Clinical Case ReportsTitle PageFull TitleA case of diffuse large B-cell lymphoma mimicking disseminated histoplasmosis with bilateral adrenal masses and adrenal insufficiencyAuthorsAyush Gandhi, MD1*Ei Moe Phyu, MD1Kodwo Bosomefi Dickson, MD1Affiliations1 Department of Hospital Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USACorresponding AuthorCorrespondence to:Ayush Gandhi, MDDepartment of Hospital MedicineThe University of Texas MD Anderson Cancer CenterHouston, TX, USAEmail: Agandhi2@mdanderson.orgKeywords:Diffuse large B-cell lymphoma; Histoplasmosis; Adrenal masses; Adrenal insufficiency; Anchoring biasKey Clinical MessageIn patients with a prior confirmed infection, progressive disease despite negative testing should prompt reconsideration of the diagnosis. Large bilateral adrenal masses with adrenal insufficiency warrant early tissue biopsy, as malignancy may masquerade as disseminated infection.AbstractDisseminated infections and hematologic malignancies frequently share overlapping clinical and radiologic features, creating substantial diagnostic challenges. We describe a woman in her forties with a history of biopsy-proven pulmonary histoplasmosis who later developed progressive constitutional symptoms, abdominal pain, and bilateral adrenal masses with adrenal insufficiency. Her clinical deterioration was initially attributed to recurrent or progressive histoplasmosis despite negative fungal testing and radiographic progression. Ultimately, adrenal biopsy confirmed aggressive diffuse large B-cell lymphoma (DLBCL). This case highlights the risk of anchoring bias in patients with prior confirmed infections and underscores the importance of reassessing the differential diagnosis and pursuing tissue diagnosis when the clinical course becomes discordant with initial assumptions.IntroductionSome of the most challenging situations in clinical medicine occur when two diseases look almost identical at the bedside. Overlapping symptoms can obscure the diagnosis and lead to delays in treatment. Disseminated fungal infections and hematologic malignancies are a classic example of this problem. (1) (2) (3)Histoplasma capsulatum, the dimorphic fungus responsible for histoplasmosis, is usually acquired through inhalation of spores from soil contaminated with bird or bat droppings. For many healthy individuals, infection is silent or causes a mild respiratory illness. In contrast, patients with impaired cellular immunity may develop disseminated disease, involving multiple organs. Clinical features often include fever, night sweats, weight loss, hepatosplenomegaly, pulmonary nodules, and adrenal involvement. (4)Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, accounting for about 30% of cases in adults. It is an aggressive neoplasm of large B-lymphocytes, typically presenting with fever, drenching night sweats, and weight loss—the same “B symptoms” seen in disseminated infections. Extranodal disease is frequent, with common sites including the gastrointestinal tract, central nervous system, and adrenal glands. (5) (6)Because both diseases can involve the same organ systems, the resulting radiographic and clinical overlap makes distinguishing them extremely difficult. Bilateral adrenal masses, in particular, create a diagnostic dilemma. This similarity also opens the door to cognitive errors such as anchoring bias, where clinicians remain fixed on a prior diagnosis despite evolving evidence. (1) (7)We describe the case of a 47-year-old woman with biopsy-confirmed pulmonary histoplasmosis whose later clinical decline was ultimately explained by DLBCL. Her course illustrates the importance of broad differentials, awareness of discordant findings, and timely pursuit of tissue diagnosis when the disease course deviates from expectations.Case History / ExaminationA woman in her 40s with a past medical history of bipolar disorder and migraines presented with recurrent abdominal pain, weight loss, fevers, and night sweats. She had a 29-pack-year smoking history and occasional alcohol use. She previously worked in poultry processing, a recognized risk factor for Histoplasma exposure.Her initial presentation was in March 2023, when she developed progressive dyspnea and cough. Chest imaging showed multiple pulmonary nodules. Bronchoalveolar lavage cultures grew Histoplasma capsulatum, and open lung biopsy confirmed pulmonary histoplasmosis. She began antifungal therapy but discontinued treatment after several months due to medication intolerance and loss of insurance coverage. While awaiting BAL and biopsy results, she received a short course of high-dose steroids for suspected sarcoidosis.In February 2025, she presented with severe abdominal pain. Imaging revealed a large left adrenal mass complicated by hemorrhage. Retrospective review showed an adrenal mass dating back to 2016. The findings were attributed to disseminated histoplasmosis, and no biopsy was performed. Over the following months, she developed adrenal insufficiency requiring chronic hydrocortisone replacement.She was later referred to our institution for evaluation of a thyroid nodule, but before this could be completed, she was admitted from the emergency room with acute pancreatitis, which was managed conservatively. She was also seen by the pulmonary team who felt that the lung nodules were too small and peripheral for biopsy and recommended noninvasive workup for histoplasmosis.The patient presented to our emergency room in September 2025 with a several-month history of worsening low-grade fevers, night sweats, anorexia, and a 30-pound weight loss, accompanied by escalating abdominal pain. She had been discharged just four days prior after a three-day admission for similar complaints.On physical examination, her vital signs were stable. The most prominent finding was marked epigastric tenderness on deep palpation. Laboratory investigations revealed a mild normocytic anemia with a hemoglobin of 11.6 g/dL and a downtrending lipase of 921 U/L (down from 2560 U/L four days prior), confirming recent pancreatitis.A full infectious workup including urine Histoplasma antigen, serum antibody testing, and T-Spot for tuberculosis, was negative.CT imaging of the chest, abdomen, and pelvis demonstrated multiple bilateral pulmonary nodules, a thyroid nodule, and bilateral adrenal masses, which were initially interpreted as stable findings consistent with the patient’s prior diagnosis of disseminated histoplasmosis.Because of the ongoing clinical decline and the discrepancy between negative serologies and radiographic findings, an MRI of the abdomen was obtained. It showed multifocal, infiltrative disease involving both adrenal glands, the pancreas, and retroperitoneum, with clear progression compared to four months prior.Figure 1: (A) Axial CT chest demonstrating a right lower lobe pulmonary nodule measuring approximately 1 cm. (B) Additional bilateral pulmonary nodules are present.Figure 2: (A) Coronal CT abdomen demonstrating a right adrenal mass measuring approximately 10 cm. (B) Left adrenal mass measuring approximately 9.8 cmDifferential DiagnosisThe initial differential diagnosis included recurrent or disseminated histoplasmosis, adrenal tuberculosis, primary adrenal lymphoma, metastatic malignancy, and other invasive fungal infections. Given the patient’s prior biopsy-proven histoplasmosis and adrenal hemorrhage, disseminated histoplasmosis was initially favored. However, progressive radiologic infiltration, negative fungal markers, and lack of response to antifungal therapy raised concern for an underlying malignancy, prompting tissue biopsy.Conclusion and Results (Outcome and Follow-up)Histology demonstrated sheets of large atypical cells with prominent nucleoli, numerous tingible body macrophages, and a high mitotic rate creating a “starry sky” pattern. Neoplastic cells extended into adjacent fat, with no normal adrenal tissue remaining.Immunohistochemistry was positive for CD20, CD79a, and LCA/CD45, and negative for CD2, CD3, CD30, CD68, and SF-1. Ki-67 showed a proliferative index of 70–80%. Special stains (PAS, GMS, AFB) were negative for fungi or mycobacteria.The findings confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL).She was transferred to the lymphoma service and started on urgent systemic chemotherapy (Pola-R-CHP: polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone). Given her history of histoplasmosis and the risk of immunosuppression, she was also started on posaconazole 300 mg daily for secondary antifungal prophylaxis.Clinical TimelineA detailed chronology of the patient’s presentation, investigations, and management is provided in Table 1.Table 1: Patient’s TimelineDiscussionThis case shows how a malignancy can slip past us when we are focused on an earlier, well-established infectious diagnosis. Several factors contributed to the delay in recognition: her confirmed history of histoplasmosis, overlapping symptoms, and the understandable tendency to attribute new findings to an existing diagnosis.Both disseminated histoplasmosis and DLBCL share the same B symptoms and often involve the reticuloendothelial system. In her case, the pulmonary and adrenal nodules seemed to fit histoplasmosis, but in hindsight, they were equally compatible with lymphoma. (8) (1)What made this case more complicated is that she likely had real histoplasmosis at first, but then developed lymphoma later so it wasn’t just one condition imitating the other. Disseminated histoplasmosis is typically associated with impaired cellular immunity. The patient did not have a known immunodeficiency at the time of her initial diagnosis in 2023, and given the natural history of untreated DLBCL (median survival of ~6 months) (5), (9)it is unlikely that the lymphoma was present at that time. However, the use of corticosteroids during the early evaluation for suspected sarcoidosis may have contributed to immunosuppression, facilitating dissemination of histoplasmosis.At first glance, this patient’s presentation could have been mistaken for primary adrenal lymphoma (PAL). PAL usually presents with bilateral adrenal enlargement, adrenal insufficiency, and is almost always of the DLBCL subtype. Our patient had these same features, which made PAL a reasonable consideration. In the end, however, the disease pattern did not fit. She also had pulmonary nodules, a thyroid nodule, and retroperitoneal and pancreatic involvement at the time of diagnosis. These findings made it more consistent with disseminated DLBCL that had spread to the adrenal glands rather than lymphoma arising primarily from them. This case shows how disseminated lymphoma can look very similar to PAL, and why a biopsy was crucial in sorting out the true diagnosis. (10) (11)The occurrence of adrenal insufficiency after adrenal hemorrhage in this setting was a significant clinical finding. While adrenal hemorrhage is more common in Histoplasmosis (7) (8), its presence in association with enlarging adrenal masses measuring up to 10 cm is strongly suggestive of an infiltrative malignant process.This case also illustrates the impact of anchoring bias. (12) (13) The initial diagnosis of pulmonary histoplasmosis shaped the interpretation of later findings. As a result, biopsy was delayed, and the diagnosis of lymphoma was only made once the disease had dramatically progressed. In addition, chronic glucocorticoid replacement for adrenal insufficiency may have attenuated early constitutional symptoms of lymphoma further obscuring clinical progression and potentially contributing to delayed diagnosis.Misdiagnosis between infection and malignancy in the literature:Misdiagnosis between tuberculosis, deep fungal infections, and malignancies has been repeatedly reported in the literature. These conditions often share overlapping symptoms and imaging features, creating significant diagnostic challenges. We summarize eight published adult cases where infection was mistaken for cancer or vice versa, highlighting lessons for clinical practice. A summary of published cases where infection was mistaken for malignancy, or vice versa, is presented in Table 2.Table 2: Cases of Misdiagnosis: Infection vs MalignancyLearning points:A past infection does not rule out the possibility of a new, unrelated illness such as lymphoma.When a patient continues to get worse despite treatment, it is important to step back and reconsider the diagnosis.Large adrenal masses with adrenal insufficiency should raise suspicion for malignancy and prompt early biopsy.Sticking too firmly to an earlier diagnosis (anchoring bias) can delay recognition of a serious new condition.In uncertain cases, a tissue biopsy is essential to get to the right diagnosis and guide treatment.References:1. Shafiee F, Soltani R, Meidani M. Invasive fungal infections in hematologic malignancies: Incidence, management, and antifungal therapy. J Res Med Sci. 2023;28:73.2. Benjamin OE, Bassey TE, Nwagboso CI, Onukak A, Nlemadim AC, Akpu BB, et al. Histoplasmosis misdiagnosed as malignancies in immunocompetent and immunocompromised patients. hLife. 2025;3(8):386–90.3. Sullivan BN, Baggett MA, O’Connell SS, Pickett KM, Steele C. A Systematic Review to Assess the Relationship between Disseminated Cerebral Aspergillosis, Leukemias and Lymphomas, and Their Respective Therapeutics. Journal of Fungi. 2022;8(7):722.4. Wheat LJ, Azar MM, Bahr NC, Spec A, Relich RF, Hage C. Histoplasmosis. Infect Dis Clin North Am. 2016;30(1):207–27.5. Sehn LH, Salles G. Diffuse Large B-Cell Lymphoma. N Engl J Med. 2021;384(9):842–58.6. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–11.7. Goodwin RA, Jr., Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore). 1980;59(1):1–33.8. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20(1):115–32.9. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116(12):2040–5.10. Yang Y, Xie W, Ren Y, Tian H, Chen T. A case report of primary adrenal lymphoma: A rare but aggressive and invasive disease. Medicine (Baltimore). 2020;99(28):e20938.11. Mozos A, Ye H, Chuang WY, Chu JS, Huang WT, Chen HK, et al. Most primary adrenal lymphomas are diffuse large B-cell lymphomas with non-germinal center B-cell phenotype, BCL6 gene rearrangement and poor prognosis. Mod Pathol. 2009;22(9):1210–7.12. Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them. Acad Med. 2003;78(8):775–80.13. Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. Arch Intern Med. 2005;165(13):1493–9.14. Kong C, Zong L, Ji S, Liu Y, Li M. Case report: Disseminated mucormycosis misdiagnosed as malignancy developed from allergic bronchopulmonary mycosis caused by Rhizopus microsporus following SARS-CoV-2 infection in a woman. Front Med (Lausanne). 2024;11:1394500.15. Hu M. A Case of Multi-Organ Tuberculosis Misdiagnosed as Lung Cancer and a Literature Review. Cancer Manag Res. 2023;15:1395–400.16. Hang T-X, Fang G, Huang Y, Hu C-M, Chen W. Misdiagnosis of a multi-organ involvement hematogenous disseminated tuberculosis as metastasis: a case report and literature review. Infectious Diseases of Poverty. 2020;9(1):66.17. Lauren B, Jane F, Nicole T, Castro-Revoredo I. Another Great Pretender: A Case of Tuberculous Peritonitis Mistaken for Malignancy. Clinical Medical Reviews and Case Reports. 2021;8.18. Sun J, Zhu Y-Z, Shao P-P, Ke J, Wang W, Sun Q-L, et al. Misdiagnosis of Systemic Metastatic Melanoma for fungal infection: A case report2021.19. Ruegg G, Zimmerli S, Trachsel M, Berezowska S, Engelbrecht S, Martin Y, et al. Pulmonary Histoplasmosis Mimicking Metastatic Lung Cancer: A Case Report. Diagnostics. 2021;11(2):328.20. Ye D, Liu X, Yang Y, Yang Y, Fei Z, Liu H, et al. Case Report: Epididymal NK/T-cell lymphoma and adrenal diffuse large B-cell lymphoma are misdiagnosed as tuberculosis: two case reports and literature review. Front Oncol. 2025;15:1529049.Patient Consent Written informed consent was obtained from the patient for publication of this case report and accompanying images.Conflict of Interest The authors declare no conflicts of interest.Funding This work received no specific funding.Author Contributions Ayush Gandhi: Conceptualization, data curation, investigation, writing (original draft), writing (review and editing). EP: Supervision, writing (review and editing). KD: Supervision, writing (review and editing).
