Co-occurrence of Primary Tracheal Diffuse Large B-Cell Lymphoma and Pulmonary AA Amyloidosis: A Unique Case Report

Abstract

Primary tracheal diffuse large B-cell lymphoma (DLBCL) is a rare, aggressive, but potentially curable malignancy that is difficult to diagnose and treat. We herein report a 93-year-old Japanese man diagnosed with primary tracheal DLBCL after presenting with progressive dyspnea due to severe upper tracheal stenosis during follow-up for pulmonary amyloidosis. Following the diagnosis, the patient was treated with corticosteroids, followed by R-CHOP chemotherapy, resulting in a therapeutic response. The patient's history of pulmonary amyloidosis may have contributed to the development of tracheal DLBCL. An evaluation of the risks and benefits of various therapeutic interventions is crucial for providing optimal patient-specific care.

Introduction

Tracheal tumors are typically classified into 4 types: benign, malignant, metastatic, or invasive. In adults, the majority of these tumors (approximately 90%) are considered malignant, and a tissue biopsy is necessary for a precise diagnosis. Primary tracheal malignancies include adenoid cystic carcinoma, squamous cell carcinoma, mucoepidermoid carcinoma, carcinoid carcinoma, and sarcoma (1), whereas malignant lymphoma is rare, accounting for less than 3% of all cases (2). Amyloidosis increases the risk of hematologic malignancies such as lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), and leukemia (3,4).

This case report describes a patient diagnosed with primary tracheal DLBCL after experiencing progressive dyspnea during follow-up for pulmonary amyloidosis.

Case Report

A 93-year-old non-smoking Japanese man presented with chronic dry cough for 6 months and progressive dyspnea for 1 week. Seventeen years prior to the onset of this disease, multiple pulmonary nodules had been identified, and partial right upper lobe resection had been performed for one growing lesion. A histopathological examination at the time revealed eosinophilic material in the lung parenchyma, which was positive for Congo Red and amyloid A (AA) and negative for immunoglobulin G (kappa and lambda) and green birefringence fibrils under a polarized microscope, leading to the diagnosis of pulmonary AA amyloidosis. As multiple similar, albeit less active, nodules remained, he was regularly monitored using chest radiography and computed tomography (CT). In addition, he had a history of myocardial infarction, hypertension, diabetes mellitus, and dyslipidemia. He was afebrile, with a respiratory rate of 20 breaths/min and an oxygen saturation of 98%.

A physical examination revealed a biphasic stridor. Chest radiography showed no changes compared with the previous visit (Fig. 1A). However, CT revealed a new mass lesion measuring 30 mm in height, 30 mm in width, and 45 mm in depth in the membranous portion of the upper trachea (Fig. 1B) and known pulmonary nodules in the right upper and left lower lobes. The levels of carcinoembryonic antigen, cytokeratin-19 fragments, neuron-specific enolase, and soluble interleukin-2 receptors were 3.0 ng/mL, 1.4 ng/mL, 7.2 ng/mL, and 368 U/mL, respectively. Bronchoscopy revealed a soft, white, hemorrhagic protruding mass 2 cm below the vocal cord (Fig. 2A, B). A histopathological examination revealed stratified squamous epithelium without atypia and numerous poorly cohesive atypical cells with enlarged pleomorphic nuclei beneath the epithelium. The tumor cells were diffusely positive for CD20 and B-cell leukemia/lymphoma 6, partially positive for CD3, and negative for CD10 and multiple myeloma oncogene 1 (Fig. 3A-F). A histological examination of the biopsy specimens revealed DLBCL of germinal center B-cell-like type. Positron emission tomography-CT with ¹⁸F-fluorodeoxyglucose (FDG) showed a high accumulation of FDG in the lesion, whereas little accumulation was observed in the known lung nodules (Fig. 1C). Based on these findings, the patient was diagnosed with stage I disease according to the Lugano Classification system.

Figure 1.

Chest findings. (A) Chest radiography showing multiple known nodules (B) Chest computed tomography (CT) showing a soft-tissue mass rising from the membranous portion of the upper trachea. (C) Positron emission tomography-CT with ¹⁸F-fluorodeoxyglucose (FDG) showing a high accumulation of FDG in the mass lesion but little accumulation of FDG in known lung nodules. (D, E) CT showing that the mass lesion had markedly reduced in size at (D) two weeks and (E) three months after the start of treatment.

Figure 2.

Bronchoscopy findings. (A, B) Bronchoscopy showing a soft, white, hemorrhagic protruding mass 2 cm below the vocal cord. (C) Bronchoscopy showing only a white, necrotic-like substance adhering to the membranous portion of the upper trachea two weeks after the start of treatment.

Figure 3.

Pathology findings. (A) Hematoxylin and Eosin staining showing diffuse infiltration of atypical lymphoid cells beneath intact stratified squamous epithelium without atypia. (B) atypical cells were negative for AE1/AE3 staining, indicating that they did not arise from the epithelium. (C-F) diffuse infiltration of large pleomorphic lymphoid cells stained diffusely positive for (C) CD20, positive for (D) Bcl-6, and negative for (E) CD10, and (F) MUM-1, indicating high-grade B-cell non-Hodgkin lymphoma, germinal center B-cell-like type (magnification, ×10).

The patient had severe upper tracheal stenosis owing to the presence of a mass. The patient had an Eastern Cooperative Oncology Group performance status score of 1. Although interventional treatments such as tracheal stenting, cryotherapy, and tracheostomy were considered, they were ultimately considered impractical because of their physical invasiveness and high risk of bleeding. Consequently, the patient was treated with corticosteroids, followed by R-CHOP chemotherapy, which consisted of rituximab [375 mg/m² intravenously (IV) on day 1], cyclophosphamide (600 mg/m² IV on day 1), doxorubicin (40 mg/m² IV on day 1), vincristine (1.4 mg/m² IV on day 1), and prednisolone (100 mg/body weight orally daily on days 1-5).

CT and bronchoscopy were performed before the second cycle of R-CHOP chemotherapy. CT revealed that the mass had markedly reduced in size (Fig. 1D), whereas the lung nodules remained unchanged. Bronchoscopy showed no evidence of subepithelial vascular growth, dilatation, or tracheoesophageal fistula (TEF) and only a white, necrotic-like substance adhering to the membranous portion of the upper trachea (Fig. 2C). The tracheal lesions subsequently recovered to normal levels three months after treatment initiation (Fig. 1E). The patient was undergoing chemotherapy and experienced resolution of respiratory symptoms.

Discussion

To our knowledge, this is the first documented case of primary tracheal DLBCL with amyloidosis. Tracheal tumors are extremely rare, with an annual incidence of 1 in 1 million people (5). Non-Hodgkin lymphoma (NHL) is particularly rare, accounting for only 0.23% of all NHL cases (6), and primary tracheobronchial NHL accounts for ＜1% of all NHL cases (7).

The relationship between chronic inflammation and carcinogenesis is well established (8), and amyloidosis, a chronic inflammatory disease, has been implicated in the development of NHL (3,4). Studies from Sweden (3) and Taiwan (4) have suggested that amyloidosis increases the risk of NHL, with a higher incidence observed in older patients, suggesting an association between pulmonary amyloidosis and tracheal DLBCL. To date, the underlying relationship has not yet been fully elucidated. However, inflammatory cytokines have been suggested to play an important role in the development of AA amyloidosis, with persistently elevated levels of amyloid precursor serum AA protein induced by inflammatory cytokines. As the etiology cannot be identified in 6% of AA amyloidosis cases, occult malignancies must be considered in addition to chronic inflammatory diseases (9,10). Further studies are required to elucidate the association between amyloidosis and malignancy.

Several mechanisms have been proposed to explain the development of malignant tracheal lymphoma, including the presence of lymphoid tissue beneath the tracheal epithelium, compression or direct invasion of the tracheal lumen by adjacent lymph node lesions, and lymphatic and hematogenous metastases (11). In this case, preservation of the stratified squamous epithelium without atypia and the absence of obvious lesions in the surrounding lymph nodes led to the diagnosis of primary tracheal DLBCL arising from the subepithelial lymphoid tissue.

When the primary tumor occupies more than 50-75% of the tracheal lumen, it can lead to cough, dyspnea, and wheezing, and treatment of airway obstruction is considered (12). Surgical resection was not deemed appropriate in this case because of the high risk of perioperative complications due to the difficulty in securing surgical margins, concerns about major bleeding, tracheal obstruction, the length of the mass and vocal cord being only 2 cm, and complexity of tracheal intubation. Radiotherapy was not considered because of the potential for radiotherapy-induced tracheal mucosal edema and subsequent airway obstruction. Interventional bronchoscopy typically encompasses various techniques such as mechanical reduction with rigid bronchoscopy, thermal therapy using YAG laser, electrocautery, argon plasma coagulation, cold therapy with cryotherapy, and placement of airway stents using silicone stents, self-expanding metallic stents, and hybrid stents (13). In the present case, placement of airway stents was not indicated because the lesion was located proximal to the cricoid cartilage. Thermal therapy was not selected because of concerns regarding bleeding, hypoxemia, and tracheal perforation. The possibility of rigid bronchoscopy and cryotherapy was also explored. However, these options are not available at our institution, so our patient would have had to be treated at a specialized center that offered these procedures.

The possibility of TEF as a rare, life-threatening complication of chemotherapy is concerning. The prognosis of TEF is extremely poor, with a median survival time of only 35 days (14). R-CHOP is a widely used chemotherapy regimen for DLBCL that has demonstrated significant efficacy in achieving favorable tumor reduction and an improved prognosis. Notably, TEF caused by malignant lymphoma, although rare, tends to have a better prognosis than that caused by lung or esophageal cancers (15). After evaluating the risks and benefits of various therapeutic interventions, we determined that chemotherapy alone was the most suitable treatment for this case.

R-CHOP is a potent combination therapy involving five drugs that specifically target and eliminate cancer cells. We planned to reduce the R-CHOP dose from the standard dose, starting with the first cycle. Although maintenance of dose intensity correlates with the cure rates of chemotherapy in patients with DLBCL, its impact on the survival is diminished in patients ≥80 years old (16). The R-miniCHOP regimen, with reduced doses of CHOP chemotherapy and a conventional dose of rituximab, improves completion rates in patients ≥80 years old and is comparable to cure rates in younger patients receiving standard doses (17). This comparison suggests that completing the planned course of treatment is more important than maintaining the dose intensity, particularly in older patients. However, standard therapy (R-CHOP) for DLBCL in patients ≥85 years old was associated with an improved survival compared with other low-dose regimens (18). Therefore, determination of the optimal dose remains a topic for future research.

We encountered a case of primary tracheal DLBCL that developed during long-term follow-up for pulmonary amyloidosis. As DLBCL can be treated using a multidisciplinary approach, a tissue diagnosis is useful. We made a rapid diagnosis of DLBCL based on an endobronchial biopsy, after which the patient achieved good tumor shrinkage with chemotherapy.

Written informed consent for the publication of this case and accompanying images was obtained from the patient.

The authors state that they have no Conflict of Interest (COI).