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Von Recklinghausen s Disease Associated withGastrointestinal Carcinoid Tumors

CPT DOUGLAS R . HOUGH, MC, USAR, MAJ ALFRED CHAN, MC, USAR,AND MAJ HOWARD DAVIDSON, MC, USA

The occurrence of both gastrointestinal carcinoid and von Recklinghausens dise ase in the sa me patientis uncommon. There seems to be a predilection for ampullary carcinoids in these patients. This articlereports the sixth case, including a review of the literature and a brief discussion of the implicationsof this finding. A carcinoid tumor should be suspec ted in any patient with von Recklinghausens d isea sepresenting with gastrointestinal bleeding, obstruction, abdominal pain, and particularly obstructivejaundice.

Cancer 51:2206-2208, 1983.

A R C I N O I D tumors of the gastrointestinal tract areC usually asymptomatic, but may be discovered asa result of gastrointestinal hemorrhage, obstruction, ab-dominal pain or symptoms of the carcinoid syndrome.A rare presentation of a carcinoid may be with obstruc-tive jaundice as a result of its para-ampullaryThe occurrence of an intestinal carcinoid tumor in apatient with von Recklinghausens disease (VRD) wasfirst described by Lee and Garber in 1970.4Four patientssubsequently have been reported with VRD and intes-tinal c a r c i n o i d ~ . ~ ~ ~ ~ ~ ~ ~his paper reports a case of am-pulla of Vater carcinoid associated with VRD.

Case ReportA 59-year-old man with VRD was admitted for evaluation

of jaundice of three weeks duration, accompanied by crampyintermittent mid-epigastric abdominal pain and frequentacholic stools. He had also noted dark urine, pruritis, and a7 kilogram weight loss over a two-month period. Family his-tory was significant for his fathers death at age 52 from stom-ach cancer.

Physical examination was remarkable for a jaundiced manwith multiple pedunculated neurofibromas, caE-au-lait spotsand elephant skin changes. His stool was hemoccult positive.Laboratory studies revealed total bilirubin was 342 pmol/L,direct bilirubin was 284 pmol/l,, SGOT was 102 U/L, LDHwas 250 U/L, and alkaline phosphatase was 1200 U/L.

From the Department of Medicine, Madigan Army Medical Center.Tacoma, Washington.Address for reprints: Cpt Douglas R. Hough, MD, MC, USAR,% Rheumatology and Clinical Immunology Division, Walter ReedArmy Medical Center, Washington, DC 20012.The views expressed herein are those of the authors and do notnecessarily reflect the views of the US Army or the Department ofDefense.Accepted for publication April 2, 1982.

An ultrasound of the hepatobiliary system demonstrateddilated intrahepatic ducts with a normal gallbladder. A liver-spleen scan revealed a homogeneously enlarged liver. Percu-taneous transhepatic cholangiography located an obstructivelesion at the level of the ampulla of Vater. A t exploratorylaparotomy, a lobulated, dense, homogeneous, yellow-whitetumor mass measuring 3 X 2 X 2 cm was identified at the am-pulla. A pancreaticoduodenectomy was performed. Micro-scopically, the tumor was characteristic for a malignant car-cinoid. The argentaffin stain was negative, but an argyrophilstain revealed many silver-positive. round granules within thecytoplasm of a majority of the neoplastic cells. There was focalinvasion of the head of the pancreas, common bile duct, majorpancreatic duct and metastasis to three ofeight regional lymphnodes. In the postoperative period there was a normalizationof the serum bilirubin and other liver enzyme abnormalities.

Seven months later, he was hospitalized for right upperquadrant abdominal pain. Nausea, vomiting, fatigue andweight loss were also present. A total bilirubin level was 6 .6pmol/L. Liver-spleen scan showed mildly irregular uptake,and a liver biopsy demonstrated metastatic carcinoid tumor.

The patient has survived after initial diagnosis. He has un-dergone several courses of combination of chemotherapy, butremains symptomatic from his metastatic disease.

DiscussionHistorical Aspects

Multiple neurofibromatosis was first described inI882 by von Re~klinghausen.~he first case ofcarcinoidtumor is credited to Merling in 1808.7,8he term car-cinoid was coined by Oberndorfer in 1907, and wasused to stress the relatively benign nature of this tu-mor.*7-9t was in 1914, that Gossert and Masson de-termined that the carcinoid cells arise from the entero-chromaffin cells or Kulchitsky cells of the intestinal ep-

0008-543X/83/06 512206 $0.95 0 American Cancer Society2206

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No . 12 VRD: GASTROINTESTINALA R C I N O I D Hough 2207TABLE . Summary of Cases

Year/Case Age/Sex Location of carcinoid Manifestations of VR D Treatment Outcome Author Ref72/M

34/F

78/F

30/M53/F5 9 f M

Duodenal

Two duodenal tumors andone malignant ampul-lary tumorIleum

Benign ampullary tumorMalignant ampullary tum orMalignant ampullary tumor

Cutaneous and visceralneurofibromatosis;pheochromocytomasCutaneous and intestinalneurofi bromatosisCutaneous and intestinalneurofibromatosis; caE-au -lait spots; kyphoscoliosisCutaneous neurofibromatosis;caE-au-lait spotsCutaneous neurofibromatosis;caE-au-lait spotsCutaneous neurofibromatosis;caE-au-lait spots

None

Pancreatico-duodenectomyIleal resection

Biliary divers ionBiliary diversionPancreatico-duodenectomy

Died Lee 19704

Alive and NE D Weichert I97 I at 18 monthsUnknown Arnesji) 19733

Recovery Barber 1976Alive and NE D Johnson 19816Died after 18 Presentmonth s from casemetastaticdisease

at 18 months

NED: No Evidence of Disease.ithelium, lining the crypts of Lieberkuhn.,7-9 n 1942,it was Lichtenstein who proposed the common neu-roectodermal embryogenesis theory as the etiology ofthe basic lesions of VRD.4 The endocrine nature of car-cinoid tumors was established in 1953, when Lembeckextracted serotonin from carcinoid Pearse,in 1969, suggested a unifying concept that the amineprecursor uptake and decarboxylation cells and the neu-roectodermal cells could have a common origin fromthe neural crest. I t has been proposed that both car-cinoid tumors and VRD may be manifestations of anoverlap syndrome with a common neuroendocrineorigin. oConditions Reported in Association with VRD

VRD, in addition to the usual cutaneous neurofibro-mas, can include gastrointestinal neurofibromas. Thestomach, the small intestines, and the rectum are themore commonly reported sites4 Neurofibromas of thebladder are also seen; other visceral sites are much less~ o m m o n . ~esides neurofibromas, other neural tumorsassociated with VRD include meningiomas, acousticneuromas, gliomas, and malignant s~hwannomas.*-~~~Neuroendocrine tumors reported in VRD patients in-clude solitary pheochromocytomas, Sipples syndrome,and carcinoids.2-6Cond itions Reported in Association withGastrointestinal Carcinoid

In several large series of patients with gastrointestinalcarcinoids, no association with VRD has been noted,

implying the case reports below are indeed rareevents.6-8*1here has been observed an increased fre-quency of second malignancies in patients with carci-noids4.9. I . I 2 and the small intestinal carcinoid is asso-ciated with the highest concurrent tumor rate. Thefrequency of second primary neoplasms in this popu-lation has been estimated to be 29% by Moertel et aL9and 32% by Kuiper et a1.I2 in independent studies.Gliomas and meningiomas are among the nervous sys-tem tumors presenting as second primary malignanciesin patients with gastrointestinal car~inoids .. ~Coexistence of VR D with Intestinal CarcinoidA summary of the case reports of VRD coexistent

with intestinal carcinoid, found in a review of the lit-erature, appears in Table 1 . The patient population wasequal in sexual distribution, with a mean age of 54.3years. Five of the six patients had carcinoids either inthe duodenal or ampullary regions, and all patients hadthe carcinoid located within the small bowel. None ofthe six patients had the carcinoid syndrome. There werethree patients with intestinal neurofibromatosis as amanifestation of their VRD. The most interesting ofthese was the patient reported b y Arnesjo et al.,3 whohad multiple intestinal neurofibromas, in one of whichactual transition into carcinoid was observed. That par-ticular observation and all six patients with coexistentVRD and intestinal carcinoid, lend support to the hy-pothesis that both disorders arise from a common(neural crest) cell line. The common ancestry of VRDand carcinoid is also supported by the association ofboth conditions with gliomas and meningiomas.

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CANCERune 15 1983 VOl. 51Significance of the Arnprillary Location

Even more remarkable than the association of VRDwith intestinal carcinoid is the fact that in four of thesesix cases, the carcinoid was located at the ampulla ofVater. Ampulla of Vater carcinoids are rare with only25 cases reported in the literature, and accounting foronly 0.2 to 0.3% of all gastrointestinal carcinoid tu-mors.'.* Because of this rarity. the relative predominanceof ampullary carcinoids among these patients with VRDmust be more than pure coincidence.6 Certainly onecould postulate that these cases came to diagnosis be-cause this location caused the patients to present withobstructive jaundice, while other carcinoids in patientswith VRD may go undiagnosed. Alternatively, a com-mon embryologicor microenvironmental reason for theappearance of carcinoid in this rare site (ampulla ofVater) in patients with VRD could be proposed.

ConclusionsIntestinal neurofibromatosis and carcinoids are with-

out symptoms in a majority of cases, but both may pre-sent with intestinal obstruction, chronic bleeding or ab-dominal pain. We suggest that a carcinoid tumor beconsidered in the differential diagnosis of any patientwith VRD and the previously mentioned gastrointes-

tinal symptoms and particularly when unexplainedjaundice is present.

REFERENCESI . Martin RG. Management of carcinoid tumors. Cancer 1970;2. Barber PV. Carcinoid tumor of the ampulla of Vater associatedwith cutaneous neurofibromatosis. PostgradMed J 1976: 52:5 14-5 17.3. Arnesjo B, ldvall 1, lhse 1, Telenius M, Tylh U. Concomitantoccurrence of neurofibromatosis and carcinoid of the intestine. ScundJ Gustroenterol 1973; 8:637-643.4. Lee HY, Garber PE. Von Recklinghausen's disease associatedwith pheochromocytoma and carcinoid tumor. Ohio Slutc, Mrd J19 70 66:583-586.5. Weichert RF, Roth LM, Krementz ET. Hewitt RL, DrapanasT. Carcinoid-islet cell tumors of the duodenum. Am J Siirg 1971;6. Johnson L, Weaver M. Von Recklinghausen's disease and gas-trointestinal carcinoids. JAMA 198 I: 245:2496.7. Postlethwait RW. Gastrointestinal carcinoid tumors. Pos/grudM e d 1966; 401445 454.8. Sanders RJ. Axtell HK. Carcinoids of the gastrointestinal tract.Sirrg Gynecol 0bstc.t 1964: I 19:369-380.9. Moertel CG, Sauer WG, Dockerty MB, Baggenstoss AH. Lifehistory of the carcinoid tumor of the small intestine. Cuncer 1961:14:90 1-9 1 2.10. Hansen OP, Hansen M, Hansen HH, Rose B. Multiple endo-crine adenomatosis of mixed type. Acta Med Scund 1976; 200:327-331.I I . Godwin JD. Carcinoid tumors: An analysis of 2837 cases. Cun-cer 1975; 36560-569 .12 . Kuiper DH, Gracie WA, Pollard HM. Twenty years of gas-trointestinal carcinoids. Cancer 1 97 0 25: 1424-1430.

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