Marginal zone lymphoma (MZL) is a type of mature B-cell non-Hodgkin lymphoma (mBC-NHL) that develops from memory B lymphocytes (post-germinal center B lymphocytes) in the marginal zone of secondary lymphoid follicles. It represents about 5–10% of all non-Hodgkin lymphomas and is categorized by the World Health Organization into three large categories: extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), splenic marginal zone lymphoma and nodal marginal zone lymphoma (Campo et al., 2022). MZL is generally a relatively indolent disease, although there is significant biological heterogeneity with sometimes extranodal involvement, lymphadenopathy, constitutional symptoms, autoimmune manifestations or a thrombotic component. Chronic antigenic stimulation due to persistent infections, autoimmune diseases, or immune activation, ultimately followed by malignant transformation of B lymphocytes, are responsible for the pathogenesis of MZL (Zucca & Arcaini, 2020). Due to these immunological interactions, MZL stands amongst the lymphoid malignancies with a strong association with immune dysregulation.

For decades, an association with auto-immune diseases has been noted with lymphoma. Individuals suffering from autoimmune disorders have a higher risk of developing B-cell lymphomas, and autoimmunity can be present prior to diagnosis, during treatment or as part of long-term follow-up (LTF) of lymphoma (Ramos-Casals et al., 2020). Persistent immune activation leads to the continuous activation and proliferation of B lymphocytes, which results in the accumulation of genetic abnormalities and thus in lymphomagenesis. On the other hand, the malignant B cells may generate auto-antibodies, break immune tolerance, change the production of cytokines and interfere with the normal regulation of T cells, which can lead to the development of autoimmune complications. These relationships are bidirectional and may suggest the complex links between immune dysfunction and lymphoid malignancies and that lymphoma may be viewed as a consequence and a potential cause of autoimmune disease.

There are several autoimmune disorders reported in association with MZL and other indolent BCLs. Some of the most well-known conditions associated with the development or progression of lymphomas include: Sjogren's syndrome, autoimmune thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, immune thrombocytopenia (ITP), autoimmune neutropenia and vasculitis (Baimpa & Dahabreh, 2022). An important point to note is that some of the autoimmune cytopenias can occur as a consequence of immune-mediated destruction of blood cells without the actual infiltration of bone marrow. Likewise, in patients with lymphoid malignancies, especially in the context of severe immune dysregulation, endocrine autoimmune diseases like autoimmune adrenal insufficiency (Addison disease) have been reported. Chemotherapy-induced immunosuppression and underlying immune dysfunction can also hinder host immune surveillance which can further complicate the clinical course by allowing for opportunities to be presented for opportunistic viral infections, such as cytomegalovirus (CMV) (Hill & Seo, 2020). Therefore the diagnosis and treatment of lymphoma can pose a diagnostic and therapeutic challenge leading to the need to carefully differentiate progression, treatment-related toxicity, secondary infections and autoimmune complication.

B-cell lymphomas have a central role in immune dysregulation in their biology. Malignant B lymphocytes are in close interaction with T lymphocytes, dendritic cells, macrophages, stromal cells and inflammatory cytokines in the tumor microenvironment. These interactions provide a conducive environment for the development and persistence of lymphoma, and they also impact the natural regulation of the immune system (Campo et al., 2022). Loss of self-tolerance and the onset of autoimmune production is due to alterations in the function of regulatory T-cells, to abnormal secretion of cytokines, to the disruption of the normal functioning of immune checkpoints and to the persistence of antigenic stimulation. In addition, cytotoxic chemotherapy, regimens containing rituximab, corticosteroids and prolonged immunosuppression can worsen the immune imbalance, causing a depletion of normal lymphocytes and a reduction in antiviral immunity. This can lead to the development of endocrine functional disorders, autoimmune cytopenias, reproductive dysfunction, opportunistic infections, or other immune-mediated complications that may occur in patients sequentially throughout the treatment of lymphoma. The recognition of these manifestations is crucial as early diagnosis could significantly affect clinical outcomes and avoid life-threatening complications.

Isolated autoimmune complications have been occasionally reported in patients with B-cell lymphomas, but a series of autoimmune disorders has previously been reported in only one patient. Published reports of mixed clinical course of reproduction dysfunction, adrenal insufficiency, immune thrombocytopenia and opportunistic CMV infection in the course of treatment of marginal zone lymphoma are very scarce. The lessons learned from such cases will shed light on the dynamic immune dysfunction seen in lymphomas and highlight the challenges of long-term treatment in these patients. Properly chronicled history and laboratory abnormalities, histopathological results, radiological investigations, and treatment outcome can enhance the understanding of the disease mechanisms and future treatment strategies.

In the present case, a young male is described with low-grade B-cell non-Hodgkin's Lymphoma, adherent to the criteria of the marginal zone B-cell non-Hodgkin's Lymphoma, initially diagnosed with abdominal pain, cervical venous thrombosis, upper limb edema and diffuse mesenteric lymphadenopathy. Post diagnosis and treatment with R-CHOP chemotherapy, the patient then suffered from a series of immune-related complications such as azoospermia, low levels of cortisol, profound thrombocytopenia with bone marrow findings of immune-mediated destruction of platelets (IMDP) and CMV reactivation, confirmed by quantitative PCR. This case emphasizes the need for a high index of suspicion for sequential immune-mediated complications in people with lymphoma in follow-up, and the importance of multidisciplinary care with hematologists, endocrinologists, infectious disease specialists and pathologists to optimize care for these patients.

Patient Information

In September 2021, a 33-year-old Pakistani male patient presented with gradually increasing abdominal pain, loss of appetite, neck pain, swelling of the left upper limb and marked distention of the neck veins, which were the first symptom. No previous history of malignancy, chronic liver disease or thromboembolic disorders were reported by the patient. No family history of lymphoma or autoimmune problems was reported.

Physical examination revealed chronic illness, with marked swelling of the left upper extremity and prominent neck veins, suggesting left upper extremity venous obstruction. The abdomen was tender and there were no organomegaly. Neurologic deficits were not found.

Initial Diagnostic Work-up

On baseline abdominal ultrasound, ascites, moderately sized spleen, edematous loops of bowel and lymph nodes of enlarged size were noted, with the largest measuring about 20 × 9 mm. These data indicated a lymphoproliferative/ inflammatory disorder.

Contrast enhanced computed tomography (CT) of the neck, chest, abdomen and pelvis showed widespread venous thrombosis of the left internal jugular vein, left subclavian vein, left brachiocephalic vein, superior mesenteric vein, right anterior portal vein, right posterior portal vein, and segment VIII portal vein branch. Moreover, several enlarged mesenteric, para-aortic, aortocaval and portocaval lymph nodes were detected. Small bowel wall thickening of the jejunum and proximal ileum and mild ascites were also observed.

A mesenteric lymph node biopsy was therefore carried out due to the widespread abdominal lymphadenopathy.

Histopathological Diagnosis

The mesenteric lymph node was slightly effaced by a uniform population of atypical lymphocytes with irregular nuclear boundaries on histological examination.

Immunohistochemistry demonstrated:

• CD20 positive
• PAX5 positive
• CD10 negative
• CD3 negative
• BCL6 negative
• BCL2 equivocal

Ki-67 proliferation index is around 10%

The results were indicative of low grade B-cell non-Hodgkin's lymphoma, in favor of marginal zone lymphoma (MZL).

Patient was referred for further management to tertiary oncology centre.

Initial Treatment

After staged complete treatment the patient was treated with eight courses of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) chemotherapy.

This treatment was tolerated well, with no significant acute complications.

After the completion of the chemotherapy, PET-CT was performed for the surveillance and showed excellent therapeutic response with apparent complete metabolic remission with no metabolically active extra-nodal or nodal disease above and below the diaphragm. Small residual non-FDG avid mesenteric lymph nodes were observed which were considered to be probably reactive.

The patient was followed up on a regular basis.

Sequential Autoimmune and Immune-mediated

Manifestations development

Although the patient had an apparent complete metabolic remission, over the next few years the patient experienced multiple immune-mediated complications.

Development of Azoospermia

A year later after chemotherapy the patient wanted an evaluation of her fertility.

Semen analysis demonstrated:

• Semen volume: 1.0 mL
• Positive fructose

Spermatzoa are completely absent.

The laboratory confirmed this to be azoospermia, meaning there were no sperm found in the specimen, even after being centrifuged.

There were no previous fertility issues that were known before treatment with lymphoma. The patient's azoospermia was thought to be a side effect of the cyclophosphamide treatment, but not an autoimmune type of disturbance.

Development of Primary Adrenal Insufficiency

Follow-up in the patient revealed progressive fatigue, generalized weakness, anorexia, and weight loss.

Biochemical evaluation showed an extremely low concentration of evening serum cortisol level of 1•29 nmol/l, much lower than the reference interval.

Given the clinical picture and the profoundly low cortisol level, the treating physicians felt they were dealing with an adrenal insufficiency usually caused by autoimmune Addison disease and began treating with replacement doses of cortisol.

Autoimmune adrenalitis is rare in patients with lymphoma, but there were no specific autoimmune tests (e.g. 21-hydroxylase antibodies) confirmed. However, the clinical picture was most suggestive of primary adrenal insufficiency, most likely autoimmune Addison disease, in an environment of ongoing immune dysregulation, rather than ongoing malignant disease.

Gastrointestinal Manifestations

The patient then presented with chronic UGIB.

An upper GI endoscopy found:

• Normal esophagus
• Normal stomach without mass lesion

Many ulcers in the first, second and third section of the duodenum.

Several biopsies were taken.

Histopathological study of the small intestine revealed ulcerated mucosa with atypical lymphoid infiltrates. Immunohistochemistry again revealed CD20 positive low grade B-cell lymphoma, suggesting gastrointestinal involvement, favoring marginal zone lymphoma.

The serologic tests done for celiac disease were:

• Anti-tissue transglutaminase IgA: < 7 U/mL (negative)
• Anti-tissue transglutaminase IgG: 4.35 U/mL (negative)

Duodenal histopathology was suggestive of celiac disease, but serologic tests for celiac disease were negative. There is a group of patients with celiac disease who do not have antibodies to the disease. Immuno thrombocytopenia is the term used for this     condition. This is called immune thrombocytopenia

The patient had progressive thrombocytopenia around four years after the initial diagnosis.

Laboratory investigations demonstrated:

• Hemoglobin: 5.7–6.1 g/dL
• White blood cell count: 2.1–3.2 × 10³/µL
• Platelet count: 22,000–23,000/µL

Due to profound thrombocytopenia a bone marrow aspirate and trephine biopsy were performed.

Bone marrow examination showed that:

Moderately cellular marrow

Markedly reduced megakaryocytes

Active erythropoiesis

Active myelopoiesis

Normal lymphopoiesis

There is no evidence of lymphoma infiltration.

No abnormal plasma cells

The pathological diagnosis was of thrombocytopenia most compatible with peripheral platelet destruction or drug induced immune-mediated thrombocytopenia, and there was no evidence of recurrent lymphoma.

With no evidence of lymphoma infiltration, an immune-mediated thrombocytopenia was the most likely diagnosis.

Cytomegalovirus Infection

At the end of the follow-up period, the patient began to experience constitutional symptoms, along with worsening cytopenias.

Using quantitative CMV PCR, it was shown:

• CMV DNA detected
• Viral load: 10,285 copies/mL

The results demonstrated that active cytomegalovirus infection was present in a background of long-standing immune impairment.

The patient then was treated with suitable anti-viral treatment while under close hematological monitoring.

Clinical Outcome

The patient had an impressive clinical history despite being treated with R-CHOP chemotherapy for the first eight cycles of induction therapy, who has developed multiple immune-mediated complications sequentially, such as azoospermia, adrenal insufficiency, severe immune thrombocytopenia and CMV reactivation. Most critically, repeated imaging and bone marrow biopsies showed no signs of recurrent lymphoma, which reinforced the idea that these complications were secondary to ongoing (rather than current) malignant disease.

The patient was still on a multidisciplinary treatment protocol at the latest follow-up, which included treatment with hematology, endocrinology, gastroenterology, infectious diseases and reproductive medicine. Continuous maintenance treatment included hormone replacement therapy, periodic checks for lymphoma recurrence, check of haematological parameters, and treatment of opportunistic infections, supportive care.

SEQUENTIAL CLINICAL COURSE

The initial presentation and diagnosis will take place.

The patient was a 33-year-old, otherwise well male who had developed progressive abdominal pain, anorexia, neck pain and swelling of the left upper limb in September 2021. On physical exam, the neck veins were prominent and left upper extremity was markedly swollen suspicious of venous obstruction. Initial abdominal ultrasound showed mild ascites, enlarged mesenteric lymph nodes, edematous bowel loops and a bulky spleen. Contrast enhanced computer tomography (CT) of the neck, chest, abdomen and pelvis also showed extensive thrombosis of the left internal jugular, left subclavian, left brachiocephalic, superior mesenteric veins and portal veins. Furthermore, several enlarged lymph nodes in the mesentery, para-aortic, aortocaval and portocaval areas were detected. A diagnosis of low grade B-cell type was confirmed by the histopathological examination of a biopsy of a mesenteric lymph node, with immunohistochemistry both for CD20 and PAX5 positive, and a low proliferation index of approximately 10% Ki-67 (Arcaini et al., 2020).

Chemotherapy and Initial Clinical Response

After diagnosis, patient was commenced on the standard immunochemotherapy consisting of eight cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone). Throughout the treatment, there were no serious immediate complications. Post-chemotherapy surveillance positron emission tomography-computed tomography (PET-CT) showed complete metabolic response (cytological or clinical complete response), with no extradiaphragmatic or extranodal disease with metabolic activity found above or below the diaphragm. Any mesenteric lymph nodes that did not show FDG uptake were believed to be reactive and not representative of active lymphoma. The patient's clinical state improved considerably and he was referred for regular oncological follow-up.

The development of Endocrine and Reproductive Dysfunction

Although the patient achieved a successful response to the lymphoma, he then developed a series of unusual immune mediated complications. This first presentation was an azoospermia which was discovered when patient was evaluated for infertility. Sperm analysis revealed no sperm in the sample even after proper processing, which indicated that the sample had a severe problem with spermatogenesis. Gonadal dysfunction is a well recognised late effect of cyclophosphamide containing therapy and the patient's azoospermia was most likely related to cyclophosphamide mediated gonadal toxicity (Howlader et al., 2024).

The patient presented several months later, with progressive fatigue, generalized weakness, anorexia and weight loss. A biochemical investigation showed a very low level of cortisol in the serum of 1.29 nmol/L, confirming adrenal insufficiency. A diagnosis of primary adrenal insufficiency (Addison disease) was suspected on the clinical and laboratory features, and corticosteroid replacement therapy was started. It had been determined that Addison disease post successful lymphoma treatment was likely to be due to ongoing immune abnormality, not active malignant infiltration.

Involvement of the gastrointestinal tract and disease surveillance.

However, on further follow up, they developed persistent upper gastrointestinal symptoms that warranted endoscopic evaluation. The esophagogastroduodenoscopy revealed marked ulceration of the first, second and third parts of the duodenum but the esophagus and stomach were normal. Multiple biopsies were performed and a diagnosis of recurrent low grade B cell lymphoma with features of marginal zone lymphoma was made. Neoplastic B-cells were again identified by immunohistochemistry. There were no positive serological markers for celiac disease (anti-tissue transglutaminase antibodies IgA and IgG). These results suggested involvement of gastrointestinal lymphoma and not autoimmune enteropathy.

Opportunistic Infection and Hematological Autoimmunity.

Progressive pancytopenia even in the late stage of the disease, and severe thrombocytopenia. Laboratory examination revealed platelet counts from 22,000 to 23,000/µL and considerable leukopenia and anemia. Bone marrow examination (aspiration and trephine biopsy) revealed moderately cellular marrow with a marked decrease in megakaryocytes, normal erythropoiesis and myelopoiesis and no evidence of infiltration by the lymphoma. These results were most supportive of immune-mediated thrombocytopenia following exclusion of lymphoma relapse and suggested peripheral platelet destruction as opposed to bone marrow involvement (Provan et al., 2019).

The patient then went on to have constitutional symptoms of deteriorating cytopenias. CMV infection was the only reactivation detected by quantitative PCR (qPCR) with a viral load of 10,285 copies/mL, suggesting high level CMV reactivation in the context of prolonged immune dysfunction. Appropriate anti-viral drugs were prescribed with close follow-up by haematology and infectious diseases. Despite the appearance of complete metabolic remission of lymphoma, there were unusual endocrine, hematological, reproductive, and infectious complications during the overall clinical course that were thought to represent persistent immune dysregulation, rather than recurrent lymphoma. This is a novel sequential course, which emphasizes the significance of long-term multi-disciplinary follow up in patients with indolent B-cell lymphomas.

Investigations

From the onset of presentation to follow-up, the patient underwent extensive laboratory, radiological, histopathological and molecular examination. Initial imaging showed a pattern of large amounts of venous thrombosis, in multiple major veins with diffuse abdominal lymphadenopathy, which suggested an underlying lymphoproliferative disorder was likely. Low grade B-cell lymphoma favoring marginal zone lymphoma (MZL) was confirmed by histopathological examination of the mesenteric lymph node. Apparent complete metabolic remission was identified by PET-CT during surveillance following immunochemotherapy. Follow-up was done serially, and endocrine dysfunction, infertility, heavy thrombocytopenia (without any relapse of the disease in the bone marrow), gastrointestinal involvement and CMV reactivation were documented, all signs of progressive immune dysregulation despite the remission of lymphoma.

Table 1. Chronological Timeline of Disease

Table 2. Laboratory Investigations

Table 3. Radiological Findings

Table 4. Histopathological Findings

Marginal Zone Lymphoma and Autoimmunity

Marginal zone lymphoma (MZL) is a type of non-Hodgkin lymphoma (NHL) of the B cells, which is an indolent disease and develops from post-germinal center memory B cells. It represents around 5-1  0% of all non-Hodgkin lymphomas and is divided in three different subtypes: extranodal, nodal and splenic (Zucca & Arcaini, 2020). MZL has a relatively indolent clinical course, but is strongly associated with chronic antigenic stimulation and immune dysregulation. The chronic activation of the immune system can favor the formation of lymphomas, as well as the development of autoimmune complications (Arcaini et al., 2022).

There is a two-way connection between lymphoma and autoimmunity. Patients with autoimmune diseases like Sjögrens, systemic lupus erythematosus, Hashimoto thyroiditis and celiac disease are at higher risk of developing MZL, as chronic immune stimulation leads to B-cell proliferation and accumulation of genetic abnormalities (Parikh et al., 2023). Autoimmune conditions can occur before, during, or after treatment because of the disruption of immune tolerance that can occur with the development of lymphoma, such as production of autoreactive antibody, cytokine dysregulation, and impaired function of regulatory T cells (Tregs).

Remarkable in this case is the fact that several years were elapsed between the onset of each of the endocrine, gastrointestinal, hematologic and infectious immune-mediated events, as well as the development of treatment-related reproductive dysfunction. This has not been described in a chronological sequence in the low-grade B-cell group of patients. The association of primary adrenal insufficiency, immune-mediated thrombocytopenia, azoospermia, seronegative celiac disease and CMV reactivation is an unusual clinical course in MZL.

Immune Dysregulation in B-cell Lymphoma

B-Cell lymphomas are characterized by dysregulation of the immune system. Malignant B lymphocytes communicate with T cells, dendritic cells, macrophages and stromal cells, leading to a pro-inflammatory microenvironment that allows the maintenance of the tumor while impairing immune homeostasis (Roschewski et al., 2022). The breakdown of self-tolerance and the onset of autoimmune disease is driven by persistent activation of autoreactive B cells, excessive secretion of cytokines (such as IL-6, BAFF and TNF-α) and defective Treg function (Mackay & Rose, 2021; Young et al., 2022).

Chemotherapy drugs containing rituximab also disrupt the immune regulatory system by causing a long-lasting reduction in normal CD20-positive B cells. While this helps to inhibit growth of malignant cells, restoration of immune function may take longer, and predisposing the susceptible patient to autoimmune phenomena and opportunities for infection (Sehn & Salles, 2021).

In this particular patient, the induction of apparent metabolic remission was achieved on PET-CT by R-CHOP, yet other immune-mediated complications such as endocrine, gastrointestinal, hematological, and infectious issues were observed during follow-up. This clinical course implies a possibility of immune dysfunction without remission and that immune dysfunction may be responsible for a worsening of autoimmune symptoms, in addition to the decrease in antiviral immunity.

Autoimmune Endocrinopathy (Primary Adrenal Insufficiency)

Primary adrenal insufficiency is caused by the destruction of the adrenal cortex and leads to the production of less glucocorticoids and mineralocorticoids. In developed countries, around 80-90% of cases are due to autoimmune adrenalitis (Bornstein et al., 2023). Addison disease has been reported in autoimmune polyglandular syndromes, but is rare in association with marginal zone lymphoma.

This patient had very low cortisol levels, which argued for primary adrenal insufficiency and was most likely autoimmune adrenalitis (Addison disease). Since adrenal autoantibody testing was not done, it was not possible to confirm autoimmune adrenalitis. The absence of any imaging features of adrenal infiltration and the apparent metabolic remission, however, made the diagnosis of adrenal infiltration unlikely.

The injury of the adrenal cortex may have been mediated by persistent immune activation, dysfunction of Tregs and autoreactive lymphocytes. The presence of primary adrenal insufficiency and seronegative celiac disease is further evidence of an autoimmune polyglandular process in the context of immune dysregulation associated with lymphoma. Primary adrenal insufficiency should therefore be considered in lymphoma survivors who have unexplained fatigue, weight loss, hypotension or generalized weakness.

Autoimmune Cytopenia

Lymphoid malignancies are associated with a variety of immune hematological disorders, one of the most prevalent being immune thrombocytopenia (ITP) (Neunert et al., 2023). The disorder is primarily caused by immune-mediated destruction of the platelets, but may also be caused by impaired production, which can happen when the maturation of megakaryocytes is blocked by autoantibodies.

Severe thrombocytopenia with platelet counts of around 22–23 × 10³/µL was seen in the patient. Bone marrow biopsy showed no infiltration by lymphoma cells or any other haematological malignancy. After excluding infiltration from lymphoma, an immune-mediated thrombocytopenia was the most likely possibility.

Immune-mediated thrombocytopenia vs chemotherapy-induced cytopenia is clinically significant as it has drastically different treatments. Immune thrombocytopenia recognition enables early treatment with corticosteroids, IVIG, rituximab, thrombopoietin receptor agonists or other appropriate therapy, as needed, depending on disease severity.

CMV Reactivation following Chemotherapy

Impairment of both humoral and cellular immunity for extended periods is known to be a risk factor for the development of cytomegalovirus (CMV) reactivation in chemotherapy patients receiving rituximab.Patients receiving chemotherapy with rituximab are known to have extended, impaired humoral and cellular immunity, increasing their risk of cytomegalovirus (CMV) reactivation (Ljungman et al., 2024). The patient went on to develop symptomatic CMV infection with a viral load of 10285 copies/mL as measured by quantitative PCR.

Reactivation of the virus was probably related to multiple factors, such as prior chemotherapy, corticosteroid exposure, continuing immune dysregulation and progressive immune defects. Treatment was further complicated by the presence of CMV infection in patients with immune-mediated cytopenia, as treatment with antiviral drugs can aggravate hematological abnormalities. This study justifies monitoring opportunistic viral infections in targeted groups of lymphoma survivors who are immunocompromised.

Relationship between Lymphoma and Autoimmune Diseases

his case highlights the close association between the persistent immune dysregulation and the occurrence of marginal zone lymphoma. Although the patient appeared to be in remission after chemotherapy, the patient developed a sequence of endocrine, reproductive, gastrointestinal, hematologic and infectious immune-mediated diseases over the years. These observations suggest a need to continue long-term follow up beyond the scope of surveillance for lymphoma recurrence to evaluate for immune-mediated complication. For optimal long-term outcomes, a multidisciplinary team of hematologists, endocrinologists, gastroenterologists, infectious disease specialists and reproductive medicine specialists is necessary.

A comparison of published cases.

Isolated autoimmune complications have been reported in patients with marginal zone lymphoma, such as autoimmune hemolytic anemia, immune thrombocytopenia, vasculitis, rheumatoid arthritis, and cryoglobulinemia. Primary adrenal insufficiency is still a very rare condition, and in the case of seronegative celiac, it has been described mainly in autoimmune polyglandular syndromes and not in lymphoma (Bornstein et al., 2023).

To our best knowledge, only few reports have been published reporting the progression of treatment-related azoospermia to primary adrenal insufficiency, seronegative celiac disease, immune-mediated thrombocytopenia and CMV reactivation in a patient with apparent remission after R-CHOP therapy and marginal zone lymphoma. The uniqueness of this case is the fact that endocrine, reproductive, hematologic, and infectious immune-mediated events occurred in sequence over a number of years in a patient with apparent remission of his marginal zone type lymphoma. The unique time-dependent changes extend the clinical spectrum of immune dysfunction associated with lymphoma.

Clinical Lessons

This case illustrates the potential for immune mediated complications to occur in sequence even though the diagnosis of marginal zone lymphoma seems to be in remission and not necessarily due to chemotherapy. High index of suspicion should be kept for endocrine, reproductive, gastrointestinal, hematologic and infectious complications in long term follow up. Multidisciplinary evaluation early in the treatment process may help earlier diagnosis, better outcomes and enhance knowledge of the long-term imm                unological effects of indolent B-cell lymphomas.

In this case, a rare and clinically important presentation of a marginal zone B-cell non-Hodgkin's lymphoma complicated by the sequential development of multiple immune-mediated manifestations despite the apparent complete metabolic remission (CRm) after R-CHOP chemotherapy. At presentation, the patient was found to have extensive venous thrombosis, after which he experienced development of azoospermia, primary adrenal insufficiency (Addison disease), severe immune thrombocytopenia and reactivation of cytomegalovirus (CMV). Importantly, repeated imaging and bone marrow tests showed no signs of lymphoma relapsing, implying that these complications were more likely due to ongoing immune dysfunction related to the lymphoma disease process rather than due to active disease.

The case highlights the interplay between lymphoid neoplastics and immune dysfunction, and demonstrates that normal immune homeostasis does not always reappear when a lymphoid neoplasm is successfully treated. Rather, patients with indolent B-cell lymphomas may be susceptible to delay opportunities for autoimmune and opportunistic complications, which can greatly affect patients' long-term morbidity and quality of life. Early recognition of endocrine disorders, haematological autoimmune disorders, reproductive dysfunction and infectious problems is therefore crucial for early diagnosis and management.

This paper builds on the scarce literature available on sequential autoimmune events in patients with marginal zone lymphoma and highlights the need to keep a high index of suspicion for immune-mediated events throughout long-term follow-up. Optimizing patient outcomes requires a multidisciplinary approach, combining the expertise of hematologists, endocrinologists, infectious disease specialists, gastroenterologists and reproductive medicine specialists. Additional clinical research is required to better understand the mechanisms underlying immune dysregulation in individuals with lymphoma and to develop evidence-based guidelines to monitor for autoimmune issues in survivors of lymphoma. This case adds to the body of knowledge surrounding the long term immunity effects of indolent B-cell lymphomas.

1. Arcaini, L., Rossi, D., & Paulli, M. (2020). Marginal zone lymphoma: Present status and future perspectives. Haematologica, 105(6), 1469–1480. https://doi.org/10.3324/haematol.2019.232082
2. Baimpa, E., & Dahabreh, I. J. (2022). Autoimmune manifestations in B-cell lymphomas: Pathogenesis and clinical implications. Mediterranean Journal of Hematology and Infectious Diseases, 14(1), e2022058. https://doi.org/10.4084/MJHID.2022.058
3. Bornstein, S. R., Allolio, B., Arlt, W., Barthel, A., Don-Wauchope, A., Hammer, G. D., Husebye, E. S., Merke, D. P., Murad, M. H., Stratakis, C. A., & Torpy, D. J. (2023). Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline update. The Journal of Clinical Endocrinology & Metabolism, 108(5), 1203–1235.
4. Campo, E., Jaffe, E. S., Cook, J. R., Quintanilla-Martinez, L., Swerdlow, S. H., Anderson, K. C., Arb
5. er, D. A., & International Consensus Classification Working Group. (2022). The International Consensus Classification of mature lymphoid neoplasms. Blood, 140(11), 1229–1253. https://doi.org/10.1182/blood.2022015851
6. Cervetti, G., Galimberti, S., Sordi, E., Buda, G., Petrini, M., & Rossi, G. (2021). Autoimmune disorders and B-cell lymphomas: From pathogenesis to treatment. Leukemia Research, 107, 106604.
7. Hill, J. A., & Seo, S. K. (2020). How I prevent viral reactivation in patients receiving hematopoietic cell transplantation and cellular therapies. Blood, 136(8), 925–935. https://doi.org/10.1182/blood.2019004045
8. Howlader, N., Noone, A. M., Krapcho, M., Miller, D., Brest, A., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., Lewis, D. R., & Cronin, K. A. (2024). SEER Cancer Statistics Review, 1975–2021. National Cancer Institute.
9. Husebye, E. S., Pearce, S. H. S., Krone, N. P., & Kämpe, O. (2021). Adrenal insufficiency. The Lancet, 397(10274), 613–629. https://doi.org/10.1016/S0140-6736(21)00136-7
10. Ljungman, P., Hakki, M., & Boeckh, M. (2024). Cytomegalovirus in hematologic malignancies and hematopoietic cell transplantation. Blood Reviews, 63, 101161.
11. Mackay, F., & Rose, N. R. (2021). Autoimmunity and B-cell biology. Nature Reviews Immunology, 21(7), 431–446.
12. Neunert, C., Terrell, D. R., Arnold, D. M., Buchanan, G., Cines, D. B., Cooper, N., Cuker, A., Kelton, J. G., Lim, W., McCrae, K. R., & Vesely, S. K. (2023). American Society of Hematology guidelines for immune thrombocytopenia. Blood Advances, 7(4), 620–650.
13. Parikh, S. A., Habermann, T. M., & Ansell, S. M. (2023). Autoimmune diseases and B-cell lymphomas: Shared mechanisms and clinical implications. Leukemia & Lymphoma, 64(2), 241–253.
14. Provan, D., Arnold, D. M., Bussel, J. B., Chong, B. H., Cooper, N., Gernsheimer, T., Ghanima, W., Godeau, B., Gonzalez-Lopez, T. J., Grainger, J., Hou, M., Kruse, C., McDonald, V., Michel, M., Rodeghiero, F., Scully, M., Tomiyama, Y., Wong, R., & Cheng, Y. (2019). Updated international consensus report on the investigation and management of immune thrombocytopenia. Blood Advances, 3(22), 3780–3817. https://doi.org/10.1182/bloodadvances.2019000812
15. Ramos-Casals, M., Brito-Zerón, P., Kostov, B., Sisó-Almirall, A., Bosch, X., & Stone, J. H. (2020). Google-driven search for big data in autoimmune diseases: Analysis of 394,827 patients with systemic autoimmune diseases. Autoimmunity Reviews, 19(12), 102689.
16. Ramos-Casals, M., Brito-Zerón, P., Kostov, B., Sisó-Almirall, A., Pérez-De-Lis, M., & Bosch, X. (2021). Autoimmune diseases associated with hematologic malignancies. The Lancet Rheumatology, 3(7), e502–e514.
17. Roschewski, M., Staudt, L. M., & Wilson, W. H. (2022). Diffuse large B-cell lymphoma—Treatment approaches and biological insights. The New England Journal of Medicine, 386(9), 842–858.
18. Sehn, L. H., & Salles, G. (2021). Diffuse large B-cell lymphoma. The New England Journal of Medicine, 384(9), 842–858. https://doi.org/10.1056/NEJMra2027612
19. Young, R. M., Phelan, J. D., & Staudt, L. M. (2022). Pathogenic B-cell receptor signaling in lymphoid malignancies. Nature Reviews Drug Discovery, 21(8), 635–654.
20. Zucca, E., & Arcaini, L. (2020). Marginal zone lymphoma: Present status and future perspectives. Hematological Oncology, 38(Suppl. 1), 84–88. https://doi.org/10.1002/hon.2705.