Esophageal stricture due to amyloidosis in plasma cell dyscrasia: A case report and review of literature

Abstract

BACKGROUND

Esophageal involvement in amyloidosis is rare and may present with progressive dysphagia from stricture formation. This report describes a rare case of esophageal amyloidosis associated with an underlying plasma cell dyscrasia.

CASE SUMMARY

A 65-year-old woman presented with a 3-month history of progressive dysphagia, weight loss, and anorexia. Her hemoglobin was 11.1 g/dL, with serum albumin 3.1 g/dL and globulin 5.1 g/dL. Barium swallow demonstrated a short, concentric stricture in the upper esophagus. Upper gastrointestinal endoscopy revealed luminal narrowing with mucosal erythema, fine nodularity, and small ulcerations. Histopathological examination of the esophageal biopsy showed abundant amorphous, eosinophilic extracellular material in the subepithelial stroma. The deposits were Congo red-positive and periodic acid-Schiff-negative. Immunohistochemistry indicated lambda light chain positivity. Serum protein electrophoresis suggested an M spike, with markedly elevated serum free lambda light chains and normal free kappa light chains. Diffuse, circumferential esophageal wall thickening was noted on whole-body positron emission tomography-computed tomography. Approximately 50% of plasma cells and immature plasmablasts, with CD38 and CD138 positivity and lambda light-chain restriction, were identified on bone marrow examination, confirming an underlying plasma cell dyscrasia. The esophageal stricture was successfully treated with endoscopic balloon dilation, resulting in significant symptomatic improvement. The patient was subsequently referred to hematology-oncology for definitive treatment of the underlying plasma cell dyscrasia.

CONCLUSION

Esophageal amyloidosis is a rare cause of esophageal stricture and progressive dysphagia and must be confirmed histopathologically via Congo red staining and amyloid typing. An underlying plasma cell dyscrasia must be identified, as definitive treatment should target the hematologic disorder.

Key Words: Amyloidosis; Dysphagia; Esophageal stricture; Plasma cell dyscrasia; Balloon dilatation; Congo red staining; Case report

Core Tip: Esophageal involvement in systemic amyloidosis is rare and presents in variable ways. We report a 65-year-old woman with progressive dysphagia, weight loss, and an upper esophageal stricture. Biopsy demonstrated Congo red-positive amyloid with lambda light-chain restriction, and bone marrow examination revealed approximately 50% lambda-restricted plasma cells, establishing an underlying plasma-cell dyscrasia. Although fat-pad and rectal biopsies were negative, a direct esophageal biopsy confirmed amyloid deposition at the site of disease. Endoscopic balloon dilation resulted in complete resolution of dysphagia, and daratumumab, bortezomib, cyclophosphamide, and dexamethasone therapy was initiated for disease modification.

INTRODUCTION

Amyloidosis comprises a heterogeneous group of disorders characterized by the extracellular accumulation of misfolded protein fibrils within tissues. These deposits can progressively interfere with normal organ structure and function. Researchers have identified multiple amyloidogenic precursor proteins in humans, each associated with distinct clinical forms of amyloidosis. Despite their biochemical diversity, amyloid fibrils share a characteristic β-sheet-rich configuration that contributes to their relative resistance to proteolytic degradation and persistence within affected tissues[1,2].

Systemic amyloidosis, the most common subtype, is characterized by the production of amyloidogenic precursor proteins at a site remote from the organ where amyloid is deposited[3]. Localized amyloidosis is characterized by the production of amyloidogenic precursor proteins at the same site where they are deposited[4,5]. It commonly involves the respiratory tract, urinary bladder, skin, or gastrointestinal (GI) tract[4].

GI involvement may occur in either systemic or localized amyloidosis. GI amyloidosis is generally established by demonstrating amyloid deposition in tissue in an appropriate clinical setting. However, the current literature suggests that GI amyloidosis with direct biopsy confirmation from the GI tract may be rare and that its prevalence varies[5]. Primary systemic light chain amyloidosis (AL) is the most common GI subtype, with a higher prevalence of lambda clones (53%) than kappa (14%)[6]. Hereditary transthyretin amyloidosis accounts for 16% of GI amyloid cases, while secondary amyloidosis accounts for 11%. Regardless of the subtype, the small bowel (duodenum) is the most commonly involved site, followed by the stomach, the colorectum, and the esophagus[7,8]. This case describes esophageal amyloid deposition associated with an underlying plasma-cell dyscrasia, presenting as an esophageal stricture.

CASE PRESENTATION

Chief complaints

A 65-year-old woman presented with 3 months of progressive dysphagia.

History of present illness

The symptoms had an insidious onset and progressed gradually. Initially limited to solids, they later involved both solids and liquids. She also reported an 8 kg weight loss over the past 3 months, with anorexia. Furthermore, the patient experienced one episode of choking on solid food. However, there was no chest pain, regurgitation, heartburn, or upper/Lower GI bleeding. There was no history of odynophagia or accidental corrosive ingestion. The patient’s Brief Esophageal Dysphagia Questionnaire (BEDQ) score over a 14-day recall period was 22 points.

History of past illness

There was no significant history of esophageal or malignant disorders, underlying addictions, or comorbidities.

Personal and family history

Personal and family history was unremarkable.

Physical examination

Mild pallor was observed. The remainder of the general physical and systemic examinations was normal.

Laboratory examinations

Hemoglobin was 11.1 g/dL, serum albumin was 3.1 g/dL, and serum globulins were 5.1 g/dL. The remaining laboratory parameters are listed in Table 1. Peripheral blood film showed normocytic, normochromic anemia with rouleaux formation.

Table 1 Baseline laboratory workup of the patient.

Parameter	Patient value	Reference range
Hemoglobin (g/dL)	11.1	12.0-15.0
Total leukocyte count (×103/mm3)	9.35	4.0-11.0
Neutrophils (%)	61.8	40-75
Platelet count (×103/mm3)	435	150-450
Total bilirubin (mg/dL)	0.56	0.2-1.2
Direct bilirubin (mg/dL)	-	0.0-0.3
AST (IU/L)	15	5-40
ALT (IU/L)	12	5-40
ALP (IU/L)	97	40-129
Total protein (g/dL)	7.8	6.0-8.3
Albumin (g/dL)	3.1	3.5-5.2
Sodium (mEq/L)	137	135-145
Potassium (mEq/L)	4.0	3.5-5.1
Urea (mg/dL)	20	15-45
Serum creatinine (mg/dL)	0.79	0.6-1.2
Serum calcium (mg/dL)	10.6	8.5-10.5
PT/INR (Sec)	15/1.4	11-13.5/0.8-1.1

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; PT: Prothrombin time; INR: International normalized ratio.

Imaging examinations

Barium swallow revealed a short-segment stricture in the upper esophagus (Figure 1A). Upper GI endoscopy showed narrowing at 19 cm from the incisors, with mucosal erythema, fine nodularity, and ulcerations, resulting in partial luminal compromise (Figure 1B and C). A biopsy was obtained from the stricture site. A whole-body positron emission tomography-computed tomography (PET-CT) scan indicated diffuse circumferential wall thickening (up to 7 mm) of the esophagus without significant radiotracer uptake, likely reflecting esophagitis.

Figure 1 Radiological and endoscopic findings of esophageal stricture. A: Barium swallow showing a short-segment stricture in the upper esophagus (black arrow); B: Upper gastrointestinal endoscopy showing luminal narrowing at 19 cm from the incisors, with mucosal erythema, fine nodularity, and ulceration (black arrow); C: Normal-appearing distal esophagus.

Diagnostic assessment: At presentation, the principal differential diagnoses for progressive dysphagia and a short-segment proximal esophageal stricture included malignant, inflammatory, caustic, infectious, structural, and infiltrative disorders. Malignancy was considered given the patient’s age, progressive dysphagia, weight loss, and endoscopic mucosal nodularity and ulceration; caustic and common inflammatory causes were considered less likely in the absence of a relevant history.

A provisional diagnosis of esophageal stricture was maintained. Histopathological examination of the stricture showed abundant amorphous eosinophilic extracellular material in the subepithelial stroma, consistent with amyloid (Figure 2A). Immunohistochemistry (IHC) revealed amorphous extracellular material in the subepithelial stroma positive for lambda light chains and negative for kappa chains, in the setting of an underlying plasma-cell dyscrasia, highly suggestive of AL amyloidosis (Figure 2B and C). Further processing indicated Congo red positivity, apple-green birefringence (Figure 3), and periodic acid-Schiff negativity.

Figure 2 Histopathological and immunohistochemical findings of esophageal amyloid deposition. A: Hematoxylin and eosin (H&E) staining showing abundant amorphous, eosinophilic extracellular material deposited within the subepithelial stroma, consistent with amyloid deposition (H&E ×100); B: Immunohistochemical staining showing positive cytoplasmic/extracellular staining for lambda light chains within the amyloid-containing subepithelial stroma (lambda ×40); C: Immunohistochemical staining showing negative kappa light-chain expression (Kappa ×40).

Figure 3 Congo red staining confirming amyloid deposition in the esophageal biopsy. A: Congo red staining demonstrating salmon-pink amyloid deposits within the subepithelial stroma (×40); B: The same deposits showing characteristic apple-green birefringence under polarized light microscopy, confirming amyloid deposition (×40).

Additionally, serum protein electrophoresis revealed an M-spike (27.8%, 2.27 g/dL) in the gamma region. The free lambda light chain assay was markedly elevated (752.40 mg/L; range, 5.70-26.30), and the free kappa/Lambda ratio was 0.02 (range, 0.26-1.65) (Table 2). Skin fat pad and rectal biopsies were normal. Bone marrow aspiration and biopsy were performed as part of further investigations, confirming plasma cell dyscrasia (Figure 4).

Figure 4 Bone marrow findings demonstrating an underlying plasma-cell dyscrasia. A: Bone marrow aspirate smear showing increased mature and immature plasma cells with eccentrically placed nuclei, abundant basophilic cytoplasm, and perinuclear hof (black circle); residual erythroid and myeloid precursors are also present (Giemsa ×200); B: Immunohistochemical staining shows plasma cells with membranous CD138 expression (x100); C: The neoplastic plasma cells demonstrated positive expression for lambda light-chain (×100); D: Negative for kappa light chain, indicating lambda light chain restriction (×100) .

Table 2 Workup for plasma cell dyscrasia.

Parameters	Patient value	Reference range
M-Spike	2.27 g/dL (27.8%) (present)	Present/absent
Serum free kappa light chain (mg/L)	16.14	3.3-19.4
Serum free lambda light chain (mg/L)	752.40	5.7-26.3
Free κ/λ ratio	0.02	0.26-1.65
Urine Bence Jones protein	Negative	Negative
Spot protein creatinine ratio	100	< 150 mg/g
Whole body PET-CT	Diffuse circumferential esophageal wall thickening (up to 7 mm) without significant FDG uptake, no hypermetabolic lesions seen elsewhere

FDG: ¹⁸F-fluorodeoxyglucose; PET-CT: Positron emission tomography-computed tomography.

FINAL DIAGNOSIS

Esophageal amyloid deposition with Congo red-positive amyloid deposits showing lambda light-chain staining in the setting of an underlying plasma-cell dyscrasia, highly suggestive of AL amyloidosis; however, definitive amyloid subtyping was not performed.

TREATMENT

To improve symptoms of dysphagia, the patient underwent stricture dilation under endoscopic and fluoroscopic guidance with a wire-guided 12-15 mm controlled radial expansion dilation balloon (Boston Scientific, Massachusetts, United States) at 5 atmospheric pressure for 45 seconds. Waist obliteration was observed on fluoroscopy. No postprocedure complications were noted.

OUTCOME AND FOLLOW-UP

The patient had resolution of dysphagic symptoms and a decrease in the BEDQ score to 4/40, from 22/40, and she was placed on a normal diet post-endoscopic dilation[9]. She was initiated on daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) in a standard 28-day cycle regimen, as described in the ANDROMEDA trial, with disease-modifying intent[10]. She had completed three cycles at the time of reporting, with three additional cycles planned. There were no treatment-related adverse events. She also gained 3 kg during the 3-month follow-up. Figure 5 illustrates the timeline of key clinical events in this case.

Figure 5 Timeline of clinical events and management. Timeline depicting the major clinical, diagnostic, therapeutic, and follow-up events during the patient’s clinical course. D-VCd: Daratumumab, bortezomib, cyclophosphamide, and dexamethasone; BEDQ: Brief Esophageal Dysphagia Questionnaire; HPE: Histopathological examination.

DISCUSSION

Systemic AL amyloidosis is a rapidly progressive, multisystem disease that can present with a wide variety of symptoms and clinical signs. Although the precise mechanisms that determine organ tropism remain unclear, increasing evidence suggests that features within the light chain variable region govern the likelihood of organ involvement. The germline gene immunoglobulin light chain variable 6-57 is more prevalent among patients with kidney involvement[11].

GI amyloidosis may occur as part of systemic amyloidosis or as localized disease limited to the GI tract[12]. Patients with GI amyloidosis can present with upper GI bleeding, nausea, vomiting, gastric and duodenal ulcers, diarrhea, malabsorption, gastric outlet obstruction, gastric and colonic perforation, local amyloid tumor, and nutritional deficiency[13]. A study by Yen et al[14] found that only 16.8% of 583 patients with amyloid had GI signs and symptoms. The most common symptom was abdominal pain, followed by nausea and vomiting, which together accounted for 50% of presenting GI complaints. Another retrospective study of 2337 patients over 13 years reported biopsy-proven GI amyloidosis in only 3.3%. In the GI tract, the duodenum had the highest diagnostic yield for biopsies, followed by the stomach, colon, and esophagus[4,15].

The endoscopic appearance of GI amyloidosis may vary depending on the type and distribution of amyloid deposition. Iida et al[15] documented that AL amyloid tends to be deposited in the submucosal and muscular layers, often forming mass-like deposits associated with polypoid protrusions or thickened folds. By contrast, AA amyloid more commonly involves the superficial mucosa, producing fine granular mucosal changes and friability. However, in the esophagus, reported experience is limited, with cases describing narrowing, ulceration, and motility abnormalities.

Our patient presented with a short-segment, concentric esophageal stricture, an uncommon structural manifestation of systemic AL amyloidosis. Esophageal amyloidosis has been reported to range from 13% in a radiologic study to 22% in an autopsy series[16,17]. As with GI amyloidosis, it is commonly seen in systemic amyloidosis, and esophageal involvement in localized amyloidosis is extremely rare[18]. The most common presentations are dysphagia, odynophagia, and hematemesis, and the condition can involve any part of the esophagus[13]. The pathophysiology of dysphagia varies. First, amyloid deposition within the muscularis mucosae, submucosa, and muscularis propria, particularly between muscle fibers, may cause pressure atrophy and disrupt coordinated contraction of esophageal smooth muscle. Second, amyloid deposition in submucosal and intramural blood vessels may compromise local blood flow and contribute to myenteric plexus dysfunction[17,19]. Third, deposition involving the muscularis propria and neural plexuses may impair esophageal neuromuscular function. These modifications can lead to a dilated, atonic esophagus with reduced peristalsis and impaired relaxation, resulting in a clinical and radiologic presentation similar to that of achalasia[17,20]. The endoscopic features of esophageal amyloidosis vary and include ulcerations, strictures, and mucosal and submucosal mass formation[18]. Mucosal involvement in amyloidosis is patchy; therefore, the yield of endoscopic biopsies increases when endoscopically visible abnormalities are present. The diagnostic yield increases from 44% to 76% for gastric biopsies with endoscopic abnormalities and from 33% to 89% for colonic biopsies[15]. Endoscopic ultrasonography can also be used in patients with subepithelial lesions[18]. However, our patient exhibited only esophageal involvement, highlighting the rarity of this case. Table 3 summarizes selected previously published case reports and case series describing esophageal amyloidosis[4,13,17,18,21-28].

Table 3 Selected previously published case reports and case series of esophageal amyloidosis.

Ref.	Study type	Age, sex	Clinical presentation	Endoscopic findings	Type of amyloidosis	Treatment and outcome
Shatnawei et al[13]	Case report	70, male	Hematemesis, Dysphagia	Ulcerated mucosa	NR	Symptom resolution
Fujiya et al[18]	Case report	72, male	Asymptomatic, Incidental findings	Subepithelial lesion in proximal esophagus	AL (λ)-type localized esophageal amyloidosis	On close follow-up, no symptoms occurred
Ailawadi et al[17]	Case report	74, male	Dysphagia	Distal esophageal stricture and endoscopically normal mucosa, but a biopsy-positive lesion in the proximal esophagus	NR	Not reported
Merchant et al[21]	Case report	79, male	Dysphagia and weight loss	Fluid-filled esophagus; manometry: Type 2 achalasia	NR	Symptoms improved with peroral endoscopic myotomy
Ranjan et al[22]	Case report	65, female	Dysphagia	Endoscopy/barium swallow normal; manometry showed low-amplitude, non-propulsive contractions	Multiple myeloma	NR
Ng et al[23]	Case report	85, male	Dysphagia	Large globular mass in the posterior pharyngeal wall and esophageal inlet	ATTR variant	Expired
Bhavani et al[24]	Case report	44, female	Dysphagia	Post-cricoid stricture	NR	NR
Cowan et al[4]	Case series (n = 76; Esophageal: 6)	Male: 62%; age: 61 (median)	Weight loss, heart burn	NR	AL - systemic	Mortality in 4%
Palchaudhuri et al[25]	Case report	69, male	Acute food bolus obstruction	Stricture and ulceration in mid esophagus	NR	Expired
Kahi et al[26]	Case report	47/male	Dysphagia	Submucosal tumor-like lesion in the esophagus	AL (κ) - Amyloidosis	Stable, without treatment
Wongjarupong et al[27]	Case report	72/male	Dysphagia	Normal endoscopy; manometry: Type II achalasia	AL (κ), associated with multiple myeloma	Localized Botulinum toxin, partial improvement
Prokaeva et al[28]	Case report	66/male	Abdominal pain, weight loss	Multiple diminutive nodules in middle third of esophagus	Hereditary AApoAI, novel APOA1 p.Trp96Arg (W72R)	Observation/follow-up; no new organ involvement over approximately 6 years

AApoAI: Hereditary apolipoprotein A-I amyloidosis; AL: Amyloid light-chain; ATTR: Transthyretin amyloidosis; NR: Not reported.

The differential diagnosis of a proximal esophageal stricture includes malignant, inflammatory, caustic, and radiation-induced causes, as well as other benign causes such as eosinophilic esophagitis, tuberculosis, esophageal webs and infiltrative disorders such as amyloidosis[29,30]. In patients with an unexplained proximal esophageal stricture without history of caustic ingestion, particularly when associated with progressive dysphagia and weight loss, endoscopic evaluation with adequate biopsies is essential. In this patient, the absence of a history of corrosive ingestion or known malignancy, together with histopathological demonstration of amyloid deposition at the stricture site, supported esophageal amyloidosis as the likely underlying cause. For short-segment esophageal stricture, guidelines prefer endoscopic balloon dilation which yields the best outcomes in simple, single, short-segment strictures[31,32]. In our case, endoscopic balloon dilation achieved a target diameter of 15 mm; the patient did not experience recurrent symptoms.

The diagnosis of systemic AL amyloidosis requires histological evidence of amyloid deposits in tissue, together with assessment for an underlying plasma-cell dyscrasia, which can be established by detecting a monoclonal protein via serum or urine immunofixation electrophoresis or an immunoglobulin free light chain assay, or by identifying lambda- or kappa-restricted plasma cells in a bone marrow biopsy, which aligns with the approach used in our case[33]. Imaging is a central component of the comprehensive assessment of suspected or confirmed systemic AL amyloidosis. PET-CT demonstrated diffuse circumferential esophageal wall thickening without significant ¹⁸F-fluorodeoxyglucose uptake, and therefore did not specifically suggest amyloid deposition, as the tracer used normally does not detect amyloid fibrils[34]. Emerging amyloid-targeted molecular imaging techniques, including ¹⁸F-florbetapir, ¹¹C-Pittsburgh compound B, and ¹²⁴I-evuzamitide, may facilitate noninvasive detection and quantification of amyloid burden, although their clinical utility and standardization require further validation[35-37].

The prognosis of GI amyloidosis depends on the extent of GI tract involvement, the quality of deposition, and the type of amyloid deposition. Patients with AL amyloidosis with GI involvement have a worse prognosis than those without GI involvement[5]. Treatment of AL amyloidosis must be tailored to the heterogeneous manifestations and severity of the disease, which vary among patients and by the extent of organ involvement. Patients at low risk may be candidates for aggressive therapy, whereas those at high risk require gentle yet rapidly acting regimens[38]. Recent advances have significantly changed how systemic AL amyloidosis is managed and evaluated. D-VCd has demonstrated superior hematologic and organ response rates compared with CyBorD alone and is now an important first-line treatment for patients with newly diagnosed AL amyloidosis[10,39-41].

The strength of this case is that it depicts rare esophageal amyloid deposition associated with an underlying plasma-cell dyscrasia and a suspected AL amyloid process. It demonstrates GI tract involvement in the form of an esophageal stricture causing dysphagia and uses a stepwise diagnostic approach. Nonetheless, the diagnosis has a few limitations. Although Congo red staining confirmed amyloid deposition and IHC showed light-chain (κ/λ) staining, definitive amyloid typing using laser microdissection followed by mass spectrometry (LMD-MS) was not performed. IHC has recognized limitations, including nonspecific/background staining and variable sensitivity and specificity. Light-chain staining alone may not definitively establish AL amyloidosis. Therefore, the possibility of other amyloid subtypes, including ALECT2 and hereditary forms of amyloidosis, cannot be ruled out. LMD-MS-based proteomic analysis would provide more definitive amyloid typing and is an important area for further evaluation[42,43]. Formal classification according to myeloma diagnostic criteria was limited by the lack of cytogenetic and fluorescence in situ hybridization studies and by the lack of detailed documentation of myeloma-defining events and skeletal findings. In addition, amyloid deposition was demonstrated only in the esophagus; fat-pad and rectal biopsies were negative, and a comprehensive evaluation for other organ involvement was not conducted. Cardiac magnetic resonance imaging, plasma-cell cytogenetic/fluorescence in situ hybridization evaluation, and 24-hour urinary protein quantification were not performed. Furthermore, definitive amyloid typing via LMD-MS was unavailable. These limitations preclude a complete characterization of the extent of systemic amyloid involvement and the precise classification of the associated plasma-cell disorder.

CONCLUSION

The esophagus is an unusual site for amyloid deposition. This case demonstrates an uncommon structural feature of esophageal amyloid deposition, appearing as a short-segment esophageal stricture and progressive dysphagia, which resulted in the diagnosis of an underlying plasma cell dyscrasia. In our case, radiologic investigations were nonspecific, and a definitive diagnosis was established with tissue biopsy and Congo red staining. Bone marrow aspiration and biopsy played a vital role in confirming the diagnosis of plasma cell dyscrasia, supporting a suspected AL amyloid process. However, definitive amyloid typing was not performed, and the incomplete systemic organ assessment limits the certainty of clinical inference regarding the extent and subtype of systemic amyloidosis. Endoscopic dilation provided effective symptomatic relief, while disease-modifying therapy was initiated for the underlying plasma cell disorder. Further research is needed to better define the clinical spectrum, systemic associations, optimal diagnostic approach, and treatment outcomes of esophageal involvement in amyloidosis.