Amyloidosis and plasma cell dyscrasias: Gastrointestinal involvement

Amyloidosis and Plasma Cell Dyscrasias: Gastrointestinal Involvement By Harley C. Carlson and Jerome AMYLOIDOSIS

T

HE CLINICAL and pathologic manifestations of amyloid disease have been observed and reported since the mid- 1800s. Many classifications of amyloid have been proposed’ and have been reviewed elsewhere in this issue. Patients with this disease often have gastrointestinal involvement. Gilat and associates* demonstrated involvement of the digestive tract at autopsy in 68 of 70 cases of systemic amyloidosis. Patients with gut involvement are often asymptomatic, but widespread dysfunction may occur. The clinical diagnosis of amyloidosis may be difficult to make; in Mathews’ series reported in 1954,3 only 12 of 50 cases were diagnosed antemortem. Recently, however, Kyle and Greipp4 reported on a series of 229 patients with primary systemic amyloidosis in which the diagnosis was made before death in 96%. Deposition of amyloid may cause widespread damage to the entire gastrointestinal tract. In their systematic study of the site of intestinal amyloid deposition, Gilat et al* found two distinct patterns. In primary amyloidosis, parenchyma1 deposition was predominantly in the muscle layers of the intestinal wall. In secondary amyloidosis, parenchymal deposition was predominantly in the mucosa. In all cases amyloid was found in blood vessels, mainly those in the submucosa. In familial amyloidosis, there is, in addition, selective deposition about the visceral nerves. Seliger et al5 reported radiographicpathologic correlation in 13 cases of small and large bowel amyloidosis, obtaining good correlation between the degree of amyloid deposition, especially vascular deposition, and that of the From the Department of Diagnostic Radiology, Mayo Clinic and Mayo Foundation, Rochester, Minn. Harley C. Carlson: Professor of Radiology, Mayo Medical School; Jerome F. Breen: Resident, Mayo Graduate School of Medicine. Address reprint requests to Harley C. Carlson, MD, Department of Diagnostic Radiology, Mayo Clinic, Rochester, MN 55905. Copyright 0 1986 Mayo Foundation. 0037-I 98X/86/21024005%05.00/0

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roentgenologic abnormality. The radiographic abnormalities most commonly reported include motor dysfunction, nodular and thickened mucosal folds, ulcerations, mucosal atrophy, malabsorption pattern, hepatosplenomegaly, distinct intraluminal and intramural masses, and obstruction at multiple sites in the gastrointestinal (GI) tract”” (Figs 1 through 8). The clinical manifestations reported are equally nonspecific and diverse, including dysphagia, bowel obstruction, diarrhea, hemorrhage, or simply diffuse abdominal discomfort with weight loss. Radiographic Findings

We briefly reviewed the charts of 230 patients with primary systemic amyloidosis seen at the Mayo Clinic over a ten-year period. In 47 patients who had amyloidosis diagnosed from a gastrointestinal biopsy site or had GI involvement at autopsy, the radiologic reports and films were studied. Of the 47 patients, 27 had normal barium examinations on one or more occasions. The remaining 20 patients with positive studies are summarized in Table 1. The radiographic findings are similar to those previously reported. Interesting yet not unexpected was the occasional patient with severe, nearly debilitating GI complaints in whom no radiographic abnormality was detected. One patient had a markedly abnormal small bowel examination without intestinal symptoms, which is most unusual (Fig 3). Any area of the GI tract may be involved. If involvement is present, typically the entire alimentary tract is infiltrated to some degree.’ Mouth. Macroglossia is common (Fig 1) and occurs in about one fifth of the patients.3 The macroglossia may be severe enough to obstruct the airway during sleep, as well as to interfere with eating solid foods. Esophagus. Hypokinesis during barium swallow is the most commonly described abnormality. A picture identical to achalasia has been reported.” Also reported are esophageal varices secondary to portal hypertension with liver infiltration.13 Esophageal carcinoma may be mimicked. Seminars in R~ntgenology,

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Amyloidosis of the tongue. This 39-year-old man Fig 1. presented with an enlarging tongue. Biopsy demonstrated amyloid. The patient died two months later, apparently of congestive heart failure secondary to amyloid involvement.

Stomach. Gastric involvement may cause diminished peristalsis with markedly delayed emptying. Ulceration and loss of rugal folds are frequent. Gastric outlet obstruction and thickening of the stomach wall may occur. Cooleyr4 pointed out the similarity to gastric carcinoma and noted that the degree of pliability is somewhat greater in amyloidosis (Figs 2 and 7A). Small bowel. A variety of changes may be seen in the small intestine, but they are nonspecific (Figs 3 through 6 and 7C). Widening and separation of the mucosal folds and impairment of motility are common. A malabsorption pattern is occasionally seen. Apparent mechanical obstruction may actually be the result of pseudoobstruction for which surgical treatment is not

Fig 2. Gastric amyloidosis in a 67-year-old man with increasing tongue size, diarrhea, nausea, and vomiting. Radiographic examination shows several submucosal masses involving the antrum with effacement of the mucosal pattern. There are thickened folds in the duodenum. Endoscopic biopsy revealed benign gastric mucosa with stains for amyloid negative. However, it is likely that the deposits of amyloid were submucosal. Biopsies of the tongue and rectum were positive for amyloid.

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only ineffectual, but dangerous.” Transient intussusception has been reported, as has been acute perforation.16 Multiple nodular amyloid deposits have been described.” Colon. Colonic amyloidosis may cause changes identical to ulcerative colitis.‘*-*’ Indeed, the disease may cause diarrhea and rectal bleeding. Along with altered haustrations, thickened folds, and coarse nodularity of the mucosa are occasionally found. Small mucosal ulcerations occur (Figs 5, 7C, and 8). Liver, gallbladder, pancreas. Infiltration of the liver is common, although hepatic dysfunction is unusual. Kyle and Greipp4 found that about one third of patients with primary amyloidosis have a palpable liver. Portal hypertension with esophageal varices secondary to hepatic amyloidosis has rarely been reported, as has been intrahepatic cholestasis with jaundice.*’ Wright and Calkins** reported 9 of 20 patients of primary amyloidosis with hepatomegaly. Although vascular infiltration of the liver was present in 19 of the 20, extensive infiltration of the liver sinusoids was found in only four, suggesting that other causes than simple infiltration, such as congestive heart failure, likely play a role in the hepatomegaly. Symptomatic involvement of the pancreas and gallbladder have not been reported, although several of our patients did have amyloid in these organs at autopsy. No abnormal radiographic findings in these organs were documented. Vascular system. While usually mild, Gl bleeding is occasionally present in patients with

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Fig 3. Diffuse nodular infiltrative amyloidosis involving the proximal half of the small bowel in a 74-year-old asymptomatic man. A diagnosis of amyloidosis was made four years previously following work-up for upper GI bleeding secondary to excessive aspirin use. The patient underwent full thickness jejunal biopsy at laparotomy, which demonstrated massive deposits of amyloid in the submucosa, including the vessels. Rectal biopsy was also positive.

amyloidosis, and rarely may be severe.23 Schroeder and associatesz4 reported angiographic abnormalities. Abrupt change in caliber with luminal irregularities in two patients with acute GI hemorrhage was attributed to the amyloid deposition within the walls of submucosal and mesenteric arteries found at autopsy. The most common presenting symptoms of amyloid disease are fatigue and weight loss that is often profound. Common also is abdominal pain. These are nonspecific symptoms, but obvious indications for investigation of the intestinal tract. Although in many cases cardiac and

Fig 4. Small bowel amyloidosis in a 57-year-old man with diarrhea and steatorrhea. There is segmental dilatation with thickened folds and flocculation of the barium. Findings were thought to be due to sprue until small bowel and rectal biopsies returned positive for amyloid.

renal involvement by amyloid may eventually dominate the clinical picture and course, GI involvement may be the cause of a patient’s symptoms and may even cause his demise. PLASMA

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Waldenstriim’s Macroglobulinemia

GI involvement in Waldenstriim’s macroglobulinemia is uncommon. Although Waldenstrom did describe diarrhea in one of his original three patients, the disease is more often characterized by fatigue, anemia, hemorrhage, lymphadenopa-

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Fig 5. Amyloidosis of small and large bowel in a 66-year-old women with diarrhea, weight loss, and steatorrhea. (AJ Small bowel examination demonstrates thickened nodular mucosal folds. (El Plain film seven days later shows residual barium and gaseous distension of long segments of small intestine consistent with pseudobstruction. Autopsy two days later showed marked small and large bowel infiltration with amyloid but no focal obstruction.

thy, and hepatospIenomegaly.24 McCaIIister and associates,” in a report of 3 1 patients seen at the Mayo Clinic in a nine-year period and a review of 196 cases from the literature, did not record a single case of diarrhea or steatorrhea as a presenting symptom or chief complaint. Cohen et a12’j found no GI complaints in their ten cases

other than abdominal pain, which was not common. Radiographic findings. Radiographic findings have been almost exclusively limited to the small bowel. Thickening of folds, dilatation, fine granular mucosa, and malabsorption pattern are common. These findings are thought to be secon-

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Fig 6. Malabsorption syndrome in a 47-year-old with chronic diarrhea. There is transient intussuception the proximal jejunum. Jejunal biopsy was positive for loid. Reprinted with permission.’

dary to pleocellular infiltrates and deposition of a homogeneous eosinophilic granular material into the lamina propria, resulting in clubbed and distorted villi.27m3’ Diarrhea and steatorrhea is associated with this GI involvement. Further separating these patients from the typical case is the lack of the usual manifestations of the disease. A case of involvement in the stomach with Waldenstrom’s disease has been reported which also lacked typical involvement elsewhere.32 Heavy infiltration with lymphocytes, plasma cells, and plasmacytoid lymphocytes were found in multiple areas of deep ulceration throughout the stomach. Involvement of the esophagus or colon has not been reported. We reviewed the roentgenologic reports in 64 cases of Waldenstrom’s macroglobulinemia treated at the Mayo Clinic over the past ten years. Only one patient had an abnormality on barium examination that might be attributable to macroglobulinemia: slightly thickened folds in the duodenum. Fig 9 demonstrates the more common hepatosplenomegaly and lymphadenopathy. Fig 10 is an unusual case from our teaching file that demonstrates a submucosal mass due to a localized infiltration of plasma cells, initially considered to be a solitary extraosseous plasma-

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man of amy-

cytoma. The diagnosis of Waldenstrom’s macroglobulinemia was subsequently made and another biopsy was consistent with that diagnosis. Plasmacytoma

and Multiple

Myeloma

Involvement of the intestinal tract by plasma cell neoplasia is rare but may be a manifestation of multiple myeloma.33-35 In an autopsy series, involvement by multiple myeloma in the GI tract was seen in <5’S, and rarely noted antemortem. Plasmacytoma of primary intestinal origin is still the subject of isolated case reports and represents only about 10% of patients with extramedullary plasmacytoma.37 Any segment of the intestinal tract may be the site of plasmacytoma, the stomach and small intestine being involved much more often than the colon; the esophagus is only rarely afflicted.38-4’ Occasionally, there are multiple areas of involvement. We reviewed 71 charts with the diagnostic code of Plasmacytoma in the Mayo Clinic files over a five-year period; three of the patients had primary solitary plasmacytoma of GI origin, two in the stomach and one in the duodenum. The clinical presentation is dependent on the

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Fig 7. Diffuse amyloidosis pain, end shortness of breath. Thickened folds are present rectum and sigmoid, giving demonstrated marked amyloid

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of GI tract. 35-year-old man with six-month history of nausea and vomiting. (A) The gastric rugae appear atrophic. There was diminished distensibility throughout the small bowel. (C) The colon is featureless with decreased the appearance of ulcerative colitis. The patient died six days after infiltration of the GI, respiratory, and cardiovascular systems.

site of involvement. A history of ulcer or outlet obstruction may be present with gastric involvement. Abdominal pain, obstruction, intussusception, and bleeding have been reported with bowel involvement. Patients are usually over 50 years of age and are more likely to be males.

fatigue. abdominal of the stomach. (6) distensibility of the admission. Autopsy

Radiographic findings may simulate primary carcinoma, lymphoma, solitary or multiple polypoid lesions of any histologic type, or inflammatory stricture (Figs 11 and 12). Radiation is often the treatment used for primary extramedullary plasmacytoma. with careful follow-up to insure

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Fig 8. Colon amyloidosis in a 64-yaarold woman with a chronic history of crampy abdominal pain and bloody diarrhea. Diffusely abnormal colon with smooth hoselike descending colon similar to ulcerative colitis. Multiple colon biopsies demonstrated benign colonic mucosa with focal atrophy consistent with ischemia. There were massive deposits of amyloid in the submucosa.

that the lesion is not a precursor myeloma.

of multiple

Heavy Chain Diseases A small number of patients have been described who produce and excrete heavy chain immunoglobulin fragments without associated light chains, as a result of a lymphoplasma cell proliferative process. Of the heavy chain diseases (alpha, gamma, and mu), alpha heavy chain disease (a = HCD) is the most common and essentially the only one that involves the GI tract. Since the first description by Seligmann and Table

1.

Esophagus

4 2

Stomach

bowel

Colon

*One

Abnormalities Amyloidosis*

No. of Patients

Site

Small

Roentgenologic With Primary

Radiographic

Decreased

Findings

to absent

Tertiary contractions creased peristalsis Reflux

2 1

pharynx Masses or prominent Multiple small ulcers Atrophic folds

1 5 2 1

had findings

of barium

peristalsis with

1

3

patient

in 20 Patients

de-

into the nasofolds

Thickened folds Malabsorption pattern Dilated loops Changes suggestive of longstanding ulcerative colitis at multiple

sites.

Mihaesco in 1971:’ more than 150 cases of LYHCD have been reported. It affects young adults, mostly non-Europeans living in the Mediterranean area, North Africa, and the Middle East. It appears to occur in areas where undernutrition, poor hygiene, and a high incidence of intestinal infections are common. It is rare in Western countries. No case of (u-HCD has been recognized at the Mayo Clinic. Diarrhea and severe malabsorption are the main and nearly universal clinical features. Abdominal pain, vomiting, weight loss, and finger clubbing are also frequent. Pathologically, there is a diffuse and extensive infiltration of lymphoid cells in the lamina propria of the small bowel, resulting in obliteration of the villous architecture.43 The process extends the entire length of the small bowel, and there is associated mesenteric lymphadenopathy. Radiologic findings are variable.44-46 The small bowel folds may be thickened with multiple nodular defects. A sprue-like pattern may also be seen. Extrinsic compression and displacement of the bowel secondary to enlarged mesenteric nodes may be seen, giving the appearance of strictures. Differential diagnostic considerations include the other plasma cell dyscrasias, lymphoma, Whipple’s disease, celiac disease, and giardiasis. The exact relationship of the N- HCD and Mediterranean lymphoma is unclear, but it is likely that they represent the same entity.

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Fig 9. (A and 9) A 49-year-old woman with Waldenstriim’s macroglobulinemia diagnosed six years before. CT scan demonstrates hepatosplenomegaly with periaortic adenopathy.

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1

Fig 10. Waldenstriim’s macroglobulinemia of the stomach. This 55-year-old man presented with upper GI bleeding, Endoscopy demonstrated a duodenal ulcer. Double contrast study demonstrated along a 4-cm greater curve intramural tilling defect with a small ulcer on its inferior aspect, as well as the duodenal ulcer. Endoscopy and biopsy of the mass showed “immature cells of the lymphocyte-plasma cell series” in the lamina propria. Further work-up demonstrated the typical laboratory findings of WaldenstrGm’s macroglobulinemia.

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Fig 11. (A and B) Gastric plasmacytoma in a 4Dyear-old woman with five-year history of vague upper abdominal pain. Single contrast stomach exam demonstrates markedly thickened folds with ulcerations. Endoscopic examination noted multiple polypoid lesions throughout the stomach with many ulcerations on the lesions. Biopsy showed plasmacytoma. Patient has not developed other lesions or evidence of multiple myeloma in the two years since the examination,

Fig 12. Duodenal plasmacytoma. 5% year-old man with right upper quadrant pain. CT scan demonstrates a large mass anterior to the pancreas and adjacent to the second and third portions of the duodenum. At laparotomy. a huge plasmacytoma was found involving the entire duodenal sweep. beginning at the pylorus.

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