Gastrointestinal Hemorrhage-An
Unusual
Manifestation of Neurofibromatosis
RICHARD B. DEVEREUX, LAWRENCE
M.D.’
W. KOBLENZ, M.D.
PAUL CIPRIANO, M.D. GEORGE F. GRAY, M.D. New York, New York
Hemorrhage from intestinal neurofibromas or leiomyomas is an infrequent but oflen life-threatening complication of neurofibromatosis. Despite typical cutaneous findings, the bleeding tumor usually cannot be demonstrated because of its inaccessible location in the jejunum or ileum. In the present case, superior mesenteric arteriography successfully demonstrated hemorrhage from a jejunal leiomyoma. Review of the literature demonstrates the difficulty of establishing the correct diagnosis by other means. Arteriography should be the contrast procedure of first choice in the patient with neurofibromatosis and gastrointestinal bleeding. Neurofibromatosis, or Von Recklinghausen’s disease, is a relatively common inherited systemic disorder defined clinically by the coexistence of multiple cafe au lait spots with subcutaneous neurofibromas [ 11. Although the pathogenesis of these peculiar lesions remains obscure, their pattern of inheritance has been established as an autosomal dominant with variable expression [2]. Most commonly, patients with neurofibromatosis present with a varied combination of cosmetic complaints, orthopedic deformities and central nervous system abnormalities [3]. Neurofibromas and related tumors may also arise from neural tissue in the gastrointestinal tract in from 2 to 10 per cent of patients [3,4]. Gastrointestinal hemorrhage, often life-threatening, due to ulceration of intestinal neurofibromas and leiomyomas is not an infrequent occurrence in this group of patients. In 4 of 29 patients with neurofibromatosis seen at the Ohio State University Hospital, gastrointestinal bleeding developed [5]. However, because of the relative rarity of these tumors as a cause of gastrointestinal bleeding, the diagnosis is often not suspected. Only at operation is the cause of bleeding appreciated. No reliable method of preoperative diagnosis has been available. This is the first report of a typical patient with Von Recklinghausen’s disease and severe gastrointestinal hemorrhage in whom the bleeding tumor was demonstrated arteriographically before surgery.
From the Departments of Medicine, Radiology and Pathology, New York Hospital-Cornell Medical Center, New York, New York. Requests for reprints should be addressed to Dr. Richard B. Devereux. Manuscript accepted March 12, 1974. * Present address: Section of Cardiology, Department of Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.
CASE REPORT A 29 year old Puerto Rican man (J.A.) presented with a 4 day history of melena, progressive weakness and vomiting of bilious gastric contents. He had had multiple subcutaneous nodules and cafe au lait spots all his life. His mother and younger brother had similar lesions, proved on biopsy to be neurofibromas. For 10 years prior to his admission, he had had epigastric pain almost daily, unrelieved by antacids, which progressively worsened in the weeks before the onset of bleeding.
January 1975
The American Journal of Medicine
Volume 58
135
GASTROINTESTINAL HEMORRHAGE AND NEUROFIBROMATOSIS-DEVEREUX
ET AL
Figure 1. Superior mesenteric arteriogram. Arterial phase demonstrates a 1.5 by 3 cm mass in the jejunum. Insert, capillary-venous phase with extravasation of dye within the small bowel.
Leiomyoma of the intestine. The intramural Figure 2. nodular mass protrudes into both the serosa and the lumen with stretching of the mucosa in which there was a small erosion.
Physical examination revealed a pale young man with a blood pressure of 1 lo/50 mm Hg and a pulse rate of 1 lO/min. Multiple cafe au lait spots, a large sacral nevus and multiple subcutaneous nodules of varying consistency were noted. The abdomen was diffusely tender, and bowel sounds were active. The stool gave a strongly positive “Hemoccult@” test for blood. On admission the hemoglobin level was 6.7 g/100 ml, the hematocrit value 19 per cent and the uncorrected reticulocyte count 2.2 per cent. The prothrombin time was normal. Nasogastric aspirate revealed no blood. Proctoscopy demonstrated maroon blood coming from above 15 cm. An x-ray series of the upper gastrointestinal tract and small bowel revealed only a small hiatus hernia. Because of continued hemorrhage during the first 2 hospital days, the patient required 7 units of blood. On the 3rd hospital day celiac, superior mesenteric and inferior mesenteric arteriography was performed and disclosed a vascular tumor in the jejunum (Figure 1). At surgery, a single dumbbell-shaped intramural tumor was found which appeared to arise within the muscularis of the jejunum. Approximately half of the lesion protruded into the serosa whereas the other half compressed the lumen with attenuation of the mucosa (Figure 2) in which there was a shallow erosion 3 mm in diameter.
136
56
January
1975
The American
Journal
of Medicine
Volume
GASTFtOlNTESTlNAL HEMORRHAGE AND NEUROFIBROMATOSIS-DEVEREUX
ET AL.
Figure 3. The Ieiomyoma consists of whorls of spindly cells with uniform nuclei without pleomorphism or mitotic figures. The appearance closely resembles that of intestinal smooth muscle. Epithelioti cell granulomas with giant cells, some containing fragments of Schistosoma eggs, were within the tumor. Similar granulomas were also in the intestinal mucosa.
Microscopically, the tumor consisted of whorls of uniform spindly cells with regular elongated nuclei exhibiting no pleomorphism or mitotic figures. The tumor closely resembled smooth muscle. Within the tumor and also in the overlying intestinal mucosa, but not involving the area of erosion, were numerous epithelioid cell granulomas surrounded by lymphocytes and containing multinucleate giant cells. A few of the giant cells contained fragments of eggs of Schistosoma mansoni (Figure 3). A 1 cm soft nodule in the mesentery was composed of the wavy fibrous bands typical of neurofibromatosis. One year after an uneventful recovery, the patient remains free of abdominal complaints, has had no blood in his stool and has a hematocrit value of 44 per cent.
COMMENTS
In the present patient mesenteric arteriography, which documented the expected small bowel tumor, was undertaken early. At surgery, the tumor proved to be a leiomyoma, which has been the case in 20 per cent of the patients described. The arteriographic appearance was typical of a leiomyoma [6,7]. Incidental schistosomal involvement appeared to play no role in the hemorrhage. Comparison with the previously reported experience will emphasize the features that should arouse suspicion of this entity and lead to early diagnosis. Nineteen well documented cases of generalized neurofibromatosis with hemorrhage from gastrointestinal tumors have been reported in the English literature [ 5,8-221. There seems to be no strong age, sex or race predominance. Patients presented most commonly with melena (eight patients, 42 per cent), rectal bleeding (five patients, 26 per cent) or chronic anemia (three patients, 15 per cent). Many recounted
obscure
abdominal
symptoms.
In only four cases
was the correct diagnosis made when bleeding first arose. As a result, 14 of 19 patients (73 per cent) had prior histories of recurrent acute bleeding or chronic anemia. Most vexing was the inability to demonstrate the lesion by extensive routine roentgenologic procedures. By the time of definitive surgery, barium studies revealed intraluminal filling defects in only 6 of 19 patients. Only seven (37 per cent) of these patients were considered to have neurofibromatosis of the bowel preoperatively. The site of bleeding ranged from the stomach to the ileum. Neurofibromas were found in the jejunum (IO patients, 53 per cent), ileum (7 patients, 37 per cent), duodenum (3 patients, 16 per cent) and stomach (2 patients, 11 per cent). One patient had, as did ours, a jejunal leiomyoma [ 181; two patients had leiomyomas of the duodenum [ 12,151. Other patients were found to have a fibromyoma [lo] and a neurofibrosarcoma [20]. Thus, 30 per cent of these patients with generalized neurofibromatosis manifested other types of associated small bowel tumors, of which leiomyomas were the most common. A small intestinal tumor must be highly suspect as the source of bleeding in any patient with neurofibromatosis, gastrointestinal hemorrhage and a negative nasogastric aspirate. Because of the low yield of xray series of the small bowel, even under the best of circumstances, arteriography should be the contrast procedure of first choice. If the bleeding emanates from a neurofibroma or leiomyoma, it will be readily demonstrated, most likely in the jejunum or ileum. Definitive resection should be undertaken in view of the frequency of recurrent life-threatening hemorrhage.
January 1975
The American
Journal
of Medicine
Volume
58
137
GASTROINTESTINALHEMORRHAGEAND NEUROFIBROMATOSIS-DEVEREUX ET AL.
REFERENCES 1. 2.
3. 4.
5. 6.
7.
8.
9.
10. 11.
138
McKusick VA: Mendelian Inheritance in Man, 3rd ed, Baitimore, Johns Hopkins Press, 1971. p 202. Crowe FW, &hall WJ, Neel JV: A Clinical, Pathological and Genetic Study of Multiple Neurofibromatosis. Springfield, Ill., Charles C Thomas, 1956. Das Gupta TK, Brasfield RD: Von Recklinghausen’s disease. Cancer 21: 174, 1971. Preston FW. Walsh WS. Clarke TH: Cutaneous neurofibromatosis (von Recklinghausen’s disease). Clinical manifestations and incidence of sarcoma in sixty-one male patients. Arch Surg 64: 813, 1952. Ghrist TD: Gastrointestinal involvement in neurofibromatosis. Arch Intern Med 112: 357, 1963. Boijsen E: Superior mesenteric arteriography. Angiography, 2nd ed (Abrams HL, ed), Boston, Little, Brown 6 Co., 1971. Boijsen E, Reuter SR: Mesenteric angiography in the evaluation of inflammatory and neoplastic disease of the intestine. Radiology 87: 1028, 1966. Grill J, Kuzma JF: Recklinghausen’s disease with unusual symptoms from intestinal neurofibroma. Arch Pathol 34: 902, 1942. Shaw RC: Von Recklinghausen’s disease of the small intestine associated with skin lesions. Am J Surg 80: 360, 1950. Kleitsch WP, Kehne JH: Gastrointestinal hemorrhage due to neurofibromatosis. JAMA 147: 1434, 195 1. Shaiken J: Tumors of the small bowel. Am Prac 3: 388,
January 1975
The American Journal of Medicine
12. 13.
14. 15. 16. 17. 18.
19. 20.
21.
22.
Volume 58
1952. Campbell RE, Young JM: Leiomyoma of the duodenum. Am J Surg 88: 618. 1954. Gompertz ML, Gourlez RD: Follow-up observations on patients with upper gastrointestinal hemorrhage of undetermined etiology. Gastroenterology 32: 528, 1957. Wilson JS, Anderson AA: Cutaneous and intestinal neurofibromatosis. Am J Surg 100: 761, 1960. Perea VD, Gregory JJ Jr: Neurofibromatosis of the stomach. JAMA 182: 259. 1962. Collins NP: Intestinal hemorrhage in Von Recklinghausen’s disease. Arch Surg 87: 374, 1963. Moffatt WP: Neurofibromatosis with bleeding from an intestinal lesion. West J Surg Obstet Gynecol 72: 246, 1964. Lukash WM. Morgan RI, Sennett CO, Nielson OF: Gastrointestinal neoplasms in Von Recklinghausen’s disease. Arch Surg 92: 905, 1966. Cowie RL: An unusual cause of gastrointestinal bleeding. S Afr Med J 41: 286, 1967. Beaven WE, Donovan DC: Lower gastrointestinal hemorrhage secondary to enteric neurofibromatosis (Recklinghausen’s disease). NY State J Med 70: 2677, 1970. Buntin PT. Fitzgerald JF: Gastrointestinal neurofibromatosis. A rare cause of chronic anemia. Am J Dis Child 119: 521.1970. Lawson FE, Latimer EO: Neurofibromatosis (von Recklinghausen’s disease) and bleeding from the gastrointestinal tract. Int Surg 55: 243, 1971.
Unusual
Manifestation of Neurofibromatosis
RICHARD B. DEVEREUX, LAWRENCE
M.D.’
W. KOBLENZ, M.D.
PAUL CIPRIANO, M.D. GEORGE F. GRAY, M.D. New York, New York
Hemorrhage from intestinal neurofibromas or leiomyomas is an infrequent but oflen life-threatening complication of neurofibromatosis. Despite typical cutaneous findings, the bleeding tumor usually cannot be demonstrated because of its inaccessible location in the jejunum or ileum. In the present case, superior mesenteric arteriography successfully demonstrated hemorrhage from a jejunal leiomyoma. Review of the literature demonstrates the difficulty of establishing the correct diagnosis by other means. Arteriography should be the contrast procedure of first choice in the patient with neurofibromatosis and gastrointestinal bleeding. Neurofibromatosis, or Von Recklinghausen’s disease, is a relatively common inherited systemic disorder defined clinically by the coexistence of multiple cafe au lait spots with subcutaneous neurofibromas [ 11. Although the pathogenesis of these peculiar lesions remains obscure, their pattern of inheritance has been established as an autosomal dominant with variable expression [2]. Most commonly, patients with neurofibromatosis present with a varied combination of cosmetic complaints, orthopedic deformities and central nervous system abnormalities [3]. Neurofibromas and related tumors may also arise from neural tissue in the gastrointestinal tract in from 2 to 10 per cent of patients [3,4]. Gastrointestinal hemorrhage, often life-threatening, due to ulceration of intestinal neurofibromas and leiomyomas is not an infrequent occurrence in this group of patients. In 4 of 29 patients with neurofibromatosis seen at the Ohio State University Hospital, gastrointestinal bleeding developed [5]. However, because of the relative rarity of these tumors as a cause of gastrointestinal bleeding, the diagnosis is often not suspected. Only at operation is the cause of bleeding appreciated. No reliable method of preoperative diagnosis has been available. This is the first report of a typical patient with Von Recklinghausen’s disease and severe gastrointestinal hemorrhage in whom the bleeding tumor was demonstrated arteriographically before surgery.
From the Departments of Medicine, Radiology and Pathology, New York Hospital-Cornell Medical Center, New York, New York. Requests for reprints should be addressed to Dr. Richard B. Devereux. Manuscript accepted March 12, 1974. * Present address: Section of Cardiology, Department of Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.
CASE REPORT A 29 year old Puerto Rican man (J.A.) presented with a 4 day history of melena, progressive weakness and vomiting of bilious gastric contents. He had had multiple subcutaneous nodules and cafe au lait spots all his life. His mother and younger brother had similar lesions, proved on biopsy to be neurofibromas. For 10 years prior to his admission, he had had epigastric pain almost daily, unrelieved by antacids, which progressively worsened in the weeks before the onset of bleeding.
January 1975
The American Journal of Medicine
Volume 58
135
GASTROINTESTINAL HEMORRHAGE AND NEUROFIBROMATOSIS-DEVEREUX
ET AL
Figure 1. Superior mesenteric arteriogram. Arterial phase demonstrates a 1.5 by 3 cm mass in the jejunum. Insert, capillary-venous phase with extravasation of dye within the small bowel.
Leiomyoma of the intestine. The intramural Figure 2. nodular mass protrudes into both the serosa and the lumen with stretching of the mucosa in which there was a small erosion.
Physical examination revealed a pale young man with a blood pressure of 1 lo/50 mm Hg and a pulse rate of 1 lO/min. Multiple cafe au lait spots, a large sacral nevus and multiple subcutaneous nodules of varying consistency were noted. The abdomen was diffusely tender, and bowel sounds were active. The stool gave a strongly positive “Hemoccult@” test for blood. On admission the hemoglobin level was 6.7 g/100 ml, the hematocrit value 19 per cent and the uncorrected reticulocyte count 2.2 per cent. The prothrombin time was normal. Nasogastric aspirate revealed no blood. Proctoscopy demonstrated maroon blood coming from above 15 cm. An x-ray series of the upper gastrointestinal tract and small bowel revealed only a small hiatus hernia. Because of continued hemorrhage during the first 2 hospital days, the patient required 7 units of blood. On the 3rd hospital day celiac, superior mesenteric and inferior mesenteric arteriography was performed and disclosed a vascular tumor in the jejunum (Figure 1). At surgery, a single dumbbell-shaped intramural tumor was found which appeared to arise within the muscularis of the jejunum. Approximately half of the lesion protruded into the serosa whereas the other half compressed the lumen with attenuation of the mucosa (Figure 2) in which there was a shallow erosion 3 mm in diameter.
136
56
January
1975
The American
Journal
of Medicine
Volume
GASTFtOlNTESTlNAL HEMORRHAGE AND NEUROFIBROMATOSIS-DEVEREUX
ET AL.
Figure 3. The Ieiomyoma consists of whorls of spindly cells with uniform nuclei without pleomorphism or mitotic figures. The appearance closely resembles that of intestinal smooth muscle. Epithelioti cell granulomas with giant cells, some containing fragments of Schistosoma eggs, were within the tumor. Similar granulomas were also in the intestinal mucosa.
Microscopically, the tumor consisted of whorls of uniform spindly cells with regular elongated nuclei exhibiting no pleomorphism or mitotic figures. The tumor closely resembled smooth muscle. Within the tumor and also in the overlying intestinal mucosa, but not involving the area of erosion, were numerous epithelioid cell granulomas surrounded by lymphocytes and containing multinucleate giant cells. A few of the giant cells contained fragments of eggs of Schistosoma mansoni (Figure 3). A 1 cm soft nodule in the mesentery was composed of the wavy fibrous bands typical of neurofibromatosis. One year after an uneventful recovery, the patient remains free of abdominal complaints, has had no blood in his stool and has a hematocrit value of 44 per cent.
COMMENTS
In the present patient mesenteric arteriography, which documented the expected small bowel tumor, was undertaken early. At surgery, the tumor proved to be a leiomyoma, which has been the case in 20 per cent of the patients described. The arteriographic appearance was typical of a leiomyoma [6,7]. Incidental schistosomal involvement appeared to play no role in the hemorrhage. Comparison with the previously reported experience will emphasize the features that should arouse suspicion of this entity and lead to early diagnosis. Nineteen well documented cases of generalized neurofibromatosis with hemorrhage from gastrointestinal tumors have been reported in the English literature [ 5,8-221. There seems to be no strong age, sex or race predominance. Patients presented most commonly with melena (eight patients, 42 per cent), rectal bleeding (five patients, 26 per cent) or chronic anemia (three patients, 15 per cent). Many recounted
obscure
abdominal
symptoms.
In only four cases
was the correct diagnosis made when bleeding first arose. As a result, 14 of 19 patients (73 per cent) had prior histories of recurrent acute bleeding or chronic anemia. Most vexing was the inability to demonstrate the lesion by extensive routine roentgenologic procedures. By the time of definitive surgery, barium studies revealed intraluminal filling defects in only 6 of 19 patients. Only seven (37 per cent) of these patients were considered to have neurofibromatosis of the bowel preoperatively. The site of bleeding ranged from the stomach to the ileum. Neurofibromas were found in the jejunum (IO patients, 53 per cent), ileum (7 patients, 37 per cent), duodenum (3 patients, 16 per cent) and stomach (2 patients, 11 per cent). One patient had, as did ours, a jejunal leiomyoma [ 181; two patients had leiomyomas of the duodenum [ 12,151. Other patients were found to have a fibromyoma [lo] and a neurofibrosarcoma [20]. Thus, 30 per cent of these patients with generalized neurofibromatosis manifested other types of associated small bowel tumors, of which leiomyomas were the most common. A small intestinal tumor must be highly suspect as the source of bleeding in any patient with neurofibromatosis, gastrointestinal hemorrhage and a negative nasogastric aspirate. Because of the low yield of xray series of the small bowel, even under the best of circumstances, arteriography should be the contrast procedure of first choice. If the bleeding emanates from a neurofibroma or leiomyoma, it will be readily demonstrated, most likely in the jejunum or ileum. Definitive resection should be undertaken in view of the frequency of recurrent life-threatening hemorrhage.
January 1975
The American
Journal
of Medicine
Volume
58
137
GASTROINTESTINALHEMORRHAGEAND NEUROFIBROMATOSIS-DEVEREUX ET AL.
REFERENCES 1. 2.
3. 4.
5. 6.
7.
8.
9.
10. 11.
138
McKusick VA: Mendelian Inheritance in Man, 3rd ed, Baitimore, Johns Hopkins Press, 1971. p 202. Crowe FW, &hall WJ, Neel JV: A Clinical, Pathological and Genetic Study of Multiple Neurofibromatosis. Springfield, Ill., Charles C Thomas, 1956. Das Gupta TK, Brasfield RD: Von Recklinghausen’s disease. Cancer 21: 174, 1971. Preston FW. Walsh WS. Clarke TH: Cutaneous neurofibromatosis (von Recklinghausen’s disease). Clinical manifestations and incidence of sarcoma in sixty-one male patients. Arch Surg 64: 813, 1952. Ghrist TD: Gastrointestinal involvement in neurofibromatosis. Arch Intern Med 112: 357, 1963. Boijsen E: Superior mesenteric arteriography. Angiography, 2nd ed (Abrams HL, ed), Boston, Little, Brown 6 Co., 1971. Boijsen E, Reuter SR: Mesenteric angiography in the evaluation of inflammatory and neoplastic disease of the intestine. Radiology 87: 1028, 1966. Grill J, Kuzma JF: Recklinghausen’s disease with unusual symptoms from intestinal neurofibroma. Arch Pathol 34: 902, 1942. Shaw RC: Von Recklinghausen’s disease of the small intestine associated with skin lesions. Am J Surg 80: 360, 1950. Kleitsch WP, Kehne JH: Gastrointestinal hemorrhage due to neurofibromatosis. JAMA 147: 1434, 195 1. Shaiken J: Tumors of the small bowel. Am Prac 3: 388,
January 1975
The American Journal of Medicine
12. 13.
14. 15. 16. 17. 18.
19. 20.
21.
22.
Volume 58
1952. Campbell RE, Young JM: Leiomyoma of the duodenum. Am J Surg 88: 618. 1954. Gompertz ML, Gourlez RD: Follow-up observations on patients with upper gastrointestinal hemorrhage of undetermined etiology. Gastroenterology 32: 528, 1957. Wilson JS, Anderson AA: Cutaneous and intestinal neurofibromatosis. Am J Surg 100: 761, 1960. Perea VD, Gregory JJ Jr: Neurofibromatosis of the stomach. JAMA 182: 259. 1962. Collins NP: Intestinal hemorrhage in Von Recklinghausen’s disease. Arch Surg 87: 374, 1963. Moffatt WP: Neurofibromatosis with bleeding from an intestinal lesion. West J Surg Obstet Gynecol 72: 246, 1964. Lukash WM. Morgan RI, Sennett CO, Nielson OF: Gastrointestinal neoplasms in Von Recklinghausen’s disease. Arch Surg 92: 905, 1966. Cowie RL: An unusual cause of gastrointestinal bleeding. S Afr Med J 41: 286, 1967. Beaven WE, Donovan DC: Lower gastrointestinal hemorrhage secondary to enteric neurofibromatosis (Recklinghausen’s disease). NY State J Med 70: 2677, 1970. Buntin PT. Fitzgerald JF: Gastrointestinal neurofibromatosis. A rare cause of chronic anemia. Am J Dis Child 119: 521.1970. Lawson FE, Latimer EO: Neurofibromatosis (von Recklinghausen’s disease) and bleeding from the gastrointestinal tract. Int Surg 55: 243, 1971.
