARNALL, W. E.,

and KILDUFFE, R. A. Carcinoma of the appendix in a gir1 of twenty. AM. J. SURG., n.s. 17: 63, 1932. 2. ELTING, A. W. Primary carcinoma of the vermiform appendix, with a report of three cases. Ann. Surg., 37: 549-574, 1903. 3. EWING, JAMES. Personal communication.

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Diseases. Ed. 2, PhiIa., 4. EWING, J. NeopIastic Saunders, 1922, pp. 708-709. 5. GASPAR, ISTVAN. Persona1 communication. “carcinoid” tumor of 6. GASPAR, I. Metastisizing jejunum. Am. J. Patb., 6: 515-524, 1930. 7. GOSSET. A.. and MASSON. P. Tumeurs endocrines de I’appehdice. Presse n&d., 22: 237-240, 1914. zu den Beziehungen 8. HORNUNG, R. Beitrage zwischen Appendix und Genitale; Karzinom, Pseudomyxom. Zentralbl. f. Gyniik., 52: 16301634, 1928. 9. LBORAT, M. L. Les tumeurs solides de I’appendice. Rtv. de cbir., 63: 296-305, 1925. IO. MASSON, P. Carcinoids (argentaffln-ceI1 tumors) and nerve hyperplasia of appendicuIar mucosa. Am. J. Patb., 4: 181-212, 1928. II. MICHOT, A. Th&se de Paris, Legrand, 1927. 12. NORMENT, W. Tumors of the appendix. Surg. Gynec. Oh., 55: 590-596, 1932. ‘3. ROLLESTON and JONES. Trans. Med. ti Cbir. Sot.. 89: 125, 1906. 14. STOUT, A. P. Human Cancer. PhiIa., Lea & Febiger, 1932, PP. 230-233. 15. THIBAUDEAU. A. A.. and BURKE, E. M. CriticaI survey of epitheiia1 tumors of appendix. J. Cancer Research, 13: 73-86, 1929.