Case report: Incidental MALT lymphoma of the left adrenal gland mimicking a metastatic spread within durvalumab maintenance treatment in inoperable stage III non-small cell lung cancer (2024)

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Case report: Incidental MALT lymphoma of the left adrenal gland mimicking a metastatic spread within durvalumab maintenance treatment in inoperable stage III non-small cell lung cancer (1)

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Front Oncol. 2024; 14: 1226422.

Published online 2024 Mar 19. doi:10.3389/fonc.2024.1226422

PMCID: PMC10985782

PMID: 38567155

Lukas Käsmann,Case report: Incidental MALT lymphoma of the left adrenal gland mimicking a metastatic spread within durvalumab maintenance treatment in inoperable stage III non-small cell lung cancer (2)1,2,3,* Esra Degerli,1 Karim El-Marouk,1 and Farkhad Manapov1,4

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Durvalumab after chemotherapy in non-operable stage III non-small cell lung cancer (NSCLC) is the standard of care worldwide. We present a patient with the incidental discovery of a unilateral MALT lymphoma of the adrenal gland and adrenalitis during durvalumab maintenance treatment detected by 18F-FDG-PET/CT. We assessed the clinical and histopathological findings, radiological examinations and overall treatment. Our work emphasizes the significance of considering other differential diagnoses and the importance of multidisciplinary treatment of the findings, especially within clinical trials.

Keywords: PET/CT, NSCLC, durvalumab, MALT lymphoma, immune-related side effect

1. Background

Immunotherapy plays a vital role in the treatment of lung cancer today. However, in some cases, immunotherapy-related adverse events (irAEs) develop during this therapy. They can be diagnosed in positron emission tomography–computed tomography (PET/CT) and may occur in every organ system, such as skin, gastrointestinal tract, endocrine system, respiratory system (1). Adverse events during immunotherapy do not always have to be related to it. Our patient had both irAE and MALT lymphoma of the adrenal gland, which was not likely caused by the therapy.

MALT lymphoma is a subtype of non-Hodgkin lymphoma and usually manifests extranodal in the gastrointestinal tract (2) but can also occur in other organ systems (3), for example the adrenal gland (4, 5). However, misdiagnosis may occur due to the low incidence (6). The adrenal gland is a common site for metastasis from lung cancer and enlargement of the adrenal gland can be misinterpreted as a metastasis (7, 8). Some possible differential diagnoses of an adrenal mass include adenoma, myelolipoma, cyst, lipoma, pheochromocytoma, primary adrenal cancer, hyperplasia, and tuberculosis (9).

We present a patient with the incidental discovery of a unilateral MALT lymphoma of the adrenal gland and adrenalitis during immunotherapy with durvalumab after chemoradiotherapy (CRT) in stage III non-small cell lung cancer (NSCLC) detected by 18F-FDG-PET/CT. We assessed the clinical as well as intraoperative findings, radiological examinations, and overall treatment.

2. Case presentation

2.1. Diagnosis and treatment

We present the case of a 67-year-old Caucasian female patient who was referred to our department in May 2021 (Figure1). The patient initially presented with progressive dyspnea and cough. A subsequent computed tomography (CT) scan revealed a suspicious malignant mass in the upper lobe of the right lung and was clinically diagnosed as locally advanced NSCLC. Histological evaluation and next-generation sequencing revealed a large cell neuroendocrine lung carcinoma (LCNEC) with S37C mutation in the CTNNB1 gene, E542 mutation in the PIK3CA gene, and inactivating mutation in the TP53 gene. Nuclear staining for Ki-67 was performed using anti-Ki67 antibody (MIB-1, 1:100, Dako). Ki-67 expression was scored as 50% evaluated semiquantitatively as a percentage of positive cells upon manual counting of 500 to 1,000 tumor cells. For the detection of programmed death-ligand 1 (PD-L1), prediluted PD-L1 rabbit monoclonal antibody (SP263; Ventana Medical Systems, Oro Valley, Arizona) was used and measured as 5% using the tumor proportion score (TPS). Both stainings were performed on a Ventana Benchmark Ultra autostainer using the ultraView diaminobenzidine kit (Ventana Medical Systems, Oro Valley, AZ).

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Timeline of patients’ treatment and follow-up.

Initial positron emission tomography/computed tomography (18-FDG-PET/CT) staging and cranial magnetic resonance imaging (cMRI) in July/August 2021 showed metastases in the hilar lymph nodes on the right side, which resulted in stage IIIB (cT3, cN2, M0) according to UICC TNM staging (8th edition) (10).

Relevant medical history findings included active smoking (50 p/y), breast cancer (diagnosed in 2006, non-active), peripheral arterial disease, and chemotherapy-associated pancytopenia CTCAE II.

Beginning in September 2021, our patient underwent induction chemotherapy with two cycles of carboplatin (AUC5) and pacl*taxel (150 mg/m²). After local response, concurrent CRT (30 fractions × 2.2 Gy/66 Gy) with two cycles of concurrent platinum-based chemotherapy was administered. The patient received carboplatin (AUC5 i.v.) on day 1 of each cycle and 25 mg/m2 vinorelbine i.v. on day 1 and day 8 of each cycle.

The patient was treated with immunotherapy with PD-L1 antibody durvalumab according to the phase III PACIFIC trial (NCT02125461) (11) starting in January 2022. Immunotherapy was given every 2 weeks. During durvalumab therapy, the patient’s general condition deteriorated in August 2022 with a diagnosis of Addison’s disease due to CTCAE grade II autoimmune adrenalitis, which was potentially immune-mediated. This led to the discontinuation of durvalumab therapy.

A further 18F-FDG PET/CT scan revealed increased metabolic activity in the right adrenal gland (SUVmax: 6.7) with suspicion of possible metastasis. After multidisciplinary discussions, a laparoscopic adrenalectomy was performed in August 2022. Histological examination of the resected soft tissue (5.5 × 4.3 × 0.4 cm) revealed an enlarged adrenal gland with a maximum diameter of 3.3 cm. In fact, the patient had histomorphologically highly atypical adrenal tissue; the medullary zone was distinguishable, and the adrenal cortex tissue was completely depleted. Using conventional light microscopy, there were neither cells of the zona glomerulosa, nor zona fasciculata or zona reticularis. Instead, immunohistological evaluation showed a band-like lympho-plasmacytoid infiltration/inflammation with a dominant diffuse and focally nodular infiltration of CD5-positive T-lymphocytes and partially grouped CD20-positive B-lymphocytes. Numerous CD38-positive plasma cells were detected with a dominance of lambda over kappa-positive plasma cells. Further molecular pathological examination detected a clonality of the IgH gene but no mutation in the MyD88 gene. In summary, an indolent non-Hodgkin’s lymphoma of the B-cell lineage was found in the right adrenal gland, suggesting a MALT lymphoma. Further endoscopic diagnostic by bioptic securing showed no evidence of other manifestations of the MALT-Lymphoma (e.g., gastrointestinal tract). A bone marrow puncture was rejected by the patient.

2.2. Outcome and follow-up

In close cooperation with our endocrinology department, a substitution therapy with Hydrocortisone 10 mg/day was initiated. Continuation of the immunotherapy with durvalumab was not planned according to the decision of the tumor board. However, adjuvant therapy for the MALT-Lymphoma was not indicated. A follow-up 18F-FDG-PET/CT performed in January 2023 showed a stable disease situation with no local progression of the NSCLC, no metastatic lesions, and no increased metabolism indicating a possible local recurrence in the field of the resected adrenal gland.

3. Discussion

This case report demonstrates the importance of histological evaluation and differential diagnoses, especially in patients with complex patient history.

Immunotherapy, particularly the use of checkpoint inhibitors (ICIs), has revolutionized treatment of NSCLC in recent years (12). While ICIs have shown remarkable efficacy in some patients, they can also lead to irAEs, which can range from mild to severe and life-threatening (13). IrAEs can affect any organ system and can present with a wide range of symptoms, including skin rash, colitis, hepatitis, pneumonitis, and endocrinopathies (1416). The incidence and severity of irAEs depend on the type of ICIs, the dose, and the duration of treatment (17).

The meta-analysis by Wang etal. evaluated 46 trials with a total of 12,808 patients treated with PD-1/PD-L1 inhibitors. In this analysis, the patients received treatment with nivolumab (21 studies, 45.65%), pembrolizumab (17 studies, 36.96%), atezolizumab (5 studies, 10.87%), durvalumab (one study, 2.17%), and avelumab (one study, 2.17%). On average, the incidence of irAE of any grade was 32.92% in every organ system. the following specific incidences of irAEs were determined after subdividing into the individual organ systems: skin (13%), gastrointestinal tract (10%–13%), respiratory system (3%), endocrine system (≤2%), liver (≤2%), and kidney (<1%) (1).

Early diagnosis and management of irAEs are crucial for improving patient outcomes (18). One diagnostic tool that has shown promise in detecting irAEs is 18F-FDG-PET/CT (19), which differentiates them from other disease processes such as infection or cancer progression (20).

In addition to detecting irAEs, 18F-FDG-PET/CT can also be used to predict the development of irAEs. A study by Nobashi etal. evaluated the use of 18F-FDG-PET/CT in predicting the possible outcomes of irAE in patients receiving ICIs. The study included 40 patients who underwent 18F-FDG-PET/CT before and after the ICI therapy. Patients with irAE that could be detected by 18F-FDG-PET/CT were significantly associated with a favorable long-term outcome (P = 0.002) (21).

In conclusion, 18F-FDG-PET/CT is a promising tool for the diagnosis and monitoring of irAEs in patients undergoing immunotherapy. While further research is needed to fully evaluate the utility of 18F-FDG-PET/CT in this context, existing studies suggest that 18F-FDG-PET/CT can provide valuable information for the early detection and management of irAEs.

18F-FDG-PET/CT is also a well-established imaging method for detecting, staging, and monitoring various cancer entities. The accuracy of 18F-FDG-PET/CT in cancer patients depends on several factors, such as the tumor size, location, type, and stage of disease. In recent studies, 18F-FDG-PET/CT has demonstrated good sensitivity and specificity for detecting different types of primary cancer and distant metastasis, including lung cancer and adrenal masses. A meta-analysis about the diagnostic accuracy of 18F-FDG-PET/CT for the characterization of adrenal masses performed by Kim etal. showed in 29 studies with 2,421 patients in total a sensitivity of 91% [95% CI (0.88–0.94)] and specificity of 91% [95% CI (0.87–0.93)] (22).

Ma etal. displayed that SUVmax of malignant lesions (10.0 ± 5.8) was higher than that of benign lesions (5.4 ± 5.3, P < 0.05), and as a result of this finding, the SUV-ROC method has a sensitivity of 81.25% and specificity of 72.91% (23). Another study by Perry etal. demonstrated a higher sensitive accuracy of 18F-FDG-PET/CT in detection of non-gastric MALT-Lymphoma versus gastric MALT-Lymphoma (75% vs. 38.9%) (24). Despite its limitations, 18F-FDG PET/CT remains a respected method for diagnosing and monitoring suspicious tumors of the adrenal gland.

In our patient, the increased metabolic activity in the right adrenal gland seen on 18F-FDG-PET/CT raised suspicion of an adrenal metastasis of NSCLC. However, histologic examination revealed a MALT lymphoma. This emphasizes the importance of histological examination of suspected metastases. A systematic review of adrenal biopsy by Bancos etal. using 32 studies found that adrenal biopsy had a sensitivity of 87% [95% CI (0.78–0.93)] and a specificity of 100% [95% CI (0.7–1.00)] for the overall diagnosis of malignancy. For the diagnosis of metastases, the sensitivity was 87% [95% CI (0.74–0.94)] and the specificity was 96% [95% CI (0.89–0.98)] (25). Stone etal. created a diagnostic algorithm that only integrates biopsy for histopathological investigation in suspected benign adenoma with SUV max < 3.1 or SUVmax > 3.1 and SUV ratio < 2.5 in PET/CT (26). Otherwise, malignant metastasis is suspected and adrenalectomy is indicated with therapeutic and diagnostic benefit by performing ex vivo histologic examinations. As stated, SUVmax analysis in PET/CT gives information whether the adenoma is benign or malignant, but the comparison of the histological finding leads to the final diagnosis.

Retroperitoneal supra-renal masses are often diagnosed coincidentally in the context of imaging of the abdomen and are then classified as incidentaloma. The origin of these suspect adrenal masses must be evaluated to discuss the following treatment, which differs if it is an adrenal (pheochromocytoma, adrenal hyperplasia, cortical adenoma) or extra-adrenal (malignancies, infections, hemorrhage) origin. As Frey etal. state in their review, 3.5% of the adrenalectomies are mistakenly performed under the indication of an adrenal disease (27). However, most incidentalomas are metastasis of other tumorous sites. Also, rare manifestations such as ganglioneuroma, hemangioendothelioma, and hemangioma must be considered. In 2016, the European Society of Endocrinology published a Clinical Practice Guideline for the management of such findings in the adrenal gland (28).

There are few clinical trials addressing PD-L1-targeted therapy with durvalumab in hematologic malignancies such as MALT-Lymphoma. The Phase 1/2 FUSION NHL 001 study by Casulo etal. aims to evaluate the security and efficacy of durvalumab as monotherapy and in combination with other full agents in patients with lymphoma (29). They found that durvalumab monotherapy and durvalumab combinations did not provide additional benefit while adding the treatment-related toxicity of PD‐L1 blockade.

In summary, this case demonstrates the importance of multidisciplinary discussion in the management of complex cases, especially when rare histologic subtypes are given and within clinical trials.

4. Conclusion

Despite its side effects, immunotherapy is an established component in the treatment of lung cancer. 18F-FDG-PET/CT plays a crucial role in diagnosis and during treatment to detect complications early. Nevertheless, if malignant processes are suspected, histologic confirmation must be performed. Otherwise, unexpected differential diagnoses may be misinterpreted. We emphasized the significance of considering other differential diagnoses in these patients and the importance of multidisciplinary treatment of the findings, especially within clinical trials.

Ethics statement

Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

Author contributions

LK, ED and KE-M wrote the manuscript. FM supervised the writing. All authors contributed to the article and approved the submitted version.

Conflict of interest

LK and FM received an unrestricted research institutional grant from AstraZeneca. LK received honoraria from AMGEN and AstraZeneca. FM received honoraria from AstraZeneca, Novartis, Roche, Lilly, Elekta and Brainlab. FM serves in the advisory board of AstraZeneca, Novartis. FM was employed by Private Practise ´Die RADIOLOGIE´.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


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Case report: Incidental MALT lymphoma of the left adrenal gland mimicking a metastatic spread within durvalumab maintenance treatment in inoperable stage III non-small cell lung cancer (2024)


Can MALT lymphoma spread to the lungs? ›

MALT lymphoma is a relatively rare disease, and the most common site is gastrointestinal, but it can also develop in many different organs, including the salivary gland, orbit, thyroid gland and lung, etc.

What is the prognosis for lymphoma in the lungs? ›

According to 2019 research, pulmonary MALT lymphoma has a 5-year overall survival rate of 87.1% . That means about seven out of every eight people with the disease are still alive 5 years after receiving the diagnosis.

What is the life expectancy of someone with MALT lymphoma? ›

What is the survival rate? One study suggests 88% of people with MALT lymphoma are alive five years after diagnosis.

How serious is MALT lymphoma? ›

“MALT lymphoma is often a very slow-growing disease, and people can live with it for long periods, sometimes without even knowing they have it,” says Gunther. “MALT lymphoma is treatable in most cases. We don't want to cause the patient more harm with the treatment than the disease itself.”

Which lymphoma has worst prognosis? ›

Mantle Cell Lymphoma

It has the worst prognosis among all lymphoma subtypes with a median overall survival of 5 years.

At what stage is lymphoma terminal? ›

Stage 4. Stage 4 is the most advanced stage of lymphoma. Lymphoma that has started in the lymph nodes and spread to at least one body organ outside the lymphatic system (for example, the lungs, liver, bone marrow or solid bones) is advanced lymphoma.

What is the survival rate for metastatic lymphoma? ›

5-year relative survival rates for NHL
SEER stage5-year relative survival rate
All SEER stages combined65%

What are the symptoms of MALT lymphoma in the lungs? ›

Pulmonary MALT lymphomas occur mostly in men aged 60–70 years, and 38–50% of patients reported in the literature can be asymptomatic and detected only incidentally on physical examination [12, 13]. Clinical symptoms manifest as fever, cough, dyspnea, hemoptysis, chest pain, and other respiratory symptoms [14].

How do you know if lymphoma has spread to lungs? ›

If lymphoma affects your lungs, you are likely to have difficulties breathing. You also have an increased risk of getting a chest infection, which your immune system might struggle to fight off.

What is a MALT lymphoma of the lungs? ›

MALT lymphoma is the most common pulmonary B-cell lymphoma, which usually occurs in the context of acquired MALT. The disease is slow-growing with an asymptomatic chronic alveolar opacity visible on radiography.

What lymphoma spreads to the lungs? ›

Secondary pulmonary lymphomas refer to pulmonary involvement with lymphoma when the condition is not limited to the lung and has mediastinal lymph node involvement or evidence of extrathoracic dissemination for at least three months after the initial diagnosis. This is a more common form of pulmonary lymphoma.


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