Laryngeal mucosa-associated lymphoid tissue (MALT) lymphoma ...

J Hematopathol DOI 10.1007/s12308-012-0141-0

Laryngeal mucosa-associated lymphoid tissue (MALT) lymphoma associated with bronchial MALT lymphoma: a case series and review of the literature Matthew K. Steehler & Kenneth Newkirk & Melissa M. Amorn & Bruce J. Davidson & Charles Read & Metin Ozdemirli

Received: 22 August 2011 / Accepted: 7 February 2012 # Springer-Verlag 2012

Abstract The objective of this study is to describe the management of two adults with laryngeal mucosa-associated lymphoid tissue (MALT) lymphoma and concurrent bronchial MALT lymphoma and to review the literature pertaining to laryngeal lymphoma and discuss appropriate evaluation and treatment options. This is a retrospective case series where a retrospective chart review was performed. Demographic data collected includes presenting symptoms, age at presentation, gender, comorbidities, course of illness, and follow-up. Operative reports, serial endoscopic examinations, and serial CT images were used to monitor for recurrence. Between 2004 and 2006, two adult subjects were diagnosed and treated for false vocal cord MALT lymphoma with concurrent low-grade bronchial MALT lymphoma. Both patients were treated with surgical debulking, adjunctive rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (RCHOP) chemotherapy, and external beam radiation. At most recent followThis paper was presented at the American Academy of Otolaryngology— Head and Neck Surgery Annual Meeting. Laryngeal lymphoma associated with bronchial associated lymphoid tissue lymphoma: a case series. San Diego, California—October 4–7, 2009 M. K. Steehler (*) : K. Newkirk : M. M. Amorn : B. J. Davidson Department of Otolaryngology—Head and Neck Surgery, Georgetown University, Gorman 1, 3800 S. Reservoir Rd. NW, Washington, DC 20007, USA e-mail: [email protected] C. Read Department of Pulmonology and Critical Care, Georgetown University Hospital, Washington, DC, USA M. Ozdemirli Department of Pathology, Georgetown University Hospital, Washington, DC, USA

up, there was no endoscopic, clinical, or radiologic evidence of recurrence. Surgical debulking, RCHOP chemotherapy, and external beam radiation show promising results in treating false vocal cord laryngeal MALT lymphomas with concurrent low-grade bronchial MALT lymphomas. Bronchoscopy and laryngoscopy should be included in the evaluation of a patient with a laryngeal or bronchial MALT lymphoma for staging and optimal treatment since MALT lymphoma can be multifocal in both larynx and bronchus as shown in this case series. Keywords Marginal zone B-cell Lymphoma . Larynx . Bronchial neoplasms . Laryngoscopy . Bronchoscopy

Introduction Mucosa-associated lymphoid tissue (MALT) lymphoma is a subclass of non-Hodgkin B-cell lymphoma that is rarely seen in the larynx: only 15 cases have been previously reviewed in the medical literature [1, 2]. Most lymphomas involving the larynx also involve sites rich in lymphatic drainage such as the salivary glands, epiglottis, thyroid, nasopharynx, and tonsils [2–5]. We present two cases of laryngeal MALT lymphomas that had concurrent bronchial MALT lymphoma and review the literature on these disorders.

Case #1 A 56-year-old male with a past medical history significant for gastric MALT lymphoma status post partial gastrectomy 9 years prior presented with symptoms of stridor after bronchoscopy, progressive dyspnea on exertion, and mild dysphagia. Two months prior to his visit, the patient had been

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intubated for elective shoulder surgery without any documented airway abnormalities. An outside chest X-ray revealed a density of the left lingula of the lung for which the patient had been referred to pulmonology. The patient’s only medication was Lansoprazole 30 mg for acid reflux. He had no history of smoking and drank only one beer per week. The patient was referred to the Otolaryngology—Head and Neck Surgery department after a diagnostic bronchoscopy showed false vocal fold lesions and postprocedure stridor. A flexible fiber optic laryngoscopy revealed bilateral false vocal cord lesions (Fig. 1a). A contrast CT scan of the neck revealed two large, submucosal, heterogeneous masses both measuring 2.4×2.0 cm at the level of the false vocal folds. The nasopharynx, epiglottis, base of the tongue, piriform sinuses, and vallecula were all unremarkable. All labs were within normal limits A direct laryngoscopy and biopsy with tracheostomy was performed in the operating room. There was normal mucosa overlying the lesions and surrounding tissues appeared unremarkable. Biopsies of the lesion were taken and tissue was debulked with a CO2 laser. Histologic sections of the laryngeal tumor showed squamous or respiratory mucosa with squamous metaplasia with an underlying dense atypical lymphoid infiltrate. There was no infiltration into overlying epithelium. The lymphocytes were small, monotonous, centrocyte-like with irregular nuclei and scant cytoplasm (Fig. 2a and b). No reactive lymphoid follicles, transformed large atypical lymphocytes or significant plasmacytosis was observed. Immunohistochemistry showed that the majority of lymphocytes stained positive for CD20 (Fig. 2c) and BCL-2 and were negative for CD3, CD5, CD10, CD23, CD43 (Fig. 2d), BCL-6, and cyclin-D1. Kappa and lambda immunostains showed occasional polyclonal plasma cells. The above findings were consistent with a MALT lymphoma of the larynx. Fig. 1 Patient #1: vocal cords (a, b). a Bilateral false vocal cord enlargement. b Larynx 8 months status postsurgical resection, chemotherapy, and radiation. Patient #2 (c, d): vocal cords. c Bilateral false vocal cord enlargement. d Larynx 28 months status post surgical resection, chemotherapy, and radiation

The patient’s lingular mass was biopsied during bronchoscopy. The endobronchial lesion demonstrated respiratory mucosa and pulmonary parenchyma with subepithelial atypical lymphoid aggregates. The atypical lymphocytes were small, centrocyte-like with irregular nuclei and had scant cytoplasm (Fig. 2e–f). There were lymphoepithelial lesions and rare reactive lymphoid follicles, but no plasmacytosis or transformed large lymphocytes were seen. Immunohistochemistry showed that the atypical lymphocytes stained positive for CD20, CD79a, and BCL-2 and were negative for CD3, CD5, CD10, CD23, CD43, BCL-6, and cyclin-D1. CD138 and kappa and lambda immunostains showed occasional polyclonal plasma cells. Because of the presence of reactive follicles and the possibility of reactive lymphoid hyperplasia, polymerase chain gene analysis was performed on this specimen for immunoglobulin heavy chain gene. This analysis showed monoclonal immunoglobulin heavy chain gene rearrangement, which supported the diagnosis of low-grade MALT lymphoma. Bone marrow examination for staging was negative for lymphomatous involvement. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy (RCHOP) was initiated after diagnosis, followed by radiotherapy with a complete response in the larynx (Fig. 1b). At 5 years, the patient shows no evidence of recurrence.

Case #2 A 62-year-old female singer with a past medical history significant for multinodular goiter, tonsillectomy/adenoidectomy, and multiple pelvic surgeries presented with a postobstructive pneumonia, for which she underwent a bronchoscopy. The patient had symptoms of intermittent hoarseness for 3 years and had a persistently raspy voice for 2 months prior to

J Hematopathol Fig. 2 Representative morphologic features from formalin-fixed paraffinembedded sections of the laryngeal tumor (first case; a–d). a Lower magnification shows respiratory mucosa with focal squamous metaplasia and underlying dense atypical lymphoid infiltrate (hematoxylin and eosin, ×40). b Higher magnification of the small atypical lymphocytes (hematoxylin and eosin, ×100). c By immunohistochemistry, the lymphocytes are predominantly of B-cell origin, positive for CD20 and d negative for CD43. Representative sections of the bronchial tumor (e–f). e Lower magnification shows bronchial mucosa with underlying dense atypical lymphoid infiltrate (hematoxylin and eosin, ×100). f Higher magnification shows small atypical lymphocytes with occasional plasma cells (hematoxylin and eosin, ×400)

her evaluation. Her medications were Neurontin 200 mg BID for shingles, hormone replacement therapy, and Mometasone Furoate nasal sprays PRN. The patient had a five pack-year history of smoking and rarely drank alcohol. Laboratory studies were all within normal limits. On bronchoscopy, a mass was biopsied near the left main stem bronchus. Histologic examination of the tissue showed monotonous proliferation of atypical lymphoid infiltrate containing small centrocytelike irregular lymphocytes with scant cytoplasm (Fig. 3a, b). There was infiltration of the overlying epithelium. No lymphoid follicles, plasmacytosis, or increased transformed large lymphocytes were observed. The immunohistochemistry showed that the atypical lymphocytes were positive for CD20 (Fig. 3c), CD43 (Fig. 3d), Bcl-2, CD79a, Pax-5, and negative for CD3, CD5, CD10, Bcl-6, cyclin D1, and CD23. A diagnosis of low-grade bronchial MALT lymphoma was made. A staging positron emission tomography-computed tomography revealed a laryngeal lesion involving the false vocal cords. Upon presentation to the Otolaryngology—Head and Neck Surgery department, flexible fiber optic laryngoscopy revealed fullness of bilateral false vocal folds. Abnormal soft tissue fullness was noted in the right false vocal cord, which obscured the right true vocal cord, and similarly in the

left anterior false vocal cord (Fig. 1c). Direct laryngoscopy with biopsy and bilateral surgical debulking was performed. Histologic examination of the laryngeal biopsy showed respiratory mucosa with atypical lymphoid infiltrate containing small irregular centrocyte-like lymphocytes with scant cytoplasm similar to cells seen in bronchial biopsy (Fig. 3e, f). The immunohistochemistry showed that the atypical lymphocytes were positive for CD20, Bcl-2, CD43, and negative for CD3, CD5, CD10, Bcl-6, cyclin D1, CD34, and TdT. A diagnosis of low-grade MALT lymphoma was made. The patient was referred to oncology. The bone marrow biopsy was negative for lymphomatous involvement. The patient was treated with six cycles of RCHOP therapy followed by external beam radiation. The patient has been followed clinically and radiologically for the past 5 years and has similarly shown no evidence of recurrence (Fig. 1d).

Discussion MALT lymphoma is a subset of lymphomas known as nonHodgkin B-cell lymphomas (NHLs). Lymphomas are the most common non-epithelial tumors of the head and neck,

J Hematopathol Fig. 3 Representative morphologic features from the bronchial tumor (second case; a–c). a, b Lower magnification shows fragments of respiratory mucosa with underlying dense atypical lymphoid infiltrate (hematoxylin and eosin, ×40). c Higher magnification of the small atypical lymphocytes (hematoxylin and eosin, ×400). By immunohistochemistry, the lymphocytes are predominantly of B-cell origin, positive for CD20 (d) and CD43 (e) (×100). Representative sections of the laryngeal tumor (f–g). f Lower magnification shows respiratory mucosa with underlying dense atypical lymphoid infiltrate and minor salivary glands (hematoxylin and eosin, ×100). g Higher magnification shows small centrocyte-like atypical lymphocytes (hematoxylin and eosin ×400)

but they are typically found in areas rich in lymphoid tissue such as Waldeyer's ring (77%), the parotid gland, and superficial cervical lymph nodes [6, 7]. In the larynx, most NHLs originate where laryngeal lymphoid tissues predominates, such as the supraglottic area. NHLs involving the false vocal fold and/or true vocal fold are rare though there have been recent reports in the literature of clinical features of these cases have been summarized in Table 1. MALT lymphomas have increased in incidence since the 1970s due to an increase in risk factors including: Helicobater pylori-induced gastric MALT lymphoma, immunosuppression, pesticides, and an aging population [1]. MALT lymphomas are believed to arise from resident lymphoid cells or lymphoid cells recruited to areas free of white cells by chronic inflammatory processes [6]. Extranodal lymphomas comprise only 3–5% of all lymphomas and are most frequently discovered in the stomach and gastrointestinal tract. Bronchial MALT lymphoma comprise more than two thirds of all primary NHL of the lung;

however, pulmonary NHLs are rare entities encompassing only 0.4% of all lymphomas. Secondary involvement of the lung in patients with a history of lymphoma is much more common (incidence of 25–40%) [8]. NHL is uncommon in the head and neck, accounting for 5% of all head and neck cancers and only 2% of all malignancies [9]. Patients with laryngeal lymphoma may have concurrent involvement of the lung (as seen in our case series) either due to secondary involvement by metastasis of MALT lymphoma or possibility of multifocal nature of MALT lymphomas. The patient in case #1 is an example of this point having had a history of gastric MALT lymphoma in the past, subsequent lymphomas could be new primary lesions or the presence of indolent multifocal disease from the previous gastric MALT lymphomas. MALT lymphomas have conventionally been diagnosed through endoscopy and treated using standard modalities that include radiation, surgery, chemotherapy, and monoclonal antibodies [3]. Gastric MALT lymphoma associated with H. pylori has been treated in a manner unique to other

J Hematopathol Table 1 Laryngeal MALT review of literature—treatment and results Study

Design

Size

Treatment

Results

Deibold [18]

Retrospective

1 Patient

Remission

Hisashi [19]

Retrospective

1 Patient

Chemotherapy radiation (40 Gy) Radiation (30 Gy)

Kato [20]

Retrospective

1 Patient

Remission—35 months

De Bree [21] Zinzani [22]

Retrospective Retrospective

1 Patient 1 Patient

Chemotherapy radiation (50 Gy) Radiation (28 Gy) Radiation

Remission—24 months Remission

Cheng [23] Gabrys [24]

Retrospective Retrospective

1 Patient 1 Patient

Radiation (30 Gy) Chemotherapy

Remission—12 months Remission

Tsang [25] Fung [26] Kania [1]

Retrospective Retrospective Retrospective

1 Patient 1 Patient 1 Patient

Recurrence Remission—31 months Remission—24 months

Arndt [27]

Retrospective

1 Patient

Radiation Radiation (44 Gy) Surgical Excision, Clarithromycin, Amoxicillin, Omeprazole Doxycycline Chemotherapy

Author

Retrospective

2 Patients

Debulking, chemotherapy radiation

Remission—60 months

MALT lymphomas. H. pylori triple therapy (proton pump inhibitor, Clarithromycin, and Metronidazole) has effectively been used as treatment for gastric MALT lymphoma [10]. A recent case report shows an effective remission of laryngeal MALT lymphoma using the unconventional treatment modalities of complete surgical resection, triple therapy for H. pylori, and close endoscopic monitoring of the esophagus and stomach [1]. Traditional treatment for MALT lymphoma of the larynx has included radiotherapy, chemotherapy, and larynxsparing surgical resection. Radiotherapy has proven to be an efficacious treatment and is indicated for all nonHodgkin lymphomas, including marginal B-cell lymphomas [10, 11]. The typical dose of radiation is from 30 to 50 Gy [12]. Patients with primary lymphoma of the larynx are also treated with combination chemotherapy, including cyclophosphamide, doxorubicin, vincristine and prednisolone for up to six cycles [3, 13]. In addition, therapy with antiCD-20 monoclonal antibody chemotherapy (Rituximab) has also been shown to be beneficial [2, 3, 10, 11]. A review of the literature regarding laryngeal MALT lymphoma treatments and outcomes can be found in Table 1. In two recent case reports of primary laryngeal lymphoma, complete remission was achieved with chemotherapy, surgical debulking, and radiotherapy [2, 3, 13]. Surgery

Remission—46 months

Remission—6 months

Comments

Found in setting of squamous cell carcinoma—subsequent laryngectomy performed

Large series of MALT lymphomas, only one laryngeal—limited information This lesion was a Hashimoto's MALT thyroid mass that invaded through the thyroid cartilage into the larynx

Concurrent gastric MALT—attempted conservative H. pylori treatment— opted for chemo given extensive disease This paper

alone has been advocated to treat small, isolated disease [1–3]. A recent article by Kania et al. has reported a case of primary laryngeal MALT lymphoma where complete surgical resection of the lymphoma was achieved [1]. Postsurgical treatment included pharmacologic triple therapy with Omeprazole 20 mg twice per day (for 6 months), Amoxicillin 500 mg four times per day and Clarithromycin 500 mg for 10 days [1]. The aforementioned treatment adheres to the specific guidelines for treating laryngoesophageal reflux (LPR) and gastroesophageal reflux disease from H. pylori from the American Academy of Otolaryngology—Head and Neck Surgery [14]. This treatment spared the patient the side effects of local radiation and chemotherapy, and appears to be a viable conservative therapeutic option in patients where the lymphoma can be completely resected [1]. Given that bronchial MALT may also be associated with laryngeal MALT, consideration should be given to the appropriate diagnosis and treatment of this entity. Bronchoscopy has been reported as the procedure of choice in establishing the initial diagnosis of bronchial MALT [8]. BAL and biopsies from this procedure with flow cytometric analysis are often helpful when working with small biopsies and limited materials [15]. Immunophenotypic staining is also helpful in establishing the diagnosis of bronchial

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MALT. Should bronchoscopy fail to identify the diagnosis: VATS or thoracotomy is recommended for definitive diagnosis [16]. Bronchial MALT lymphoma is treated in a similar manner as laryngeal MALT lymphoma with the same controversies. Surgery, chemotherapy, and radiotherapy all have all been proven to be therapeutic alone or in combination, but there are no consensus guidelines [15]. Regardless of treatment, bronchial MALT lymphomas have a slow rate of progression and a favorable course [17]. RCHOP and cyclophosphamide, vincristine, and prednisone have both been shown to be viable therapeutic options in treatment of bronchial MALT lymphomas [15, 16]. Surgical resection and local radiotherapy have also both been shown to be both effective and curative [15]. There has never been a report of laryngeal MALT lymphoma and bronchial MALT lymphoma occurring concurrently. Due to the relative dearth of literature regarding these two pathologies, this case series presents strong evidence that laryngeal and bronchial MALT lymphomas have a significant association with one another. Given the relative rarity of these lesions, the most plausible conclusion is that bronchial MALT lymphoma and laryngeal MALT lymphoma are strong risk factors for one another. This theoretically may be due to secondary involvement by metastatic spread or due to multifocal nature of the disease. Molecular characterization of the immunoglobulin heavy or light chain genes with sequencing would be necessary to answer these questions. These studies could not be performed in the current cases due to very small nature of the biopsies obtained. When laryngeal and/or bronchial MALT lymphoma is found, further work-up in search of the other disease entity is paramount. The presence of concurrent MALT lymphomas will undoubtedly change the treatment of the patient: including extension of the fields of radiation and requiring larger areas of disease surveillance.

Conclusion Laryngeal MALT lymphoma and bronchial MALT lymphomas are both exceedingly rare malignancies. Treatment of both laryngeal MALT and bronchial MALT consists primarily of chemotherapy and radiation with surgery reserved for isolated lesions and for cases that require surgical intervention for airway management. Management of concurrent inflammatory disorders such as LPR and H. pylori may play a significant role in the management of all MALT lymphomas. Based on our cases, we feel bronchoscopy is indicated in the finding of solitary laryngeal MALT because concurrent bronchial MALT may be present. Subsequently, chemotherapy and more extensive local radiation should be instituted as treatment (as well as more thorough post-treatment surveillance). In patients with

bronchial MALT lymphomas, laryngoscopy is indicated to rule out concurrent laryngeal lymphoma.

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