Clinical History:
A 53-year-old man presented with a several month history of fatigue and vague abdominal pain.
Laboratory evaluation revealed mild anemia but no other abnormalities in his complete blood count or
electrolyte studies. The patient subsequently presented with massive upper gastrointestinal bleeding.
Endoscopy revealed bleeding from multiple ulcerated sites in the gastric mucosa. No masses were seen.
An emergent subtotal gastrectomy was performed to control the bleeding.
Case 4 - Figure 1 - Low power view of section from gastric resection shows diffuse, extensive infiltration of the submucosa by amyloid.
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Case 4 - Figure 2 - Higher power view shows extensive perivascular amyloid deposition with associated hemorrhage.
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Case 4 - Figure 3 - Amyloid appears as an amorphous, waxy, eosinophilic material on H&E staining (3A)...
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Case 4 - Figure 4 - ...and upon Congo red staining has a red/green birefringent appearance under polarized light (3B).
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Pathologic Findings:
Grossly, the stomach
was filled with freshly clotted blood. The mucosal surface contained multiple areas of ulceration with
associated hemorrhage. Upon sectioning through the wall of the stomach, the hemorrhage was extensively
present throughout the submucosa as well. The gastric wall felt somewhat stiff to palpation, but no
masses were identified.
Microscopically, sections showed massive deposition of a waxy, amorphous pink substance in the
submucosa of the stomach, with associated edema and hemorrhage. The amorphous substance was present in a
perivascular distribution, but was also present within the connective tissues of the submucosa, focally
in the interstitium between muscle fibers, and around nerve fibers in the myenteric plexus. The
overlying mucosa was focally ulcerated.
Congo red staining with examination under polarized light confirmed that the amorphous pink substance
was amyloid.
Subsequent biopsies of liver and small bowel were negative for significant amyloid deposition. Upon
initial evaluation, the patient did not have urine or serum monoclonal proteins, and an initial
evaluation of the bone marrow showed a mild plasmacytosis with perivascular amyloid. Over the next year,
however, the patient did develop a serum IgG/lambda monoclonal protein, and eventually developed plasma
cell myeloma within the bone marrow.
Diagnosis:
Gastric Involvement by Amyloid Deposition
Discussion:
Amyloidosis is characterized by
the deposition of an insoluble extracellular protein. This disease was once classified into distinct
primary and secondary types, but is now regarded as a more heterogeneous group of disorders in which the
aberrant protein can be any one of a variety of polypeptides with the physical and morphologic properties
of amyloid. All types of amyloid may involve the gastrointestinal tract at any level. A general
classification of amyloid by composition of the amyloid fibrils is as follows:
- AL: primary and myeloma associated
- SAA or AA: secondary, associated with longstanding chronic inflammation and familial Mediterranean
fever
- AF: familial amyloidosis
- AS: senile amyloidosis (including cardiac amyloid and brain amyloid)
- AE: endocrine associated, such as that associated with medullary carcinoma of thyroid.
AL and AA are the most common (excluding senile amyloidosis), and of these about 2/3 are AL type.
Rarely, patients develop amyloidosis but no associated plasma cell dyscrasia or other inflammatory
condition is ever discovered. Amyloid deposition in the gastrointestinal tract has also been reported in
chronic dialysis patients.
Pathogenesis:
Amyloid is not a single protein, but a variety of proteins
seen in the context of multiple disease processes in which abnormal extracellular proteins sharing a
common tertiary molecular structure are produced. The pathogenesis in part depends on the underlying
disorder leading to the production of amyloid. In AL amyloidosis, the abnormal protein consists of
portions of immunoglobulin light chain. Most of these patients have abnormal monoclonal proteins in
serum and/or urine, even in the absence of detectable plasma cell myeloma. In SAA amyloidosis, the
abnormal protein consists of portions of acute phase reactant serum proteins. In familial and senile
amyloidosis, prealbumin is the precursor protein for the fibrils. The amyloid associated with medullary
carcinoma of thyroid is derived from calcitonin.
The protein itself is not toxic or injurious; however, the accumulation in tissues affects adjacent
cells, causing vascular obliteration, mucosal diffusion problems, and pressure atrophy of mesenchymal
tissues.
Clinical and Pathologic Features:
Amyloidosis of all types frequently involves the gastrointestinal tract (approximately 70%
of cases of AL amyloidosis and 55% of AA). However, it is often asymptomatic. When symptomatic, the
symptoms depend on the area of the gut and the type of tissue that is involved.
Esophageal involvement occurs in about 2/3 of patients, and may lead to reflux and dysphagia. Gastric
involvement may manifest as bloating, pain, outlet obstruction, hematemesis, or frank hemorrhage.
Intestinal involvement may also cause obstruction or bleeding, either chronic or acute and massive.
Weight loss, nausea, vomiting, diarrhea, constipation, and melena have been reported in both primary and
secondary amyloidosis.
Infiltration around blood vessels, perhaps the most commonly seen pattern, is the cause of hemorrhage
and/or ischemia. Infiltration of the mucosa may result in ulceration and bleeding as well. In addition,
malabsorption can result from both diffusion problems from mucosal amyloid, and bacterial stasis from
muscular involvement and decreased motility. Infiltration of the muscularis and/or enteric nerves may
result in pseudo-obstruction and other motility disorders.
Grossly, any level of the gastrointestinal tract may be involved, and involvement may be in a patchy
distribution. Deposition is usually diffuse, but isolated tumor masses or strictures may be formed.
Endoscopic findings include ulcers, mucosal friability, and superficial erosions. Hypertrophic gastric
folds and pseudopolypoid lesions throughout the gut have been described as well. If there is mucosal
infiltration or ischemic injury, the mucosa may be markedly ulcerated and hemorrhagic. Often, however,
the gross and endoscopic evaluation of the gut in gastrointestinal amyloidosis is essentially
unremarkable, thus biopsy of normal mucosa in a patient who is being evaluated for amyloidosis is
absolutely warranted.
Histologically, amyloid deposits on routine H&E stains consist of amorphous, waxy, pink material
that often has chatter artifact. Congo red staining shows red/green birefringence under polarized light;
Thioflavin immunofluorescence stains are also useful, and some consider them more sensitive than Congo
red staining. Electron microscopy shows a characteristic fibrillary structure consisting of twisted
beta-pleated sheets; the interlocking fibrils measure 7.5-10 nanometers in length. Immunohistochemical
staining can be employed to subclassify the actual type of amyloid fibril.
The areas most often affected include the perivascular areas of small vessels in the submucosa; the
muscularis propria and muscularis mucosa; and around myenteric nerves. Infiltration of the lamina
propria and mucosa are less commonly seen.
Diagnosis:
Some authorities believe that
rectal biopsy gives the highest yield in terms of diagnosing gastrointestinal amyloidosis, and it is
probably the most commonly employed diagnostic procedure. Others, however, believe that stomach and
small bowel biopsies provide a higher diagnostic yield. If gastrointestinal amyloidosis is a
consideration, multiple biopsies of several sites are often helpful. It is important to have biopsies
that are sufficiently deep to include superficial submucosal vessels, as these are often the most heavily
involved regions in the gut.
In cases of primary (AL) amyloidosis, patients often have monoclonal serum and/or urine proteins, as
well as elevated total serum protein. Bone marrow evaluation is usually undertaken as well, to look for
plasma cell dyscrasias.
Differential Diagnosis:
Amyloidosis with patchy ulceration and/or
strictures may be confused with other forms of inflammatory bowel disease; however, the histologic
appearance of course is quite different. Amyloid forming tumor masses may mimic carcinoma and other
polypoid lesions both radiographically and clinically. Light chain deposition disease (LCDD) may look
identical to amyloid deposits on H&E; however, in LCDD the deposits are granular rather than
fibrillar by electron microscopy, stain monotypically with light chain immunostains; and do not have the
typical apple green birefringent appearance with polarized light on Congo red staining.
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