Introduction
Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease first described by Liebow et al. [ 1 ]. LYG is characterized by angiocentric and angiodestructive infiltration of EBV-positive B-cells and is often accompanied by necrosis [ 2 ]. The clinical course varies widely, ranging from spontaneous remission to progression into aggressive lymphoma. High-grade LYG has a poor prognosis, with median progression-free survival and overall survival of approximately one and two years, respectively, even with rituximab-based regimens such as R-CHOP (rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone) [ 2 , 3 ]. Waldenström’s macroglobulinemia (WM), a subtype of lymphoplasmacytic lymphoma (LPL), is a rare B-cell malignancy characterized by monoclonal IgM production and bone marrow infiltration. The age-adjusted incidence rate of WM/LPL in the United States is approximately 0.63 per 100,000 person-years, with the highest rates observed among White populations (0.74 per 100,000). In Japan, the reported incidence is approximately 0.28 per 100,000 person-years [ 4 ]. Even more rarely, LYG is an EBV-associated B-cell lymphoproliferative disorder for which precise epidemiological data are lacking due to its extreme rarity. Although LYG is recognized as a disorder often associated with immunodeficiency states [ 2 ], its coexistence or sequential development with LPL/WM has not been reported. The coexistence or sequential development of LPL/WM following other EBV-related lymphoproliferative disorders is extremely rare and, to our knowledge, has not been reported before. In this report, we describe a unique case of LYG that later developed LPL/WM and highlight the diagnostic challenges, disease progression, and therapeutic strategies.
Case presentation
A 73-year-old woman presented with left chest and arm pain that had persisted for three months and was accompanied by a gradually enlarging palpable tumor in the left neck region. She had no significant medical history, smoking history, or family history of systemic disease or cancer. Physical examination revealed left eyelid ptosis, neck swelling, and tenderness. Laboratory results showed elevated C-reactive protein and soluble interleukin-2 receptor levels but normal immunoglobulin M levels (Table 1 ). Hyponatremia was likely secondary to the syndrome of inappropriate antidiuretic hormone secretion associated with the tumor or inflammatory cytokine release.
Table 1
Complete blood test of the patient at diagnosis
| Complete blood test | Observed value | Reference range |
| White blood cell | 9,800/μL | 3,300-8,600/μL |
| Band neutrophil | 11.3% | 2.0%-13.0% |
| Segmented neutrophil | 57.0% | 38.0%-58.9% |
| Lymphocyte | 23.7% | 26.2%-46.6% |
| Monocyte | 7.7% | 2.3%-7.7% |
| Basophil | 0.3% | 0.0%-0.6% |
| Eosinophil | 0.0% | 0.0%-1.0% |
| Red blood cell | 446 × 10 4 /μL | 410-510 × 10 4 /μL |
| Reticulocyte | 12‰ | 2‰-17‰ |
| Hemoglobin | 11.9 g/dL | 13.7-16.8 g/dL |
| Platelet | 27.2 × 10 4 /μL | 15.8-34.8 × 10 4 /μL |
| Albumin | 3.7 g/dL | 4.1-5.1 g/dL |
| Total bilirubin | 0.4 mg/dL | 0.2-1.0 mg/dL |
| Aspartate aminotransferase | 28 U/L | 13-30 U/L |
| Alanine aminotransferase | 12 U/L | 8-20 U/L |
| Lactate dehydrogenase | 290 U/L | 124-222 U/L |
| Blood urea nitrogen | 8.8 mg/dL | 8.0-20.0 mg/dL |
| Creatinine | 0.65 mg/dL | 0.65-1.07 mg/dL |
| Sodium | 131 mEq/L | 138-145 mEq/L |
| Potassium | 4.3 mEq/L | 3.6-4.8 mEq/L |
| Chloride | 95 mEq/L | 101-108 mEq/L |
| Calcium | 9.5 mg/dL | 8.8-10.1 mg/dL |
| Ferritin | 632.1 ng/mL | 40-188 ng/mL |
| C-reactive protein | 6.20 mg/dL | 0.00-0.14 mg/dL |
| Carcinoembryonic antigen | 0.79 ng/mL | 0.0-5.0 ng/mL |
| Cytokeratin 19 fragment | 0.0 ng/mL | 0.0-3.5 ng/mL |
| Pro-gastrin-releasing peptide | 29.8 pg/mL | <80 pg/mL |
| Soluble interleukin-2 receptor | 2,140 U/mL | 145-519 U/mL |
| Immunoglobulin G | 924 mg/dL | 870-1,700 mg/dL |
| Immunoglobulin A | 162 mg/dL | 110-410 mg/dL |
| Immunoglobulin M | 49 mg/dL | 33-190 mg/dL |
| Epstein-Barr virus-viral capsid antigen-immunoglobulin M | <10 | <10 |
| Epstein-Barr virus-viral capsid antigen-immunoglobulin G | 1:40 | <10 |
| Epstein-Barr virus nuclear antigen | 1:10 | <10 |
| Human immunodeficiency virus antibody | Negative | Negative |
Contrast-enhanced computed tomography (CT) revealed a 9-cm mass extending from the left pulmonary apex to the neck, along with left adrenal metastasis as shown in Figure 1A - 1 to Figure 1A - 3 .
Although a transbronchial biopsy (TBB) was rapidly performed, it yielded seemingly insufficient diagnostic material due to prominent necrosis observed on hematoxylin-eosin staining. An incisional biopsy of the supraclavicular lesion was also performed to obtain a certain amount of tumor specimens. While the additional biopsy confirmed only large B-cell lymphoma, TBB ultimately established a diagnosis of grade 3 LYG through histopathological findings, including angiodestruction, angioinvasion, coagulative necrosis, and EBV-encoded RNA (EBER) positivity (Figure 2 ).
Given the diagnosis of high-grade LYG with Pancoast syndrome (Horner’s syndrome and brachial plexus involvement), R-CHOP therapy was initiated immediately. After one cycle, the patient experienced rapid pain relief, obviating the need for analgesics. Following six R-CHOP cycles and three cycles of additional rituximab monotherapy, complete remission (CR) was achieved. Follow-up CT performed one year after the initial chemotherapy revealed a suspected residual lesion in the left lung apex. Subsequent TBB of this area led to a diagnosis of organizing pneumonia, suggesting that the lesion represented post-chemotherapy scarring rather than residual malignancy as shown in Figures 1B - 1 , 1B - 2 .
However, 2.5 years later, the patient developed retinopathy due to hyperviscosity, a rapidly elevated IgM level (5,534 mg/dL, reference range: 33-190 mg/dL), and thrombocytopenia (platelet count: 24,000/μL, reference range: 15.8-34.8 × 104/μL). Bone marrow biopsy confirmed LPL/WM, which was characterized by monoclonal IgM-kappa production and EBER negativity (Figure 3 ). The markedly elevated IgM level was indicative of a hyperviscosity syndrome, explaining the development of retinopathy. Thrombocytopenia likely resulted from bone marrow infiltration by lymphoplasmacytic cells. The detection of monoclonal IgM-kappa protein confirmed the diagnosis of WM. EBER negativity in the bone marrow further supported the notion that the newly diagnosed lymphoma was unrelated to prior EBV-driven LYG.
At the time of WM diagnosis, when LYG was still in remission, six cycles of bendamustine-rituximab (BR) were administered for LPL/WM, resulting in the clinical improvement of retinopathy, IgM levels, and platelet counts. However, follow-up CT after six cycles of BR revealed progressive thoracic mass enlargement and internal fluid retention. CT-guided biopsy confirmed LYG recurrence with concurrent Aspergillus fumigatus infection as shown in Figures 1C - 1 , 1C - 2 . The patient declined further chemotherapy, opting for the best supportive care. Despite antifungal treatment with voriconazole, the patient succumbed to COVID-19-related complications. The entire treatment trajectory is shown in Figure 4 .
Discussion
To our knowledge, this is the first reported case of WM developing after high-grade LYG, highlighting a potentially underrecognized association between these rare B-cell malignancies. This case underscores three critical aspects of LYG and its management: diagnostic challenges, secondary hematologic malignancies, and therapeutic strategies.
Diagnostic challenges
The diagnosis of LYG is inherently challenging because the disease is exceedingly rare and exhibits very subtle histological features [ 5 ]. The initial differential diagnoses in this case included lung cancer, granulomatosis with polyangiitis, other EBV-associated lymphoproliferative disorders, and infectious causes. However, histopathological findings such as angiocentric and angiodestructive infiltration, necrosis, and EBER positivity in B-cells by in situ hybridization were highly characteristic of LYG and allowed us to distinguish it from these other conditions. TBB has emerged as a less invasive alternative to surgical lung biopsy in lung cancer diagnosis, although its diagnostic yield and sensitivity are slightly lower than those of surgical biopsy [ 6 ]. TBB may occasionally fail to provide an accurate diagnosis due to tissue contusion caused by mechanical clamping, necessitating subsequent surgical biopsy. Nevertheless, the TBB specimen in this case was analyzed successfully and presented the features of LYG grade 3, including angiocentric infiltration, coagulative necrosis, and EBER positivity. This observation is interesting, as lesions at the leading edge of the tumor may not consistently exhibit the hallmark histopathological findings of LYG. Although the exact mechanism underlying this phenomenon remains unclear, these findings emphasize the importance of the multidimensional evaluation of LYG. The detection of EBER positivity via TBB highlighted its diagnostic value even when the incisional biopsy is inconclusive. Furthermore, transbronchial lung cryobiopsies can provide larger, higher-quality tissue samples [ 7 ], which may enhance the LYG diagnosis.
Cooccurrence of hematologic malignancies
This is the first reported case of WM developing after high-grade LYG, highlighting a potentially underrecognized association between these rare B-cell malignancies. Previous reports have described the development of LYG in patients with immunodeficiency disorders, such as Wiskott-Aldrich syndrome and acquired immunodeficiency syndrome [ 8 , 9 ]. Several LYG cases also developed secondary to multiple myeloma, T-cell large granular lymphocytic leukemia, and chronic lymphocytic leukemia [ 10 - 13 ]. These findings demonstrate that the pathogenesis arises from defective immune surveillance. To better highlight the rarity and clinical significance of our case, previously reported cases of LYG associated with other hematologic malignancies have been summarized in Table 2 .
Table 2
Cases of lymphomatoid granulomatosis and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia related to other hematologic malignancy LYG: lymphomatoid granulomatosis; LPL/WM: lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia
| Case | Authors | Journal | Year | Associated hematologic malignancy | Timing of onset | Summary |
| LYG with hematologic malignancy cases | ||||||
| 1 | Ragage et al. | Ann Pathol | 2006 | Acute myeloid leukemia (AML) | Prior to LYG | Case of pulmonary LYG developed in an immunocompromised state after AML treatment [ 14 ] |
| 2 | Kim | Korean J Spine | 2012 | Acute lymphoblastic leukemia (ALL) | Prior to LYG | Spinal LYG after treatment for childhood ALL [ 15 ] |
| 3 | Michot et al. | Leuk Lymphoma | 2013 | T-large granular lymphocyte leukemia (T-LGL) | Prior to LYG | T-LGL preceded the diagnosis of LYG by 3 years, suggesting that LG is secondary to T-LGL [ 12 ] |
| 4 | De Luca et al. | Leuk Lymphoma | 2018 | T-LGL | Prior to LYG | Pulmonary LYG occurred after T-LGL leukemia development [ 11 ] |
| 5 | Rezvani et al. | Case Rep Pulmonol | 2019 | Chronic lymphocytic leukemia (CLL) | Prior to LYG | Report of rapidly progressive pulmonary LYG in a patient with CLL [ 13 ] |
| 6 | Lee et al. | Intern Med | 2019 | Multiple myeloma (MM) | Simultaneous | Simultaneous onset of CNS/pulmonary LYG and MM under immunosuppressive conditions [ 10 ] |
| 7 | Szczepanek et al. | Front Neurol | 2020 | CNS Hodgkin lymphoma (HL) | Simultaneous | Simultaneous onset of CNS HL and pulmonary LYG during immunosuppressive therapy for ulcerative colitis [ 16 ] |
| 8 | Bi et al. | Front Oncol | 2022 | Chronic myeloid leukemia (CML) | Prior to LYG | CML patient developed LYG and pulmonary infection during treatment [ 17 ] |
| LPL/WM after B-cell malignancy cases | ||||||
| 9 | Uğur et al. | Tepecik Eğit Hast Derg | 2014 | Non-Hodgkin lymphoma (NHL) | WM after NHL treatment | WM occurred 3 years after NHL treatment; reported as secondary malignancy [ 18 ] |
| 10 | Samsuddoha et al. | Cureus | 2024 | Chronic lymphocytic leukemia (CLL) | WM after CLL | Very rare case of CLL transforming into WM during ibrutinib therapy [ 19 ] |
| LYG-WM/LPL association case | ||||||
| 11 | Melegh et al. | Pathol Res Pract | 2009 | Lymphoplasmacytic lymphoma (LPL) | LYG after LPL treatment | Cervical LYG occurred under immunosuppression after treatment for LPL [ 20 ] |
This comparison highlights the unique sequence and diagnostic complexity of the present case. In the present case, however, immunodeficiency in the patient was not evident. Although the risk of developing LPL/WM increases after developing LYG or administering immunochemotherapy remains unknown [ 4 ], two hypotheses were considered: (1) a shared tumorigenic origin and (2) LPL/WM emergence secondary to immunosuppression. Although the absence of elevated IgM levels and EBER positivity at LYG onset might be evidentiary against a shared etiology, favoring the latter hypothesis, we could not perform genetic analysis to support this hypothesis. This highlights a major limitation of this study, indicating the need for further molecular studies to elucidate the mechanisms underlying this lymphomagenesis.
Therapeutic challenges
While the patient achieved CR after R-CHOP, BR was ineffective against early-stage recurrent LYG despite demonstrating some efficacy against LPL/WM. Recent evidence indicates that dose-adjusted-EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a promising first-line therapy for high-grade LYG [ 21 ]. However, an effective regimen has not yet been established for refractory/relapsed cases. To date, only two cases of LYG treated with bendamustine have been documented. However, these cases were treated by brentuximab-vedotin combination therapy. No cases treated with BR therapy have been reported [ 22 , 23 ]. These studies indicate that unregulated immune control of EBV may contribute to disease relapse after chemotherapy, signifying the critical need for novel immunotherapies, including programmed cell death protein-1 blockade. The results of the ongoing prospective study will be of interest (Clinical Trials number: NCT03258567 ).
Conclusions
This case illustrates an exceptionally rare clinical trajectory in which LPL/WM developed sequentially after high-grade LYG. The diagnostic complexity presented in this case due to overlapping clinical features, evolving histopathological findings, and limitations in biopsy sampling emphasizes the importance of comprehensive and multidimensional diagnostic approaches. Furthermore, the treatment course highlights the therapeutic challenges in managing relapsed LYG, for which standardized regimens are lacking. Although the coexistence or sequential development of these rare B-cell malignancies is extremely uncommon, this case underscores the importance of long-term surveillance and consideration of secondary hematologic malignancies in patients with EBV-associated lymphoproliferative disorders. Future research is warranted to elucidate the underlying pathogenesis and to develop more effective therapeutic strategies.
Disclosures
Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study.
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:
Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.
Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Author Contributions
Concept and design: Makoto Ito, Norio Takagi, Yusei Mizumoto, Satsuki Nakano, Yasushi Murakami
Acquisition, analysis, or interpretation of data: Makoto Ito, Norio Takagi, Yusei Mizumoto, Satsuki Nakano, Yasushi Murakami
Drafting of the manuscript: Makoto Ito, Norio Takagi, Satsuki Nakano, Yasushi Murakami
Critical review of the manuscript for important intellectual content: Makoto Ito, Norio Takagi, Yusei Mizumoto, Satsuki Nakano, Yasushi Murakami
Supervision: Makoto Ito, Norio Takagi, Satsuki Nakano, Yasushi Murakami
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