Non-gastric mucosa-associated lymphoid tissue lymphomas: a narrative review of pathogenesis, diagnosis, and treatment strategies

Introduction

Background

Extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) are indolent B-cell neoplasms arising in acquired lymphoid tissue due to chronic antigenic stimulation. This antigenic stimulation can occur in the form of immune activation due to bacteria, viruses, or autoimmune conditions. The prototypical example of this is gastric MALT lymphoma, which comprises 30% of all MALT lymphomas (1), is strongly associated with Helicobacter pylori (H. pylori) gastritis, and is often curable with antibiotic eradication therapy (2). However, non-gastric MALT lymphomas can arise in virtually any organ, even those usually devoid of lymphoid tissue, because of chronic inflammation. Common non-gastric sites include the ocular adnexa, salivary glands, skin, lungs, the thyroid, and the small intestine (3). Together, MALT lymphomas are reported to account for 5–15% of all non-Hodgkin lymphoma (NHL) cases in the Western world (1). The clinical presentation of MALT lymphoma varies with the site of involvement, and each site has a unique etiologic association. Despite histologic similarities, these lymphomas differ in clinical behavior, diagnosis, and management.

Each MALT lymphoma involves an interplay between chronic immune stimulation and genetic alterations affecting B-cell survival. The molecular and biochemical pathogenesis of MALT lymphomas begins with chronic antigenic stimulation, either through infection by microorganisms or autoimmune processes, which drives persistent B-cell receptor signaling and nuclear factor-κB (NF-κB) pathway activation (4). The NF-κB pathway promotes cell survival through activation of anti-apoptotic genes such as BCL2, drives inflammation through proinflammatory cytokine activation, and overall enhances immune response and supports immune cell proliferation. Over time, antigen-selected B-cell clones may acquire genetic alterations that can lead to constitutive activation of the NF-κB pathway. Oncogenic translocations such as t(14;18)(q32;q21), which activates MALT1, and t(1;14)(p22;q32), which activates BCL10 (5,6) all allow for autonomous growth. This constitutive activation of NF-κB is what is believed to be linked to the development of MALT lymphomas. However, only a minority of individuals with chronic inflammation develop MALT lymphomas, which suggests that other factors may be at play as well.

From a clinical perspective, MALT lymphomas are usually localized (Ann Arbor stage I) at diagnosis and follow an indolent course. Nodal or bone marrow spread can present with multifocal and disseminated disease; however, non-gastric MALT lymphomas are significantly more prone to dissemination than gastric MALT lymphomas (7). Patients with advanced-stage disease have worse prognoses and require different therapeutic strategies compared to patients with localized disease (8).

Rationale and knowledge gap

Gastric MALT lymphomas are by far the most common of the MALT lymphomas and are well characterized with regard to etiology, diagnosis, and treatment options. However, non-gastric MALT lymphomas are less common, more clinically diverse, and are often underrepresented in large trials or reviews concerning MALT lymphomas. Their etiology, clinical presentation, diagnostic pathways, and optimal management strategies are not standardized. Few comprehensive or unified resources have synthesized what is currently known across all non-gastric MALT sites to inform clinicians seeking guidance on management. This paper aims to bridge this gap in the field. Associations, diagnostic and treatment recommendations for all the neoplasms discussed can be found summarized in Table 1.

Objective

This review examines six major sites of non-gastric MALT lymphoma: ocular, salivary, thyroid, pulmonary, small intestinal, and cutaneous. We outline current understanding of pathogenesis, recommend diagnostic workup including staging, and site-specific treatment approaches. Emphasis is placed on advances within the last decade, including recognition of unique associations and tailored therapies. We present this article in accordance with the Narrative Review reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-25-114/rc).

Methods

This narrative review was conducted using a structured literature search from June 15^th, 2025 to July 20^th, 2025, designed to identify peer-reviewed publications on non-gastric MALT lymphomas. A comprehensive search of the PubMed database was performed, covering studies published between January 1^st, 2015 and July 1^st, 2025. The search strategy utilized both medical subject headings (MeSH) and free-text terms relevant to non-gastric MALT lymphomas, including: “mucosa-associated lymphoid tissue lymphoma”, “extranodal marginal zone B-cell lymphoma”, “lymphoma”, “B-cell”, “non-gastric MALT lymphoma”, “intestinal MALT”, “pulmonary MALT”, “ocular adenxal lymphoma”, “IPSID”, “treatment of MALT lymphoma”, and “etiology of MALT lymphoma”. Searches were limited to human studies published in English with full-text availability. Titles and abstracts were screened independently by all authors and discrepancies were resolved through group consensus. The search strategy summary is summarized and presented in Table 2.

Ocular adnexal MALT lymphoma (OAML)

Etiology and pathophysiology

Primary ocular adnexal lymphoma includes MALT lymphoma of the orbit, conjunctiva, eyelids, or lacrimal glands. Although orbital lymphomas are rare, NHLs account for 55% of all malignancies in the orbit, and most NHLs of the orbit and the ocular adnexa are MALT lymphomas (9). Similar to the role H. pylori plays in gastric MALT lymphomas, Chlamydia psittaci (C. psittaci) is said to play a pivotal role in the pathogenesis of OAML (10). C. psittaci is a bacterium often found in birds (natural hosts). Infection with this agent can lead to chronic conjunctival inflammation and lymphoid follicle formation, thus driving clonal B-cell expansion. However, this association does not seem to be universal. A previous study has found associations between concomitant OAML and C. psittaci infection as high as 47% in Germany and 35% in the USA (11). In contrast, other studies have found no positive cases in Korean (12) and Chinese (13) cohorts of OAML patients. This may indicate geographic variation in etiologic factors. However, trials have shown that even C. psittaci-negative OAML cases can respond to doxycycline therapy (14), the usual first-line therapy choice for bacterial treatment, implying that other doxycycline-sensitive microbes or anti-inflammatory antibiotic effects may be at play. Aside from C. psittaci, no other infection has been definitively linked to OAML, nor have any autoimmune conditions.

Clinical presentation and diagnostic workup

Patients with OAML typically present with insidious, painless swelling of the orbital or ocular surface. Hallmark signs can include unilateral orbital mass causing proptosis or ptosis, or a salmon-colored patch infiltrating the conjunctiva. Diplopia and vision changes can occur if the tumor impinges on ocular muscles or the optic nerve, but many cases can also be asymptomatic aside from cosmetic changes. OAML symptoms can often overlap with other benign eye conditions, such as chronic conjunctivitis. Therefore, patients with persistent unilateral orbital lesions warrant a biopsy. Imaging is a critical first step and is conducted through orbital magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) (15). These modalities can show well-defined masses in characteristic locations, such as the lacrimal gland fossa or conjunctival space, without bone destruction. Another modality that is gaining popularity is the fluorine-18-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/CT (16) due to OAML’s high FDG-avidity. It has been touted for its superior soft tissue resolution combined with metabolic data, which can reveal unsuspected systemic disease and improve staging. However, as mentioned previously, definitive diagnosis requires tissue biopsy with histopathology. Histology reveals dense infiltration of orbital tissues by small lymphocytes. Lymphoepithelial lesions are diagnostic hallmarks, which are composed of malignant lymphocytes invading adnexal epithelial structures (17). However, cytologic atypia can be minimal, and OAML can be confused with reactive lymphoid hyperplasia. Therefore, demonstration of B-cell clonality through polymerase chain reaction (PCR) can help confirm lymphoma in equivocal cases.

Immunophenotyping is also essential; OAML cells characteristically express B-cell antigens called cluster of differentiation (CD), such as CD20, CD79a, BCL-2, and CD43, and are negative for CD3, CD10, and cyclin D1, distinguishing them from mantle or follicular lymphomas (18,19). In summary, a combination of imaging, B-cell morphology, follicular colonization, lymphoepithelial lesions, and supportive immunohistochemistry is essential for an accurate OAML diagnosis. C. psittaci DNA testing can be done on a biopsy specimen if the patient is from an endemic region; however, this is not routine.

Staging and management

Historically, the Ann Arbor system was used for staging purposes, and most OAML presented as a stage IE. Approximately 69–76% of OAML patients present as IE (20,21). However, the Ann Arbor system cannot account for specific orbital features such as laterality or local extension (conjunctiva vs. orbital invasion), leading to most cases being lumped into stage IE. A tumor-node-metastasis (TNM) staging system has been established (22), which allows for the assessment of local tumor extent. T1 is conjunctival spread only, T2 is orbit, eyelid, or lacrimal gland; T3 is bone or sinus invasion, and T4 is extension beyond the orbit. Findings indicate that the new TNM staging system correlates with outcomes (22); however, treatment protocols are quite similar across stages. It is recommended to utilize both staging modalities, as TNM is not as widespread as the Ann Arbor system currently. Advanced stage features, such as T4 or N1, are more indicative of recurrence risk and warrant more aggressive staging and follow-up with PET/CT imaging, which has been shown to upstage disease and change management in 71% of cases (23).

The standard of care for localized OAML is radiotherapy, especially for Ann Arbor stage IE. Multiple retrospective studies have reported excellent control rates ranging from 95% to 100% and a 5-year progression-free survival (PFS) of 85–95% with doses of 24–30 Gy in 12–15 fractions (24). Side effects commonly included cataracts and dry eyes in approximately 50% of patients (25), which underscores the importance of lens sparing and dose optimization. For small isolated conjunctival lesions (salmon spots), biopsy or limited resection followed by observation is a viable option (25), but relapse rates over 5 years were noted to be elevated. Systemic therapy is reserved for stage > II Ann Arbor or OAML with systemic involvement. The treatment of choice is rituximab + chemotherapy. Systemic therapy had lower long-term efficacy compared to localized radiotherapy, with higher relapse rates (25). Treatment of localized disease with systemic therapy often requires adjunctive radiotherapy for complete resolution of the OAML (25). Given the possible etiologic role of C. psittaci, doxycycline therapy has also been explored as a potential initial therapy for OAML. It can be considered for patients with localized conjunctival OAML in C. psittaci regions who want to avoid radiation therapy and can attend close follow-up. A recent trial has demonstrated that a 6-month course of doxycycline resulted in the resolution of conjunctival OAML, with an overall response rate of 65% and a 2-year PFS of 60% (26).

Prognosis

OAML has an excellent prognosis with 5-year survival rates exceeding 95% in most series (27,28). Even among the indolent lymphomas, OAML stands out for low lymphoma-related mortality, which is similar to that for the general population (29). The primary challenge is local relapse, which can occur years after treatment. A long-term follow-up study shows that relapse most often occurs 5 years after treatment (30). This reinforces the need for long-term observation periods to ensure reduced morbidity and mortality.

Salivary gland MALT lymphoma

Etiology and pathophysiology

Salivary gland MALT lymphoma most commonly involves the parotid glands and is strongly associated with Sjögren’s syndrome (SS), an autoimmune disease characterized by chronic lymphocytic sialadenitis. Sjögren’s patients have a markedly elevated risk of developing B-cell lymphoma, most often of the MALT type, in their salivary glands, and salivary MALT lymphoma is often seen as a sequela of long-standing SS. SS is associated with a 7–15× increased risk of developing MALT lymphoma, and MALT lymphomas occur in 5–10% of SS patients (31). Conversely, autoimmune conditions, primarily Sjögren’s, are associated with 70% of salivary MALT lymphoma cases (32). The pathogenesis includes exocrine glands being infiltrated by polyclonal T and B cells. Over the years, germinal centers form in the glands, and specific B cell clones can expand due to acquired genetic mutations. A key molecular event in SS-associated MALT Lymphoma is the loss of function of tumor necrosis factor alpha-induced protein 3 (TNFAIP3), found in 70% of salivary MALT lymphomas, which leads to unchecked NF-κB activity (33). Recurrent t(14;19)(q32;q13) involving G-protein-coupled receptor 34 (GPR34) occurs almost exclusively in salivary MALT lymphoma (34), underscoring unique oncogenic pathways in this site.

Clinical presentation and diagnostic workup

Salivary MALT typically presents as a painless, persistent swelling of the parotid or submandibular glands (35). In a patient with known Sjögren’s, one should suspect lymphoma if there is asymmetrical enlargement within a diffusely inflamed gland. The mass is typically slow growing; rapid enlargement indicates a high-grade transformation. Ultrasound (US) will show a discrete hypoechoic or enhancing lesion within the gland. CT and MRI can delineate the extent of gland involvement and check for lymphadenopathy. ¹⁸F-FDG PET/CT may also be helpful as salivary MALT lymphomas tend to be FDG-avid, compared to benign SS inflammation (36). Fine needle aspiration (FNA) is conducted for preliminary work in cytology and flow cytometry, but a core needle/excisional biopsy is required for definitive diagnosis.

Histology of the FNA would reveal a diffuse infiltration of the gland by lymphoma cells, often centered around residual ducts that form lymphoepithelial islands (37). These can resemble lymphoepithelial sialadenitis, a benign autoimmune lesion also associated with Sjögren’s. Therefore, demonstrating monoclonality is critical for diagnosis (38). Immunohistochemistry can confirm marginal zone B-cell phenotype and monoclonality, or PCR can confirm a monoclonal immunoglobulin heavy chain (IGH) gene arrangement. Flow cytometry can also aid by showing a monoclonal B-cell population.

Staging and management

Once diagnosed, staging is performed to assess if the disease is truly localized to the salivary glands. Approximately 70–80% of salivary MALT lymphomas are localized, stage IE or IIE at diagnosis (39). Staging workup includes CT or PET/CT of the neck, chest, and abdomen to look for lymphadenopathy or other extranodal lesions. For localized salivary gland MALT lymphoma, long-term remission or cure is achievable with regional therapy. Treatment of the region with ultra-low dose radiotherapy using 4 Gy demonstrated high control, preservation of salivary function, and minimal toxicity (40,41). A superficial or total parotidectomy often completely excises the lymphoma, with no residual disease on imaging, and is comparable to radiotherapy alone. However, the lack of significant differences in survival across treatment modalities suggests that the choice of initial treatment may not be a critical factor (42). For multifocal or radiotherapy-refractory cases, rituximab-based regimens remain the standard. The combination of rituximab and bendamustine has demonstrated high overall and complete response rates, durable remission, and tolerability in all extranodal MALT lymphoma cases (8,43). Bruton tyrosine kinase (BTK) inhibitors such as zanubrutinib and acalabrutinib have also been shown to demonstrate efficacy in relapsed/refractory extranodal marginal zone B-cell lymphoma (44,45).

Prognosis

Salivary MALT lymphomas have excellent outcomes, with a 5-year overall survival (OS) rate of 90–95% in most cases (46). Relapses may occur, sometimes in the contralateral gland or other MALT sites such as the stomach or lung, so long-term surveillance is recommended. Some patients with localized salivary MALT lymphoma can be observed due to the indolent nature of the lymphoma; however, this is not a common occurrence (46). With appropriate therapy, most patients achieve prolonged remission or cure with either surgery or low-dose radiotherapy. Advances such as rituximab have made systemic relapses more manageable and further improved the prognosis.

Thyroid MALT lymphoma

Etiology and pathophysiology

Primary thyroid lymphomas are rare, accounting for 2–5% of thyroid malignancies, and approximately 20% of these cases are MALT lymphoma (47). Nearly all thyroid MALT cases arise with a background of Hashimoto’s thyroiditis/chronic autoimmune thyroiditis. Chronic autoimmune thyroid inflammation provides the breeding ground for intrathyroidal MALT, similar to Sjögren’s in the salivary glands. Hashimoto’s patients have a 40–80× higher increased lymphoma risk compared to the general population (48). Genetically, thyroid MALT lymphomas share common aberrations and recurrent mutations in GPR34 and TBL1XR1 have been found in some cases (49). Hashimoto’s thyroiditis can be thought of as a precursor lesion for thyroid MALT lymphoma. Chronic antigen stimulation from thyroid proteins, combined with a cytokine-rich inflammatory microenvironment, supports the development of B cell clones that eventually become autonomous. When a lymphoma occurs, it often coexists with residual autoimmune thyroiditis in the gland.

Clinical presentation and diagnostic workup

Patients with thyroid MALT lymphoma typically present with a rapidly enlarging thyroid mass in the background of known Hashimoto’s disease (50). Patients may notice a goiter that’s been present for years, suddenly enlarges, or becomes nodular. Patients can present with compressive symptoms such as dysphagia, hoarseness, and dyspnea if the mass is significant. Systemic symptoms are typically absent. Initial evaluation often involves neck US to identify hypoechoic masses with internal vascularity (51), and contrast-enhanced CT/MRI to help assess local invasion and nodal disease (43). FNA with flow cytometry can be performed alongside the US; however, a core needle biopsy is preferred for definitive diagnosis (50). The FNA can often be nondiagnostic due to Hashimoto’s and MALT both showing an abundance of lymphocytes. Histology shows effacement of thyroid architecture by sheets of small lymphocytes. Lymphoepithelial lesions are also seen as tumor cells invade thyroid follicles. Differentiating between lymphoma and Hashimoto’s disease involves a monotonous B cell infiltrate forming diffuse sheets rather than lymphocytes forming follicles, plasma cell differentiation with light chain restriction, and monoclonal immunoglobulin (IG) rearrangement on molecular studies (52). Immunohistochemistry and flow cytometry can help confirm clonality among a background of reactive T cells and thyroid epithelial cells (53).

Staging and management

Thyroid MALT lymphomas are usually localized to the thyroid at presentation, which is classified as IE or IIE (54). Staging involves cross-sectional imaging of the neck, chest, and abdomen using CT or PET/CT to identify other potentially involved sites. Chronic Hashimoto’s disease can cause diffuse mild FDG uptake in the thyroid on PET, so a focal intense uptake is more indicative of a lymphoma (47). For localized thyroid MALT lymphoma, low-dose radiotherapy is the primary treatment modality of choice. A multicenter Japanese series has demonstrated a 5-year survival of 94% when radiotherapy is used alone (55). Surgery can be utilized if the patient is displaying compressive symptoms, but it risks recurrent laryngeal nerve injury or parathyroid damage, so it is avoided. For advanced or disseminated disease (stage III–IV), chemotherapy is the standard. Rituximab-based systemic therapy, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), is a common first-line choice that demonstrates efficacy, but data are limited for thyroid MALT lymphomas (47).

Prognosis

The prognosis for thyroid MALT lymphomas is excellent if localized, as early-stage disease has a 93–94% 5-year survival if treated early (55). Compared to diffuse large B-cell lymphoma, the most common form of primary thyroid lymphoma, which has a 5-year survival rate of 71–75% (47). Given that Hashimoto’s remains an ongoing immune stimulus, periodic follow-up through US is recommended.

Pulmonary MALT lymphoma

Etiology and pathophysiology

Extranodal marginal zone lymphoma of the lung, also known as bronchus-associated lymphoid tissue lymphoma (BALT), is a rare form of lung neoplasm. Still, it is the most common primary pulmonary lymphoma (56). There may be a link between Achromobacter xylosoxidans (A. xylosoxidans), which was found in 46% of BALT patients in Europe (57). However, this was not seen in a Japanese cohort (58), which may indicate geographic variation in prevalence. Chronic lung inflammation can also be associated with BALT, as seen in cases of autoimmune disease (59), but thus far, there are no causal links. Molecularly, BALT has the highest rate of t(11;18) translocations at 30–40% amongst all MALT lymphomas, which increases the activation of NF-κB (60).

Clinical presentation and diagnostic workup

BALT is often discovered incidentally on imaging such as chest X-ray (CXR) or CT. Symptomatic patients may experience a chronic cough, mild dyspnea, or, rarely, hemoptysis. On CT, primary MALT lymphoma presents as solitary or multiple nodules or consolidations, often peripherally located and ill-defined (61). Most cases featured prominent air bronchograms and bronchiectasis within lesions, consistent with lymphoid infiltration around airways (61). Definitive diagnosis requires a tissue biopsy, which can be conducted through bronchoscopy and transbronchial biopsy. However, in many cases, a video-assisted thoracoscopic surgery (VATS) wedge resection is performed to obtain adequate tissue and excise the lesion (62). Histology of the biopsy will show dense lymphoid infiltrates expanding into alveolar septa and forming lymphoepithelial lesions involving the bronchioles (63). The immunophenotype is similar to other MALT lymphomas. Monoclonal B cell population (IGH arrangement) confirmed through PCR or next-generation sequencing (NGS) to confirm the diagnosis.

Staging and management

Most BALT present as Stage IE or IIE, and bilateral lung involvement is also classified as IE and IIE (60). The initial workup includes a CT/PET scan of the chest and abdomen to assess the spread of the disease. Management is individualized to the patient. A unique aspect of BALT is that an asymptomatic, localized case can often be observed initially without treatment (64). If the lesion is small and the patient is asymptomatic, a period of watchful waiting with serial imaging is a reasonable approach. Treatment can be indicated due to lesion growth, symptoms, or patient preference. Surgical resection of a solitary nodule through VATS can either be a wedge resection or lobectomy and can be curative (65). Other options for treatment include low-dose radiotherapy and Rituximab-based therapy (66-68), with up to 95% of patients achieving a complete response with minimal side effects. However, there does not seem to be a difference in survival irrespective of first-line treatment modality, including watchful waiting (64,69).

Prognosis

Because BALT often progresses slowly, some experts continue to favor observation until progression, especially in cases without symptoms. Overall, survival for BALT is excellent regardless of initial therapy, and many patients will die with their lymphoma rather than from it (64). Five-year survival was noted to be 91% and 10-year survival was 76% with a median PFS of 7 years (56). Relapse typically remains localized to the lungs and can be managed with surgery or localized radiotherapy if needed. Close monitoring with periodic CT scans is recommended for early detection of progression or relapse.

Cutaneous MALT lymphoma

Etiology and pathophysiology

Cutaneous MALT lymphoma, or primary cutaneous marginal zone B cell lymphoma (PCMZL), is an indolent extranodal marginal zone lymphoma confined to the skin. Chronic antigenic stimulation due to Borrelia burgdorferi (B. burgdorferi) has been implicated in its pathogenesis. A meta-analysis demonstrated that B. burgdorferi DNA positivity was significantly associated with PCMZL in European regions (70) where it is endemic; however, the result was not replicated in non-endemic areas such as North America and Asia (71). Aside from B. burgdorferi, other antigenic stimuli have been postulated, as there have been reports of PCMZL arising at sites of prior insect bites or trauma, which induces a pseudo-lymphoma that can evolve into a lymphoma (72). Genetically, PCMZL shows t (14;18) (q32;q21) IGH MALT1 mutations and is present in 25% of PCMZL (73,74). Notably, PCMZL lacks the MYD88^L265P mutation, which is found in lymphoplasmacytic lymphoma, which can help distinguish PCMZL from a systemic lymphoma that has secondarily involved the skin (75).

Clinical presentation and diagnostic workup

PCMZL typically presents as pink to violaceous papules, plaques, or small nodules on the arms or trunk. Lesions can be solitary or multiple, are non-tender, and usually slow-growing. There are typically no associated symptoms. Diagnosis requires a skin biopsy. Histology of the sample would demonstrate dense dermal lymphoid infiltrate arranged in a vaguely nodular or diffuse pattern (76). This infiltrate usually fills the dermis and extends to the hypodermis without any epidermal ulceration. Reactive germinal centers are present, surrounded by sheets of marginal zone cells and scattered plasma cells, which can resemble benign cutaneous pseudolymphomas. The two are differentiated through the detection of monotypic plasma cells and a clonal B cell population through IGH PCR. Immunophenotype is as expected for a marginal zone lymphoma; CD20⁺, BCL2⁺, CD5⁻, and CD10⁻.

Staging and management

Staging involves making sure the disease is skin-limited. This can be done through US and CT for solitary or localized cases, and PET/CT for multifocal cases to confirm there is no extracutaneous involvement (76). The majority of PCMZL cases present with stage T1–T2a/b (solitary lesion or regional multiple lesions within a defined area) (77), with extra-cutaneous involvement being rare, at 4–8.5% of cases (78).

PCMZL is very indolent, and management aims for local disease control as well as a favorable cosmetic outcome. For solitary lesions or a localized cluster (T1a–T1b), local therapy through surgery or radiotherapy is curative. Radiotherapy is preferred as a first line because it is non-scarring and can cover a margin around the lesion. Ultra-low dose radiotherapy (4–8 Gy) has shown excellent local control (79) with a complete response rate equal to that of surgical excision, 89%, with significantly longer time to subsequent treatment (445 vs. 154 days) (80). Intralesional or topical steroids can also induce remission and lengthen time to subsequent therapy (359 days) in localized presentations (80). Watchful waiting can be an option if the patient is asymptomatic, the lesion is localized, and the treatment risks outweigh the benefits. For multifocal, systemic disease or when local treatment fails, intravenous (IV) or intralesional rituximab therapy can be considered as an option and has demonstrated efficacy (81,82). Case series and systematic reviews have shown that treatment with antibiotics such as doxycycline, ceftriaxone, and penicillin in B. burgdorferi-positive PCMZL patients led to an overall response rate of 40% and a complete response in 23% of cases (83). However, antibiotic therapy is not standard therapy regardless of Borrelia positive status, given the inconsistency in lymphoma response.

Prognosis

The prognosis of PCMZL is outstanding, as 5-year disease-specific survival is 95% (84), and although relapse rates are quite high at 44–50%, these relapses are confined to the skin and remain indolent (85,86). Relapsed lesions can be managed with further local therapy or rituximab-based regimens as needed. Long-term follow-up is recommended to monitor for new lesions or disease progression.

Small intestine MALT lymphoma

Etiology and pathophysiology

Small intestinal MALT lymphoma is relatively uncommon and occurs in two primary forms: immunoproliferative small intestinal disease (IPSID) and non-IPSID (sporadic) intestinal MALT lymphoma. IPSID typically affects young adults in regions such as the Mediterranean and North Africa. It involves the duodenum and jejunum and is characterized by the production of abnormal immunoglobulin A (IgA) molecules in the patient’s serum and other body fluids (87). This IgA molecule lacks light chains and has a truncated heavy chain protein and is sometimes called alpha-chain disease or IPSID (88). Chronic infections with Campylobacter jejuni (C. jejuni) are strongly implicated in IPSID (89,90), as chronic enteritis in endemic areas, which provides continual antigenic stimulation to intestinal lymphoid tissue. IPSID is considered a variant of MALT lymphoma as it is characterized by lymphoplasmacytic infiltration, which can range from benign reactive plasmacytosis to overt lymphoma in advanced stages. Non-IPSID intestinal MALT lymphoma typically occurs in older adults; however, it is not linked to any particular infectious etiology, unlike IPSID.

Clinical presentation and diagnostic workup

IPSID usually presents with chronic profuse diarrhea, steatorrhea, weight loss, abdominal pain, finger clubbing, and possible signs of malnutrition (91). Patients often have had a history of intermittent diarrheal illness misdiagnosed as infection or celiac disease, but the presence of monoclonal IgA in the serum or intestinal fluid can provide a clue about etiology (92). If IPSID is suspected, stool cultures and stool ova and parasite studies are conducted to exclude chronic infections or malabsorption syndromes. Testing for C. jejuni can also be indicated through stool culture, but that is dependent on geographic location.

Diagnosis is done primarily through upper gastrointestinal (GI) endoscopy with biopsy, which will show polypoidal, nodular, or granular lesions (91). Biopsy of the intestinal wall would reveal small-to-medium-sized B cells, including centrocyte-like, monocytic, and plasmacytoid forms, alongside lymphoepithelial lesions invading epithelial structures and disrupting glandular architecture (53). Clonality testing, such as IGH PCR, can also be diagnostic when morphological patterns show diffuse or fused marginal zones, which can resemble benign reactive marginal zone expansion (93). Non-IPSID MALT lymphoma usually presents with more localized symptoms such as abdominal pain, intussusception, or GI bleeding (94). However, evaluation of the small bowel can be difficult due to inaccessibility by conventional endoscopy, especially if the tumor is in the distal jejunum and proximal ileum. In these cases, balloon enteroscopy can be utilized, but has its risks associated with perforation and post-interventional abdominal pain (94). Diagnosis can often require a surgical biopsy in 44% of cases, if not achievable through endoscopy (95).

Staging and management

Staging of intestinal MALT lymphoma involves imaging such as CT/MRI enterography to assess the extent of bowel involvement, as well as CT of chest/abdomen for signs of metastases. IPSID is classified into three stages (A, B, C) based on its histopathologic features, namely the type of cellular infiltrate and mesenteric nodal involvement (92). Stage A is characterized by lymphoplasmacytic infiltration of the lamina propria with inconstant and variable villi atrophy. Stage B has atypical lymphoplasmacytic infiltration of lamina propria and atypical immunoblast-like cells spreading to submucosa alongside subtotal or total villi atrophy. Mesenteric and other abdominal lymph nodes can also be involved. And stage C is the most advanced, with proliferation of lymphocytes in all layers of the intestinal wall as well as mesenteric and abdominal lymph nodes.

Treatment varies for IPSID and non-IPSID intestinal MALT lymphoma. Early stage IPSID/Galian stage A, which is confined to the small intestine, is treated primarily with antibiotics. Tetracycline-based regimens, with and without the addition of metronidazole and corticosteroids, demonstrated a 77.1% remission rate (91). Guidelines recommend a 6-month course of antibiotics as first line for IPSID to prevent clinical and histologic remission. The goal is to eradicate possible C. jejuni and any other chronic bacteria that could be causing antigenic stimulation. If, after 6 months, there is no improvement as determined through endoscopic biopsy, escalation of therapy is required. Progression into an intermediate or high-grade MALT lymphoma requires systemic chemotherapy, primarily using the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone), often with the addition of rituximab (88,96). Surgery plays a limited role in IPSID because the disease is frequently diffuse and not a single resectable mass. However, if the tumor has developed into a large, bulky mass, surgery and/or radiotherapy can be utilized as a palliative strategy to be used before chemotherapy/immunotherapy (88).

For non-IPSID localized MALT lymphoma of the bowel (e.g., isolated ileal lesion), surgical resection induces long-term remission and can be curative in stage I disease (97). In disseminated or multifocal intestinal lymphoma, the treatment of choice is the same CHOP/R-CHOP regimen used for late-stage IPSID.

Prognosis

Prognosis is excellent for early IPSID, as 2-year OS was 90% and all patients alive beyond 3.5 years were disease-free (98). In the advanced stage, IPSID outcomes are worse, but many patients can still be cured with combination chemotherapy, as 5-year OS rates are 70% (99). Non-IPSID MALT lymphomas behave like other MALT lymphomas and, compared to IPSID, have a more indolent course and high survival if localized (97). The only caveat with intestinal MALT lymphomas is that they can cause life-threatening complications due to perforation or malabsorption if not managed appropriately. Therefore, prompt treatment and regularly scheduled follow-up are advised.

Conclusions

Non-gastric MALT lymphomas represent a group of indolent B-cell malignancies arising in diverse extranodal sites due to chronic antigenic stimulation. Over the past decade, significant progress has been made in understanding their etiologies and developing tailored treatments. A thorough workup to identify underlying infection or autoimmune conditions is crucial, as treating the cause can sometimes treat the cancer. Imaging such as US, CT, and PET scans can help stage the disease and determine treatment modalities. As a whole, these lymphomas are highly responsive to localized therapy such as radiation therapy or surgical resection, which yields long-term control in the majority of localized cases (100). Antibiotics, which work exceedingly well for gastric MALT lymphoma, have also been trialed in non-gastric sites, especially Doxycycline for OAML and IPSID to target the inciting microbes. Immunotherapy with Rituximab has also become a valuable tool for the treatment of rare disseminations of the disease. Watchful waiting is also a strategy in managing patients due to the indolent nature of most of these neoplasms. Across all sites of the MALT lymphomas discussed, survival is exceptionally high, with most crossing >90% survival at 5 years, with most patients never requiring chemotherapy. The indolent nature of these tumors allows clinicians to utilize the least toxic therapy and prioritize the patient’s quality of life. With close follow-up, relapses can be detected early and treated. Non-gastric MALT lymphomas are an example of a highly curable lymphoma where a less is more approach to therapy and a deep understanding of the pathogenesis can directly translate into successful tailored patient care. Future research should focus on elucidating the molecular underpinnings of site-specific MALT lymphomas, such as any unique mutations that may be candidates for novel targeted therapies. Additionally, there is a lack of research concerning the efficacy of treatment options for many of the non-gastric MALT lymphomas, perhaps due to their rarity. And the studies that do exist contain small sample sizes. Future research may focus on prospective studies and meta-analyses to compare the different treatment modalities and their effects on long-term survival to determine a standardized treatment regimen for patients.

Acknowledgments

None.

Footnote

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