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Diarrhea and abdominal pain in a 64-year-old man
CLlNlCOPATHOLOGlC
CONFERENCE
Diarrhea and Abdominal Pain in a 64-Year-Old Man
Stenographic reports of weekly clinicopatholqic conferences held in Barnes and Wohl Hospitals are published in each issue of the Journal Members of the Departments of Internal Medicine, Radiology, and Pathology of the Washington University School of Medicine participate jointly in these conferences. Kenneth M. Ludmerer, M.D., and John M. Kissane, M.D., are the editors of this feature. A 64-year-old white man was admitted to Barnes Hospital on June 18, 1985, for abdominal distension, diarrhea, edema, and weight gain. In August 1983, he presented to an outside hospital with right-sided abdominal pain. The history at that time included the recent repair of a right inguinal hernia, cholecystectomy, and appendectomy. Hospital studies consisted of an upper gastrointestinal series, which showed duodenal diverticuli; a barium enema, which revealed colonic diverticulosis; intravenous pyelography, which demonstrated a left renal calculus and mild prostatic enlargement; and abdominal and renal sonography, which showed two small renal cysts. At discharge, the cause of his abdominal pain was still uncertain. The pain persisted, prompting a second radiographic evaluation, upper endoscopy, and colonoscopy on an outpatient basis; no additional findings were discovered. Anemia was noted, and oral iron therapy was initiated. In April 1985, he presented again with intermittent right lower quadrant abdominal pain, watery diarrhea, malaise, anorexia, and weight loss of 15 pounds over eight months. Physical examination revealed a right periumbilical, firm, 4 by 3 cm abdominal mass, and guaiac-positive stool. The white blood cell count was 8,200/mm3 with a normal differential; the hemoglobin level was 11.7 g/dl; and the reticulocyte count was 1.2 percent. Computed tomography of the abdomen revealed a 3 by 3 cm mass in the right lobe of the liver and retroperitoneal lymph nodes. Computed tomographic-directed liver biopsy showed a region of necrosis and periportal fibrosis. Upper endoscopy demonstrated hypertrophic gastritis; colonoscopy showed only uncomplicated diverticulosis. Bone marrow biopsy revealed mild erythroid hyperplasia, abundant iron stores, and no evidence of malignancy or an infectious process. A second computed tomographic-directed liver biopsy again showed a region of necrotic tissue. Microscopic hematuria was noted, but results of cystoscopy and retrograde pyelography were unremarkable. At presentation to Barnes Hospital, the patient complained of a worsening of his diarrhea over the previous two weeks. He was having four or five sometimes explosive bowel movements daily, and his stool was poorly formed and watery. Physical examination revealed normal vital signs, decreased breath sounds at the left lung base, a grade II/VI systolic
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scanning demonstrated an increase in ascites from April 1985, and also confirmed the presence of a 3 by 3 cm mass in the liver, which showed enhancement after injection of contrast medium. Several other 1 to 1.5 cm nodules were also visualized. Increased soft tissue was seen adjacent to the left aspect of the lumbar spine and in the periaottic region, and vascular congestion of the small bowel mesentery was observed. An upper gastrointestinal series with small bowel examination demonstrated multiple nodular densities in the duodenum and jejunum. Results of serum and urine protein electrophoreses were unremarkable. A procedure was performed on June 25, 1985. CLINICAL DISCUSSION
Figure I. Pressed-out nodules (arrows) .
view of jejunum
shows
Dr. Lewis Chase: The major findings that need to be explained in this case are watery diarrhea with abdominal pain, multiple nodular densities in the small intestine, liver masses with contrast enhancement, chylous ascites, a left pleural effusion, and thickening of the mesentery. Additional pertinent features include a prolonged course, anemia, hemoglobin-positive stools, malaise, anorexia, weight loss, a systolic murmur heard best at the right sternal border, and hematuria. I would like to begin by considering the causes of multiple nodular densities in the small intestine. Dr. Levitt will describe the small bowel radiographic finding from this patient. Dr. Robert Levitt: An upper gastrointestinal series and small bowel examination revealed nodules in the duodenum and proximal jejunum (Figure 1). Differential diagnosis includes Whipple’s disease, amyloidosis, and neoplasm, such as leiomyoma, neurofibroma, adenoma, lymphoma, and carcinoid. Dr. Chase: Let us consider the possible causes of nodules in the small intestine. The multiple polyposis syndromes result in filling defects on radiography, but they do not involve the liver and they do not cause diarrhea. Hemangiomas can involve the intestine and the liver. They are vascular lesions and therefore enhance with contrast medium. They can bleed, but they generally do not cause diarrhea or constitutional symptoms. Leiomyomas and leiomyosarcomas are common tumors of the small bowel that can be multicentric and can extend into the mesentery. They can be associated with pain and bleeding but not with diarrhea. Additional causes include neurofibromas, parasites, food particles, foreign bodies, pills, gallstones, blood clots, and varices. There is no evidence that this patient had any of the neurofibromatosis syndromes. The patient had no abnormalities on stool examination for parasites, so it would certainly be a “fluke” if he had parasites in the bowel. No evidence of retained food particles, seeds, foreign bodies, or retained pills was present in the bowel. The nodules did not have the appearance of gallstones or retained blood clots, and there was no history to suggest portal hyperten-
multiple
heart murmur at the upper right sternal border, pedal edema, and a distended, protuberant abdomen containing an irregular 4 by 4 cm mass in the right upper quadrant. No hepatosplenomegaly was present, but there was a suggestion of ascites. Admission laboratory data were as follows: white blood cell count 6,000/~1, hemoglobin 10.9 g/dl, mean corpuscular volume 85 pm3, sodium 139 mmol/liter, potassium 3.5 mmol/liter, chloride 110 mmol/liter, total carbon dioxide 22.7 mmol/liter, creatinine 0.9 mg/dl, serum urea nitrogen 9 mg/dl, glucose 82 mg/dl, total protein 6.0 g/dl, albumin 3.3 g/dl, calcium 8.7 mg/dl, cholesterol 136 mg/dl, bilirubin 0.5 mg/dl, alkaline phosphatase 90 units/liter, aspartate transaminase 19 units/liter, lactate dehydrogenase 149 units/liter, and prothrombin time 12.8 seconds. Urinalysis showed trace albuminuria and 16 red blood cells and one white blood cell per highpower field. Chest and abdominal radiography demonstrated blunting of the left costophrenic angle and a 1 cm calcified stone in the left kidney. Pericentesis was performed; 500 ml of cream-colored fluid was obtained. Fluid analysis demonstrated the following values: 4,150 total cells, 1,250 nucleated cells, pH 7.42, protein 1.9 g/dl, glucose 112 mg/dl, lactic dehydrogenase 52 units/liter, amylase 32 units/liter, cholesterol 33 mg/dl, and triglycerides 489 mg/dl. No chylomicrons were observed, and results of bacterial cultures and cytologic studies were negative. A subsequent fluid leak was appreciated. Stool examination and culture revealed no enteric pathogens. Abdominal computed tomographic
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sion and varices. Disorders that cannot readily be excluded are metastases and lymphomas. The most common carcinomas metastatic to the small bowel are melanoma, breast, and lung. No evidence for a breast tumor was observed in this male patient, and chest radiography did not suggest carcinoma of the lung. Melanomas can be subtle, but there was no evidence for this either. Another tumor to consider is an islet cell carcinoma of the pancreas. These tumors spread throughout the abdomen and are associated with unique systemic manifestations. There are four major cell types in the islet, each of which produces a specific humoral agent. These hormones are insulin, glucagon, somatostatin, and pancreatic polypeptide. Each of these four cell types can become neoplastic, can metastasize, and can hypersecrete its unique humoral agent. It should also be recognized that islet cells are part of the so-called APUD system. These APUD cells are derived from neuroectoderm and have the capacity for amine precursor uptake and decarboxylation (APUD). An example would be decarboxylation of 5hydroxytryptamine to serotonin. When these cells become neoplastic, they dedifferentiate and have the capacity to secrete not only the hormone that the original benign cell was capable of producing but also a variety of other hormones, including but not limited to gastrin, vasointestinal peptide, calcitonin, neurotensin, corticotropin, and serotonin. Most but not all of these secretory products have been associated with a particular syndrome. There is no suggestion that this patient was ever hypoglycemic and had an insulinproducing tumor. Glucagonomas are associated with a characteristic skin rash similar to that seen in toxic epidermal necrolysis. It is called necrolytic migratory erythema. These patients can be mildly diabetic because of the increased glucagon secretion. They have ill-defined psychiatric disturbances, and they can have watery diarrhea and a proclivity toward venous thromboses. Somatostatin, named because it inhibits growth hormone secretion, is also an inhibitor of both insulin and glucagon. Patients with somatostatinomas present with dyspepsia, glucose intolerance, an increased incidence of gallstones, steatorrhea but not necessarily watery diarrhea, and hypochlorhydria. PPomas, islet cell tumors that secrete pancreatic polypeptide, have been described, but this hormone currently has no known definite function. There have been a few reports of PPomas associated with secretory diarrhea. Gastrinomas produce the Zollinger-Ellison syndrome, major features of which are severe recurrent peptic ulcer disease and secretory diarrhea. VlPomas cause the WDHH syndrome consisting of watery diarrhea, hypokalemia, and hypochlorhydria. Medullary carcinomas of the thyroid secrete calcitonin and are associated with watery diarrhea. Tumors secreting neurotensin have been described, but not in relation to a unique clinical syndrome. One patient had marked esophageal reflux, but it could not
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be determined whether the neurotensin was responsible for that symptom. Even when they have metastasized, not all islet cell tumors produce symptoms. In fact, about 50 percent of these tumors are not associated with characteristic clinical syndromes. What is of interest concerning islet cell tumors in regard to the current case is that they commonly metastasize to the liver, and these metastases are usually quite vascular. Distant metastases, although described, are very rare. The tumors can spread to local nodes and into the peritoneum and result in extensive involvement of the mesentery. Finally, islet cell tumors are frequently characterized by a long survival period. I think it is distinctly possible that this patient had a metastatic pancreatic tumor, but it is less likely in view of the absence of a pancreatic mass and a characteristic clinical syndrome. Although the actual pancreatic tumor can be very small in some cases, and some are associated only with watery diarrhea, I could not find reports of metastatic pancreatic tumors that caused nodules in the small intestine. However, if these tumors metastasized to the mesentery and obstructed the lymphatics, I think it would be possible that they could produce this complex. I would now like to consider one of the other major findings in this case, chylous ascites. The definition of chylous ascites is grossly milky ascitic fluid with increased fat. Increased fat in ascitic fluid can be detected by either extracting the fluid with ether, staining it with Sudan-Ill, detecting fat globules microscopically, or measuring triglyceride levels directly. From the literature, the triglyceride concentration in “normal” ascitic fluid is 37 Ifr 9 mg/dl. The “normal” white blood cell count is usually less than 200/mm3, and the cholesterol concentration is less than 100 mg/dl. In a recent series [l] of 24 patients with chylous ascites, triglyceride values ranged from 218 to 8,100 mg/dl, with a mean of 1,591 mg/dl; white blood cell counts were 232 to 2,560/mm3, with a mean of 1 ,046/mm3; and cholesterol levels were within the normal range. Our patient had a triglyceride concentration of 489 mg/dl and a white blood cell count of 1,250/mm3. These values are clearly consistent with chylous ascites. Furthermore, the fluid was milky and the cholesterol level was not elevated. When the triglyceride concentration is increased in ascitic fluid, verification that this value is greater than the serum triglyceride level should always be carried out. A serum triglyceride determination was not performed on this patient, but there is no reason to believe that he had hyperlipoproteinemia. What are the causes of chylous ascites? In the older literature, the predominant causes were mesenteric adenitis and tuberculosis. In the pediatric literature, the most common diagnosis is congenital obstruction of the lymphatic system. In the “modern” adult literature, which is sparse, the most common diagnosis is malignancy. In the series of 24 adult patients with chylous ascites, 21 had
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malignant disease. Of the 21 cases of malignancy, 13 were iymphomas and eight were metastatic tumors. The sources of the metastases were pancreas, breast, colon, prostate, ovary, and kidney. Did this patient have a lymphoma? He did not have diffuse adenopathy and he had a normal bone marrow biopsy result. His clinical disorder, except for the pleural effusion, was localized to the abdomen. I think the diagnosis that needs to be considered is a primary lymphoma of the small intestine [2]. Lymphoid cells are dispersed throughout the lamina propria at all levels of the small intestine, and lymphoid cells are also present in follicular aggregates in both the mucosa and the submucosa of the intestine. Therefore, lymphoma can originate from any of these cells, and when it does, small intestinal lymphoma can present in a variety of patterns. It can be localized to the area in the bowel in which it arose, and adjacent involvement of the mesenteric nodes may or may not be present. Primary intestinal lymphomas are multifocal in 25 percent of the cases. They involve multiple segments of the small intestine, and the small bowel is radiographitally similar to that in the patient being discussed. Finally, intestinal lymphomas can be diffuse and involve the major portion of the small intestine. A wide variety of symptoms are associated with intestinal lymphomas. They can cause intermittent obstruction with intermittent abdominal pain, or irreversible or at least only surgically reversible obstruction. They can ulcerate and/or perforate and they can be the site of intussusception. If they involve the intestine diffusely, they can cause malabsorption, and the malabsorption in turn can lead to diarrhea. Lymphatic drainage of the bowel and peritoneum is commonly involved, resulting in chylous ascites and a protein-losing enteropathy. Our patient had a minimally diminished serum albumin level and slight peripheral edema, so I do not think he had a protein-losing enteropathy. Finally, lymphomas can spread to cause extensive involvement of mesenteric nodes, and they can produce nodules in the liver. In recent years, several different patterns of small bowel lymphoma have been recognized. I have asked Dr. Fred Regenstein if he would review these patterns of small bowel lymphoma and contrast their clinical and pathologic features. Dr. Fredrick Regenstein: Most primary small intestinal lymphomas are of the non-Hodgkin’s variety. As Dr. Chase has already mentioned, primary small intestinal lymphoma most often involves a single segment of small bowel, usually the ileum. Multifocal or diffuse intestinal involvement occurs in up to 25 percent of cases. Symptoms tend to be nonspecific and usually include abdominal pain, anorexia, nausea, vomiting, weight loss, and less frequently diarrhea or gastrointestinal bleeding. An abdominal mass may be palpable on physical examination. Infrequently, patients present with ascites, as a result of
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invasion and obstruction of the intestinal lymphatics. Peripheral lymphadenopathy, hepatomegaly, and splenomegaly are unusual at the time of initial presentation. Mild anemia is probably the most common laboratory abnormality in patients with intestinal lymphoma, but laboratory tests are rarely helpful in establishing the diagnosis. Barium radiography of the small bowel almost always demonstrates abnormalities in patients with small intestinal lymphoma. The diagnosis should be suspected when radiography reveals thickening of the bowel loops with nodular@ or distortion of the normal mucosal folds, segmental narrowing, or the presence of an intraluminal polypoid lesion. Complications most often arise as a result of either intestinal obstruction, bleeding, or perforation. In certain underdeveloped areas of the world (Middle East, South and Central Africa, South and Central America, Southeast Asia, Mediterranean nations), a peculiar type of lymphoma known as immunoproliferative small intestinal disease or “Mediterranean lymphoma” occurs with some frequency [3,4]. In this disorder, diarrhea, malabsorption, and abdominal pain are usually the presenting symptoms. As a consequence of the malabsorption, patients typically present with cachexia and profound weight loss. In addition, clubbing of fingers and toes, dependent edema, and an abdominal mass may be apparent on physical examination. The peak incidence of this disease is in the second and third decades of life, in contrast to the “Western-type” lymphoma, which primarily occurs in middle-aged persons. lmmunoproliferative small intestinal disease usually involves a long segment of the small bowel, most often the duodenum and jejunum. Histologic study of the involved bowel segments reveals a dense plasma cell or polymorphous lympoid infiltrate in the lamina propria and submucosa with a reduction in the number of crypts and villi and with flattening of the villi. Total villous atrophy may occur in severe cases. Barium radiography of the small bowel typically shows long segments of thickened, nodular folds in the duodenum and jejunum. The diagnosis can be confirmed by obtaining multiple peroral small bowel biopsy specimens. Some cases of immunoproliferative small intestinal disease are associated with the presence of incomplete heavy chains of IgA in serum, urine, or jejunal secretions. Genetic and environmental factors may be involved in the pathogenesis of immunoproliferative Small intestinal disease. In particular, environmental factors prevalent in areas in which this disorder is common include low socioeconomic status, poor hygiene, and a high rate of parasitic infestation. Chronic antigenic stimulation, as a result of intestinal infections, may be involved in the eventual development of lymphoma in these patients. In contrast, no geographic or socioeconomic factors appear to be associated with the “Western-type” intestinal lymphoma. Dr. Chase: Dr. Regenstein, if the patient had a Western-
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multiple. They can be polypoid, annular, or deeply invasive. They metastasize to regional nodes, to other sites along the intestine, and to the liver. The intestinal meta&+ ses produce a nodular pattern, and liver metastases can be highly vascular. As with pancreatic tumors, distant metastases occur, but they are uncommon. A distinguishing feature of carcinoids is the induction Of an intense desmoplastic or fibrotic reaction in the mesentery, which can cause marked distortion of the normal architecture of both the intestine and the mesentery. The clinical features of carcinoids can be divided into three major categories: those related to the localized tumor, those related to the carcinoid syndrome, and those related to fibrosis. The local tumor can cause pain, nausea, vomiting, and intermittent or permanent obstruction. The obstruction can either be secondary to direct infiltration by the tumor or to the desmoplastic reaction in the mesentery that causes kinking and retraction of the loops of bowel. There can be a mass in the abdomen that can represent the primary tumor, tumor metastatic to the mesentery, or a fibrotic reaction in the mesentery. The carcinoid syndrome occurs in about 7 percent of patients with carcinoid tumors. It is much more common in small bowel carcinoid tumors (50 percent). The syndrome only occurs if liver metastases are present. If the humoral agents that caused the syndrome are secreted from the intestine into the portal circulation, they are detoxified in the liver and no systemic symptoms occur. If the humoral agents are derived from liver metastases, they are secreted directly into the systemic circulation. Thus, a carcinoid syndrome cannot develop without metastases, even though only 45 percent of persons who have carcinoid tumors with liver metastases have the syndrome. The three major features of the carcinoid syndrome are flushing, diarrhea, and bronchospasm. Our patient did not have the characteristic violaceous flush involving the face and the upper torso that typically occurs in paroxysms. He did not have bronchospasm, but he did have marked watery diarrhea. Less common features of the syndrome are telangiectasias, glucose intolerance, arthropathies, and hypotension associated with the flushing episodes. None of these characteristics were present in this patient. If he had the carcinoid syndrome, how could he have diarrhea without bronchospasm and flushing? These tumors produce many different substances. The best evidence suggests that the diarrhea is attributable to serotonin, whereas the flushing and the bronchospasm are not. Diarrhea can be reproduced with serotonin, and diarrhea can be blocked with inhibitors of serotonin synthesis. This is not true of the flushing or the bronchospasm. So, I can propose a scenario in which the major and perhaps only product of this tumor was serotonin, therefore causing diarrhea, but not flushing or bronchospasm, in this patient. Lastly, some symptoms of the carcinoid syndrome are
type lymphoma, would it be possible that he could have watery diarrhea with this syndrome, or is this highly unlikely? Dr. Regenstein: The nature of the diarrhea was not well characterized in this case. In particular, no mention was made of stool volumes, stool weights, or whether or not steatorrhea was present. It is conceivable that this patient had diarrhea on the basis of an intestinal lymphoma. Although diarrhea is more often a feature of immunoproliferative small intestinal disease, it can occur in patients with “Western-type” lymphoma. As for the cause of diarrhea, several potential mechanisms can explain why diarrhea occurs in some persons with small bowel lymphoma of the “Western type.” First, malabsorption and associated diarrhea can develop in patients with diffuse, extensive lymphomatous involvement of the small bowel or the mesenteric lymphatics. Second, small bowel bacterial overgrowth can occur as a result either of stasis proximal to a malignant stricture or of altered bowel motility secondary to lymphomatous invasion. Third, several conditions associated with diarrhea (e.g., nontropical sprue, acquired hypogammaglobulinemia) may precede and possibly contribute to the development of intestinal lymphoma. Thus, patients with the “Western-type” small bowel lymphoma occasionally present with diarrhea as a major complaint. Dr. Chase: The final diagnosis I would like to consider is the malignant carcinoid syndrome. Carcinoid cells are part of the APUD system that we discussed previously. They are enterochromaffin cells that originate in their benign form as Kulchitsky cells in the crypts of Lieberktihn. These cells secrete primarily serotonin, but they are also capable of secreting other hormones such as gastrin, calcitonin, ACTH, vasointestinal peptide, prostaglandins, and bradykinin. Carcinoids represent almost a quarter of all tumors in the small intestine. They are the most common benign tumor of the small bowel and represent almost half of malignant tumors of the small bowel. They can arise from three separate areas: the foregut, midgut, and hindgut. Foregut tumors arise from the oral pharynx to the mid-duodenum; midgut tumors originate from the small bowel and the proximal colon; hindgut tumors arise from the descending colon and rectum. The most common site for carcinoids is the appendix, where they are usually benign. The second most common site is the ileum, where they are usually malignant. Carcinoids can also occur in the jejunum and the duodenum. In one series of 192 patients [5], 7 percent of the carcinoids arose in the jejunum and 3 percent in the duodenum. Malignant carcinoids frequently metastasize. The probability of metastases is related to the size of the primary lesion. If the lesion is less than 1 cm, only 2 percent are metastatic. If the lesion is greater than 2 cm, more than 80 percent are metastatic. Pathologically, they are characterized by small submucosal nodules that are often
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Figure 3. Computed tomographic scan through inferior edge of liver (I) shows ascites (a) loculated around the liver tip, thickening of jejunal wall (arrows), thickening of the small bowel mesentery (arrowheads), and air and contrast medium in a duodenal diverticulum (d).
Figure 2. camp lesion six seconds after bolus injection of intravenous contrast medium. Lesion (arrows) is hypervascular and fed by a branch of the hepatic artery (arrowhead). Marked ascites (a) is present. Bottom, computed tomographic scan through liver lesion 4 I seconds after intravenous injection of contrast medium. The lesion (arrows) is now hypodense corn pared with the enhancing normal liver parenchyma, indica ting rapid blood flow through the liver.
Figure 4. Metastatic neoplasm in the liver consists of cellular nests separated by vascular stroma (hematoxylin and eosin stain; original magnification X 100, reduced by 5 percent).
related to the fibrotic reaction. The desmoplastic reaction in the abdomen and the mesentery can cause obstruction and infarction in the bowel. The fibrotic process can also involve the heart, producing thickening of the endocardiurn, the atrium, the ventricle, or the valves. Fibrosis of the valves can cause distortion and lead to flow abnormalities. Right-sided lesions are more predominant than left, although both can occur. The most common right-sided fibrotic lesions of the heart are pulmonic stenosis and tricuspid insufficiency. It is intriguing that the patient had a systolic murmur best heard to the right sternal border. Finally, let us review the radiologic findings again. Two
major diagnoses are being considered: lymphoma and carcinoid syndrome. Each of these can cause intestinal nodular infiltration, diarrhea, mesenteric lymphadenopathy, and liver metastases. Dr. Levitt, would you please describe the results of computed tomographic scanning? Dr. Levitt: Computed tomographic scanning of the abdomen was performed during the Barnes Hospital admission. Noncontrast scanning of the liver revealed a 3 cm hypodense lesion in the posterior right lobe. Postcontrast scanning showed rapid uptake and clearing of intravenous contrast medium, indicating hypervascularity and rapid blood flow within the lesion (Figure 2). A large amount of
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ascites filled the abdomen. Scanning at the inferior margin of the liver demonstrated ascites, thickening of jejunal loops, and thickening of the small bowel mesentery (Figure 3). Dr. Chase: To conclude, I have considered three major diagnoses. One is a metastatic pancreatic islet tumor. Second is primary intestinal lymphoma. Third is the malignant carcinoid syndrome. Liver metastases occur in all of these disorders, but contrast enhancement is more likely in the endocrine tumors. I did not say much about the ability of carcinoids to cause chylous ascites, but it seems likely that they could. The nodules in the mesentery were not unique but were more characteristic of carcinoids. The prolonged course, heme-positive stools, and nonspecific symptoms could have been caused by any of the three possible diagnoses. The systolic murmur is probably unrelated, but if the establishment of an association between it and a diagnosis in this case is desired, the murmur would be very compatible with carcinoid. I cannot explain the hematuria by any of these disorders. I predict that the procedure was exploratory laparotomy, and the major finding at surgery was a malignant carcinoid tumor.
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5.
Uniform tumor cells contain argentaffin-positive at the periphery of the nests (Fontana-Masson stain; original magnification X 250, reduced by 5 percent).
granules, most prominent
PATHOLOGIC DISCUSSION Dr. Keith Fulling: The procedure performed was exploratory laparotomy with wedge biopsy of the liver. Microscopic examination of the liver biopsy specimen disclosed a discrete metastasis with the characteristic histologic appearance of a neuroendocrine neoplasm (Figure 4). Uniform, medium-sized cells with regular round nuclei were separated into nests by a vascular stroma. Occasional mitotic figures were present. Subclassification of this tumor and speculation regarding probable primary site of origin can be attempted through analysis of the pattern of reaction with silver stains, morphologic study of the ultrastructural neurosecretory granules, and immunohistochemical hormone identification. Argentaffin cells contain endogenous reducing agents that transform ionic silver to metallic silver, precipitating it in the tissue section. Argyrophil cells also incorporate silver, but do not precipitate it unless an exogenous reducing agent is added. Although exceptions exist, and the sensitivity of the various silver stains differs, foregut neuroendocrine tumors (lung, stomach, duodenum, pancreas, etc.) are usually argentaffin-negative but argyroPhil-positive; midgut tumors (jejunum, ileum, appendix, ascending colon) are argentaffin- and argyrophil-positive; and hindgut tumors (mid and distal large bowel, rectum) are argentaffin- and argyrophil-negative [6]. The metastatic tumor under discussion was both argentaffin- and argyrophil-positive (Figure 5). Electron microscopy disclosed numerous pleomorphic, dense-core cytoplasmic granules, many of which were elongated and separated from their limiting mem-
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Figure 6. Electron micrograph pleomorphic, membrane-bound, (original magnification X 58,000,
of tumor
cell containing
cytoplasmic enlarged
granules
by 5 percent).
brane by a distinct clear space (Figure 6). This granule structure is characteristic of midgut carcinoids and is similar to that found in normal enterochromaffin cells containing serotonin or substance P and located in great numbers in the small intestine and appendix [6]. The first ultrastructural description of a midgut carcinoid was given by Drs. Sarah Luse and Paul Lacy [7] of the Washington University Department of Pathology in 1960. A wide variety of biogenic amines and polypeptide
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hormones have been identified in neuroendocrine tumors, and a significant proportion of carefully studied tumors are immunopositive, with staining demonstrating more than one hormone [8]. The spectrum of polypeptide hormones is especially varied in neuroendocrine tumors of foregut origin. Serotonin is the most frequently identified hormone in midgut tumors. Results of immunohistochemical stains for serotonin, substance P, bombesin, pancreatic polypeptide, insulin, glucagon, gastrin, and somatostatin were all negative in this metastasis. The granules may contain a
product for which staining was not performed. Metastases may not have the same hormonal content as the primary tumor. Finally, the negative result of staining may reflect loss of immunoreactivity following formalin fixation. Dr. Chase: Dr. Orland, was a 5hydroxyindoleacetic acid assay performed subsequently in this patient? Dr. Matt Orland: Yes. A value of 119 mg per 24 hours (normal, 1.8 to 6.0 mg per 24 hours) was obtained after the histologic diagnosis was made. Final pathologic diagnosis: Metastatic carcinoid tumor.
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Press OW, Press NO, Kaufman SD: Evaluation and management of chylous ascites. Ann Intern Med 1982; 96: 358-364. Lewin KJ, Ranched M, Dorfman RF: Lymphomas of the gastrointestinal tract, a study of 117 cases presenting with gastrointestinal disease. Cancer 1978; 42: 693707. Khojasteh A, Haghshenass M, Haghighi P: Immunoproliferative small intestinal disease. A “third-world lesion.” N Engl J Med 1983; 308: 1401-1405. Lewin KJ, Kahn LB, Novis BH: Primary intestinal lymphoma of “Western” and “Mediterranean” type, alpha chain disease and massive plasma cell infiltration. A comparative study of 37 cases. Cancer 1976; 38: 251 l-2528.
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Obey JR, Urdaneta LF, Al-Jurf AS, Jochimsen PR, Shirazi SS: Carcinoid tumors of the gastrointestinal tract. Am Surg 1985; 51: 37-41. Lechago J: The endocrine cells of the digestive and respiratory systems and their pathology. In: Bloodworth JMB Jr, ed. Endocrine pathology general and surgical, 2nd ed. Baltimore: Williams and Wilkins, 1982; 513-555. Luse SA, Lacy PE: Electron microscopy of a malignant argentaffin tumor. Cancer 1960; 13: 334-346. Yang K, Ulich T, Cheng L, Lewin K: The neuroendocrine products of intestinal carcinoids. An immunoperoxidase study of 35 carcinoid tumors stained for serotonin and eight polypeptide hormones. Cancer 1983; 51: 1918-1926.
CONFERENCE
Diarrhea and Abdominal Pain in a 64-Year-Old Man
Stenographic reports of weekly clinicopatholqic conferences held in Barnes and Wohl Hospitals are published in each issue of the Journal Members of the Departments of Internal Medicine, Radiology, and Pathology of the Washington University School of Medicine participate jointly in these conferences. Kenneth M. Ludmerer, M.D., and John M. Kissane, M.D., are the editors of this feature. A 64-year-old white man was admitted to Barnes Hospital on June 18, 1985, for abdominal distension, diarrhea, edema, and weight gain. In August 1983, he presented to an outside hospital with right-sided abdominal pain. The history at that time included the recent repair of a right inguinal hernia, cholecystectomy, and appendectomy. Hospital studies consisted of an upper gastrointestinal series, which showed duodenal diverticuli; a barium enema, which revealed colonic diverticulosis; intravenous pyelography, which demonstrated a left renal calculus and mild prostatic enlargement; and abdominal and renal sonography, which showed two small renal cysts. At discharge, the cause of his abdominal pain was still uncertain. The pain persisted, prompting a second radiographic evaluation, upper endoscopy, and colonoscopy on an outpatient basis; no additional findings were discovered. Anemia was noted, and oral iron therapy was initiated. In April 1985, he presented again with intermittent right lower quadrant abdominal pain, watery diarrhea, malaise, anorexia, and weight loss of 15 pounds over eight months. Physical examination revealed a right periumbilical, firm, 4 by 3 cm abdominal mass, and guaiac-positive stool. The white blood cell count was 8,200/mm3 with a normal differential; the hemoglobin level was 11.7 g/dl; and the reticulocyte count was 1.2 percent. Computed tomography of the abdomen revealed a 3 by 3 cm mass in the right lobe of the liver and retroperitoneal lymph nodes. Computed tomographic-directed liver biopsy showed a region of necrosis and periportal fibrosis. Upper endoscopy demonstrated hypertrophic gastritis; colonoscopy showed only uncomplicated diverticulosis. Bone marrow biopsy revealed mild erythroid hyperplasia, abundant iron stores, and no evidence of malignancy or an infectious process. A second computed tomographic-directed liver biopsy again showed a region of necrotic tissue. Microscopic hematuria was noted, but results of cystoscopy and retrograde pyelography were unremarkable. At presentation to Barnes Hospital, the patient complained of a worsening of his diarrhea over the previous two weeks. He was having four or five sometimes explosive bowel movements daily, and his stool was poorly formed and watery. Physical examination revealed normal vital signs, decreased breath sounds at the left lung base, a grade II/VI systolic
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scanning demonstrated an increase in ascites from April 1985, and also confirmed the presence of a 3 by 3 cm mass in the liver, which showed enhancement after injection of contrast medium. Several other 1 to 1.5 cm nodules were also visualized. Increased soft tissue was seen adjacent to the left aspect of the lumbar spine and in the periaottic region, and vascular congestion of the small bowel mesentery was observed. An upper gastrointestinal series with small bowel examination demonstrated multiple nodular densities in the duodenum and jejunum. Results of serum and urine protein electrophoreses were unremarkable. A procedure was performed on June 25, 1985. CLINICAL DISCUSSION
Figure I. Pressed-out nodules (arrows) .
view of jejunum
shows
Dr. Lewis Chase: The major findings that need to be explained in this case are watery diarrhea with abdominal pain, multiple nodular densities in the small intestine, liver masses with contrast enhancement, chylous ascites, a left pleural effusion, and thickening of the mesentery. Additional pertinent features include a prolonged course, anemia, hemoglobin-positive stools, malaise, anorexia, weight loss, a systolic murmur heard best at the right sternal border, and hematuria. I would like to begin by considering the causes of multiple nodular densities in the small intestine. Dr. Levitt will describe the small bowel radiographic finding from this patient. Dr. Robert Levitt: An upper gastrointestinal series and small bowel examination revealed nodules in the duodenum and proximal jejunum (Figure 1). Differential diagnosis includes Whipple’s disease, amyloidosis, and neoplasm, such as leiomyoma, neurofibroma, adenoma, lymphoma, and carcinoid. Dr. Chase: Let us consider the possible causes of nodules in the small intestine. The multiple polyposis syndromes result in filling defects on radiography, but they do not involve the liver and they do not cause diarrhea. Hemangiomas can involve the intestine and the liver. They are vascular lesions and therefore enhance with contrast medium. They can bleed, but they generally do not cause diarrhea or constitutional symptoms. Leiomyomas and leiomyosarcomas are common tumors of the small bowel that can be multicentric and can extend into the mesentery. They can be associated with pain and bleeding but not with diarrhea. Additional causes include neurofibromas, parasites, food particles, foreign bodies, pills, gallstones, blood clots, and varices. There is no evidence that this patient had any of the neurofibromatosis syndromes. The patient had no abnormalities on stool examination for parasites, so it would certainly be a “fluke” if he had parasites in the bowel. No evidence of retained food particles, seeds, foreign bodies, or retained pills was present in the bowel. The nodules did not have the appearance of gallstones or retained blood clots, and there was no history to suggest portal hyperten-
multiple
heart murmur at the upper right sternal border, pedal edema, and a distended, protuberant abdomen containing an irregular 4 by 4 cm mass in the right upper quadrant. No hepatosplenomegaly was present, but there was a suggestion of ascites. Admission laboratory data were as follows: white blood cell count 6,000/~1, hemoglobin 10.9 g/dl, mean corpuscular volume 85 pm3, sodium 139 mmol/liter, potassium 3.5 mmol/liter, chloride 110 mmol/liter, total carbon dioxide 22.7 mmol/liter, creatinine 0.9 mg/dl, serum urea nitrogen 9 mg/dl, glucose 82 mg/dl, total protein 6.0 g/dl, albumin 3.3 g/dl, calcium 8.7 mg/dl, cholesterol 136 mg/dl, bilirubin 0.5 mg/dl, alkaline phosphatase 90 units/liter, aspartate transaminase 19 units/liter, lactate dehydrogenase 149 units/liter, and prothrombin time 12.8 seconds. Urinalysis showed trace albuminuria and 16 red blood cells and one white blood cell per highpower field. Chest and abdominal radiography demonstrated blunting of the left costophrenic angle and a 1 cm calcified stone in the left kidney. Pericentesis was performed; 500 ml of cream-colored fluid was obtained. Fluid analysis demonstrated the following values: 4,150 total cells, 1,250 nucleated cells, pH 7.42, protein 1.9 g/dl, glucose 112 mg/dl, lactic dehydrogenase 52 units/liter, amylase 32 units/liter, cholesterol 33 mg/dl, and triglycerides 489 mg/dl. No chylomicrons were observed, and results of bacterial cultures and cytologic studies were negative. A subsequent fluid leak was appreciated. Stool examination and culture revealed no enteric pathogens. Abdominal computed tomographic
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sion and varices. Disorders that cannot readily be excluded are metastases and lymphomas. The most common carcinomas metastatic to the small bowel are melanoma, breast, and lung. No evidence for a breast tumor was observed in this male patient, and chest radiography did not suggest carcinoma of the lung. Melanomas can be subtle, but there was no evidence for this either. Another tumor to consider is an islet cell carcinoma of the pancreas. These tumors spread throughout the abdomen and are associated with unique systemic manifestations. There are four major cell types in the islet, each of which produces a specific humoral agent. These hormones are insulin, glucagon, somatostatin, and pancreatic polypeptide. Each of these four cell types can become neoplastic, can metastasize, and can hypersecrete its unique humoral agent. It should also be recognized that islet cells are part of the so-called APUD system. These APUD cells are derived from neuroectoderm and have the capacity for amine precursor uptake and decarboxylation (APUD). An example would be decarboxylation of 5hydroxytryptamine to serotonin. When these cells become neoplastic, they dedifferentiate and have the capacity to secrete not only the hormone that the original benign cell was capable of producing but also a variety of other hormones, including but not limited to gastrin, vasointestinal peptide, calcitonin, neurotensin, corticotropin, and serotonin. Most but not all of these secretory products have been associated with a particular syndrome. There is no suggestion that this patient was ever hypoglycemic and had an insulinproducing tumor. Glucagonomas are associated with a characteristic skin rash similar to that seen in toxic epidermal necrolysis. It is called necrolytic migratory erythema. These patients can be mildly diabetic because of the increased glucagon secretion. They have ill-defined psychiatric disturbances, and they can have watery diarrhea and a proclivity toward venous thromboses. Somatostatin, named because it inhibits growth hormone secretion, is also an inhibitor of both insulin and glucagon. Patients with somatostatinomas present with dyspepsia, glucose intolerance, an increased incidence of gallstones, steatorrhea but not necessarily watery diarrhea, and hypochlorhydria. PPomas, islet cell tumors that secrete pancreatic polypeptide, have been described, but this hormone currently has no known definite function. There have been a few reports of PPomas associated with secretory diarrhea. Gastrinomas produce the Zollinger-Ellison syndrome, major features of which are severe recurrent peptic ulcer disease and secretory diarrhea. VlPomas cause the WDHH syndrome consisting of watery diarrhea, hypokalemia, and hypochlorhydria. Medullary carcinomas of the thyroid secrete calcitonin and are associated with watery diarrhea. Tumors secreting neurotensin have been described, but not in relation to a unique clinical syndrome. One patient had marked esophageal reflux, but it could not
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be determined whether the neurotensin was responsible for that symptom. Even when they have metastasized, not all islet cell tumors produce symptoms. In fact, about 50 percent of these tumors are not associated with characteristic clinical syndromes. What is of interest concerning islet cell tumors in regard to the current case is that they commonly metastasize to the liver, and these metastases are usually quite vascular. Distant metastases, although described, are very rare. The tumors can spread to local nodes and into the peritoneum and result in extensive involvement of the mesentery. Finally, islet cell tumors are frequently characterized by a long survival period. I think it is distinctly possible that this patient had a metastatic pancreatic tumor, but it is less likely in view of the absence of a pancreatic mass and a characteristic clinical syndrome. Although the actual pancreatic tumor can be very small in some cases, and some are associated only with watery diarrhea, I could not find reports of metastatic pancreatic tumors that caused nodules in the small intestine. However, if these tumors metastasized to the mesentery and obstructed the lymphatics, I think it would be possible that they could produce this complex. I would now like to consider one of the other major findings in this case, chylous ascites. The definition of chylous ascites is grossly milky ascitic fluid with increased fat. Increased fat in ascitic fluid can be detected by either extracting the fluid with ether, staining it with Sudan-Ill, detecting fat globules microscopically, or measuring triglyceride levels directly. From the literature, the triglyceride concentration in “normal” ascitic fluid is 37 Ifr 9 mg/dl. The “normal” white blood cell count is usually less than 200/mm3, and the cholesterol concentration is less than 100 mg/dl. In a recent series [l] of 24 patients with chylous ascites, triglyceride values ranged from 218 to 8,100 mg/dl, with a mean of 1,591 mg/dl; white blood cell counts were 232 to 2,560/mm3, with a mean of 1 ,046/mm3; and cholesterol levels were within the normal range. Our patient had a triglyceride concentration of 489 mg/dl and a white blood cell count of 1,250/mm3. These values are clearly consistent with chylous ascites. Furthermore, the fluid was milky and the cholesterol level was not elevated. When the triglyceride concentration is increased in ascitic fluid, verification that this value is greater than the serum triglyceride level should always be carried out. A serum triglyceride determination was not performed on this patient, but there is no reason to believe that he had hyperlipoproteinemia. What are the causes of chylous ascites? In the older literature, the predominant causes were mesenteric adenitis and tuberculosis. In the pediatric literature, the most common diagnosis is congenital obstruction of the lymphatic system. In the “modern” adult literature, which is sparse, the most common diagnosis is malignancy. In the series of 24 adult patients with chylous ascites, 21 had
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malignant disease. Of the 21 cases of malignancy, 13 were iymphomas and eight were metastatic tumors. The sources of the metastases were pancreas, breast, colon, prostate, ovary, and kidney. Did this patient have a lymphoma? He did not have diffuse adenopathy and he had a normal bone marrow biopsy result. His clinical disorder, except for the pleural effusion, was localized to the abdomen. I think the diagnosis that needs to be considered is a primary lymphoma of the small intestine [2]. Lymphoid cells are dispersed throughout the lamina propria at all levels of the small intestine, and lymphoid cells are also present in follicular aggregates in both the mucosa and the submucosa of the intestine. Therefore, lymphoma can originate from any of these cells, and when it does, small intestinal lymphoma can present in a variety of patterns. It can be localized to the area in the bowel in which it arose, and adjacent involvement of the mesenteric nodes may or may not be present. Primary intestinal lymphomas are multifocal in 25 percent of the cases. They involve multiple segments of the small intestine, and the small bowel is radiographitally similar to that in the patient being discussed. Finally, intestinal lymphomas can be diffuse and involve the major portion of the small intestine. A wide variety of symptoms are associated with intestinal lymphomas. They can cause intermittent obstruction with intermittent abdominal pain, or irreversible or at least only surgically reversible obstruction. They can ulcerate and/or perforate and they can be the site of intussusception. If they involve the intestine diffusely, they can cause malabsorption, and the malabsorption in turn can lead to diarrhea. Lymphatic drainage of the bowel and peritoneum is commonly involved, resulting in chylous ascites and a protein-losing enteropathy. Our patient had a minimally diminished serum albumin level and slight peripheral edema, so I do not think he had a protein-losing enteropathy. Finally, lymphomas can spread to cause extensive involvement of mesenteric nodes, and they can produce nodules in the liver. In recent years, several different patterns of small bowel lymphoma have been recognized. I have asked Dr. Fred Regenstein if he would review these patterns of small bowel lymphoma and contrast their clinical and pathologic features. Dr. Fredrick Regenstein: Most primary small intestinal lymphomas are of the non-Hodgkin’s variety. As Dr. Chase has already mentioned, primary small intestinal lymphoma most often involves a single segment of small bowel, usually the ileum. Multifocal or diffuse intestinal involvement occurs in up to 25 percent of cases. Symptoms tend to be nonspecific and usually include abdominal pain, anorexia, nausea, vomiting, weight loss, and less frequently diarrhea or gastrointestinal bleeding. An abdominal mass may be palpable on physical examination. Infrequently, patients present with ascites, as a result of
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invasion and obstruction of the intestinal lymphatics. Peripheral lymphadenopathy, hepatomegaly, and splenomegaly are unusual at the time of initial presentation. Mild anemia is probably the most common laboratory abnormality in patients with intestinal lymphoma, but laboratory tests are rarely helpful in establishing the diagnosis. Barium radiography of the small bowel almost always demonstrates abnormalities in patients with small intestinal lymphoma. The diagnosis should be suspected when radiography reveals thickening of the bowel loops with nodular@ or distortion of the normal mucosal folds, segmental narrowing, or the presence of an intraluminal polypoid lesion. Complications most often arise as a result of either intestinal obstruction, bleeding, or perforation. In certain underdeveloped areas of the world (Middle East, South and Central Africa, South and Central America, Southeast Asia, Mediterranean nations), a peculiar type of lymphoma known as immunoproliferative small intestinal disease or “Mediterranean lymphoma” occurs with some frequency [3,4]. In this disorder, diarrhea, malabsorption, and abdominal pain are usually the presenting symptoms. As a consequence of the malabsorption, patients typically present with cachexia and profound weight loss. In addition, clubbing of fingers and toes, dependent edema, and an abdominal mass may be apparent on physical examination. The peak incidence of this disease is in the second and third decades of life, in contrast to the “Western-type” lymphoma, which primarily occurs in middle-aged persons. lmmunoproliferative small intestinal disease usually involves a long segment of the small bowel, most often the duodenum and jejunum. Histologic study of the involved bowel segments reveals a dense plasma cell or polymorphous lympoid infiltrate in the lamina propria and submucosa with a reduction in the number of crypts and villi and with flattening of the villi. Total villous atrophy may occur in severe cases. Barium radiography of the small bowel typically shows long segments of thickened, nodular folds in the duodenum and jejunum. The diagnosis can be confirmed by obtaining multiple peroral small bowel biopsy specimens. Some cases of immunoproliferative small intestinal disease are associated with the presence of incomplete heavy chains of IgA in serum, urine, or jejunal secretions. Genetic and environmental factors may be involved in the pathogenesis of immunoproliferative Small intestinal disease. In particular, environmental factors prevalent in areas in which this disorder is common include low socioeconomic status, poor hygiene, and a high rate of parasitic infestation. Chronic antigenic stimulation, as a result of intestinal infections, may be involved in the eventual development of lymphoma in these patients. In contrast, no geographic or socioeconomic factors appear to be associated with the “Western-type” intestinal lymphoma. Dr. Chase: Dr. Regenstein, if the patient had a Western-
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multiple. They can be polypoid, annular, or deeply invasive. They metastasize to regional nodes, to other sites along the intestine, and to the liver. The intestinal meta&+ ses produce a nodular pattern, and liver metastases can be highly vascular. As with pancreatic tumors, distant metastases occur, but they are uncommon. A distinguishing feature of carcinoids is the induction Of an intense desmoplastic or fibrotic reaction in the mesentery, which can cause marked distortion of the normal architecture of both the intestine and the mesentery. The clinical features of carcinoids can be divided into three major categories: those related to the localized tumor, those related to the carcinoid syndrome, and those related to fibrosis. The local tumor can cause pain, nausea, vomiting, and intermittent or permanent obstruction. The obstruction can either be secondary to direct infiltration by the tumor or to the desmoplastic reaction in the mesentery that causes kinking and retraction of the loops of bowel. There can be a mass in the abdomen that can represent the primary tumor, tumor metastatic to the mesentery, or a fibrotic reaction in the mesentery. The carcinoid syndrome occurs in about 7 percent of patients with carcinoid tumors. It is much more common in small bowel carcinoid tumors (50 percent). The syndrome only occurs if liver metastases are present. If the humoral agents that caused the syndrome are secreted from the intestine into the portal circulation, they are detoxified in the liver and no systemic symptoms occur. If the humoral agents are derived from liver metastases, they are secreted directly into the systemic circulation. Thus, a carcinoid syndrome cannot develop without metastases, even though only 45 percent of persons who have carcinoid tumors with liver metastases have the syndrome. The three major features of the carcinoid syndrome are flushing, diarrhea, and bronchospasm. Our patient did not have the characteristic violaceous flush involving the face and the upper torso that typically occurs in paroxysms. He did not have bronchospasm, but he did have marked watery diarrhea. Less common features of the syndrome are telangiectasias, glucose intolerance, arthropathies, and hypotension associated with the flushing episodes. None of these characteristics were present in this patient. If he had the carcinoid syndrome, how could he have diarrhea without bronchospasm and flushing? These tumors produce many different substances. The best evidence suggests that the diarrhea is attributable to serotonin, whereas the flushing and the bronchospasm are not. Diarrhea can be reproduced with serotonin, and diarrhea can be blocked with inhibitors of serotonin synthesis. This is not true of the flushing or the bronchospasm. So, I can propose a scenario in which the major and perhaps only product of this tumor was serotonin, therefore causing diarrhea, but not flushing or bronchospasm, in this patient. Lastly, some symptoms of the carcinoid syndrome are
type lymphoma, would it be possible that he could have watery diarrhea with this syndrome, or is this highly unlikely? Dr. Regenstein: The nature of the diarrhea was not well characterized in this case. In particular, no mention was made of stool volumes, stool weights, or whether or not steatorrhea was present. It is conceivable that this patient had diarrhea on the basis of an intestinal lymphoma. Although diarrhea is more often a feature of immunoproliferative small intestinal disease, it can occur in patients with “Western-type” lymphoma. As for the cause of diarrhea, several potential mechanisms can explain why diarrhea occurs in some persons with small bowel lymphoma of the “Western type.” First, malabsorption and associated diarrhea can develop in patients with diffuse, extensive lymphomatous involvement of the small bowel or the mesenteric lymphatics. Second, small bowel bacterial overgrowth can occur as a result either of stasis proximal to a malignant stricture or of altered bowel motility secondary to lymphomatous invasion. Third, several conditions associated with diarrhea (e.g., nontropical sprue, acquired hypogammaglobulinemia) may precede and possibly contribute to the development of intestinal lymphoma. Thus, patients with the “Western-type” small bowel lymphoma occasionally present with diarrhea as a major complaint. Dr. Chase: The final diagnosis I would like to consider is the malignant carcinoid syndrome. Carcinoid cells are part of the APUD system that we discussed previously. They are enterochromaffin cells that originate in their benign form as Kulchitsky cells in the crypts of Lieberktihn. These cells secrete primarily serotonin, but they are also capable of secreting other hormones such as gastrin, calcitonin, ACTH, vasointestinal peptide, prostaglandins, and bradykinin. Carcinoids represent almost a quarter of all tumors in the small intestine. They are the most common benign tumor of the small bowel and represent almost half of malignant tumors of the small bowel. They can arise from three separate areas: the foregut, midgut, and hindgut. Foregut tumors arise from the oral pharynx to the mid-duodenum; midgut tumors originate from the small bowel and the proximal colon; hindgut tumors arise from the descending colon and rectum. The most common site for carcinoids is the appendix, where they are usually benign. The second most common site is the ileum, where they are usually malignant. Carcinoids can also occur in the jejunum and the duodenum. In one series of 192 patients [5], 7 percent of the carcinoids arose in the jejunum and 3 percent in the duodenum. Malignant carcinoids frequently metastasize. The probability of metastases is related to the size of the primary lesion. If the lesion is less than 1 cm, only 2 percent are metastatic. If the lesion is greater than 2 cm, more than 80 percent are metastatic. Pathologically, they are characterized by small submucosal nodules that are often
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Figure 3. Computed tomographic scan through inferior edge of liver (I) shows ascites (a) loculated around the liver tip, thickening of jejunal wall (arrows), thickening of the small bowel mesentery (arrowheads), and air and contrast medium in a duodenal diverticulum (d).
Figure 2. camp lesion six seconds after bolus injection of intravenous contrast medium. Lesion (arrows) is hypervascular and fed by a branch of the hepatic artery (arrowhead). Marked ascites (a) is present. Bottom, computed tomographic scan through liver lesion 4 I seconds after intravenous injection of contrast medium. The lesion (arrows) is now hypodense corn pared with the enhancing normal liver parenchyma, indica ting rapid blood flow through the liver.
Figure 4. Metastatic neoplasm in the liver consists of cellular nests separated by vascular stroma (hematoxylin and eosin stain; original magnification X 100, reduced by 5 percent).
related to the fibrotic reaction. The desmoplastic reaction in the abdomen and the mesentery can cause obstruction and infarction in the bowel. The fibrotic process can also involve the heart, producing thickening of the endocardiurn, the atrium, the ventricle, or the valves. Fibrosis of the valves can cause distortion and lead to flow abnormalities. Right-sided lesions are more predominant than left, although both can occur. The most common right-sided fibrotic lesions of the heart are pulmonic stenosis and tricuspid insufficiency. It is intriguing that the patient had a systolic murmur best heard to the right sternal border. Finally, let us review the radiologic findings again. Two
major diagnoses are being considered: lymphoma and carcinoid syndrome. Each of these can cause intestinal nodular infiltration, diarrhea, mesenteric lymphadenopathy, and liver metastases. Dr. Levitt, would you please describe the results of computed tomographic scanning? Dr. Levitt: Computed tomographic scanning of the abdomen was performed during the Barnes Hospital admission. Noncontrast scanning of the liver revealed a 3 cm hypodense lesion in the posterior right lobe. Postcontrast scanning showed rapid uptake and clearing of intravenous contrast medium, indicating hypervascularity and rapid blood flow within the lesion (Figure 2). A large amount of
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ascites filled the abdomen. Scanning at the inferior margin of the liver demonstrated ascites, thickening of jejunal loops, and thickening of the small bowel mesentery (Figure 3). Dr. Chase: To conclude, I have considered three major diagnoses. One is a metastatic pancreatic islet tumor. Second is primary intestinal lymphoma. Third is the malignant carcinoid syndrome. Liver metastases occur in all of these disorders, but contrast enhancement is more likely in the endocrine tumors. I did not say much about the ability of carcinoids to cause chylous ascites, but it seems likely that they could. The nodules in the mesentery were not unique but were more characteristic of carcinoids. The prolonged course, heme-positive stools, and nonspecific symptoms could have been caused by any of the three possible diagnoses. The systolic murmur is probably unrelated, but if the establishment of an association between it and a diagnosis in this case is desired, the murmur would be very compatible with carcinoid. I cannot explain the hematuria by any of these disorders. I predict that the procedure was exploratory laparotomy, and the major finding at surgery was a malignant carcinoid tumor.
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5.
Uniform tumor cells contain argentaffin-positive at the periphery of the nests (Fontana-Masson stain; original magnification X 250, reduced by 5 percent).
granules, most prominent
PATHOLOGIC DISCUSSION Dr. Keith Fulling: The procedure performed was exploratory laparotomy with wedge biopsy of the liver. Microscopic examination of the liver biopsy specimen disclosed a discrete metastasis with the characteristic histologic appearance of a neuroendocrine neoplasm (Figure 4). Uniform, medium-sized cells with regular round nuclei were separated into nests by a vascular stroma. Occasional mitotic figures were present. Subclassification of this tumor and speculation regarding probable primary site of origin can be attempted through analysis of the pattern of reaction with silver stains, morphologic study of the ultrastructural neurosecretory granules, and immunohistochemical hormone identification. Argentaffin cells contain endogenous reducing agents that transform ionic silver to metallic silver, precipitating it in the tissue section. Argyrophil cells also incorporate silver, but do not precipitate it unless an exogenous reducing agent is added. Although exceptions exist, and the sensitivity of the various silver stains differs, foregut neuroendocrine tumors (lung, stomach, duodenum, pancreas, etc.) are usually argentaffin-negative but argyroPhil-positive; midgut tumors (jejunum, ileum, appendix, ascending colon) are argentaffin- and argyrophil-positive; and hindgut tumors (mid and distal large bowel, rectum) are argentaffin- and argyrophil-negative [6]. The metastatic tumor under discussion was both argentaffin- and argyrophil-positive (Figure 5). Electron microscopy disclosed numerous pleomorphic, dense-core cytoplasmic granules, many of which were elongated and separated from their limiting mem-
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Figure 6. Electron micrograph pleomorphic, membrane-bound, (original magnification X 58,000,
of tumor
cell containing
cytoplasmic enlarged
granules
by 5 percent).
brane by a distinct clear space (Figure 6). This granule structure is characteristic of midgut carcinoids and is similar to that found in normal enterochromaffin cells containing serotonin or substance P and located in great numbers in the small intestine and appendix [6]. The first ultrastructural description of a midgut carcinoid was given by Drs. Sarah Luse and Paul Lacy [7] of the Washington University Department of Pathology in 1960. A wide variety of biogenic amines and polypeptide
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hormones have been identified in neuroendocrine tumors, and a significant proportion of carefully studied tumors are immunopositive, with staining demonstrating more than one hormone [8]. The spectrum of polypeptide hormones is especially varied in neuroendocrine tumors of foregut origin. Serotonin is the most frequently identified hormone in midgut tumors. Results of immunohistochemical stains for serotonin, substance P, bombesin, pancreatic polypeptide, insulin, glucagon, gastrin, and somatostatin were all negative in this metastasis. The granules may contain a
product for which staining was not performed. Metastases may not have the same hormonal content as the primary tumor. Finally, the negative result of staining may reflect loss of immunoreactivity following formalin fixation. Dr. Chase: Dr. Orland, was a 5hydroxyindoleacetic acid assay performed subsequently in this patient? Dr. Matt Orland: Yes. A value of 119 mg per 24 hours (normal, 1.8 to 6.0 mg per 24 hours) was obtained after the histologic diagnosis was made. Final pathologic diagnosis: Metastatic carcinoid tumor.
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Press OW, Press NO, Kaufman SD: Evaluation and management of chylous ascites. Ann Intern Med 1982; 96: 358-364. Lewin KJ, Ranched M, Dorfman RF: Lymphomas of the gastrointestinal tract, a study of 117 cases presenting with gastrointestinal disease. Cancer 1978; 42: 693707. Khojasteh A, Haghshenass M, Haghighi P: Immunoproliferative small intestinal disease. A “third-world lesion.” N Engl J Med 1983; 308: 1401-1405. Lewin KJ, Kahn LB, Novis BH: Primary intestinal lymphoma of “Western” and “Mediterranean” type, alpha chain disease and massive plasma cell infiltration. A comparative study of 37 cases. Cancer 1976; 38: 251 l-2528.
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Obey JR, Urdaneta LF, Al-Jurf AS, Jochimsen PR, Shirazi SS: Carcinoid tumors of the gastrointestinal tract. Am Surg 1985; 51: 37-41. Lechago J: The endocrine cells of the digestive and respiratory systems and their pathology. In: Bloodworth JMB Jr, ed. Endocrine pathology general and surgical, 2nd ed. Baltimore: Williams and Wilkins, 1982; 513-555. Luse SA, Lacy PE: Electron microscopy of a malignant argentaffin tumor. Cancer 1960; 13: 334-346. Yang K, Ulich T, Cheng L, Lewin K: The neuroendocrine products of intestinal carcinoids. An immunoperoxidase study of 35 carcinoid tumors stained for serotonin and eight polypeptide hormones. Cancer 1983; 51: 1918-1926.