Pictures at Bedside and Bench
初回治療から10年後に再発したリンパ形質細胞リンパ腫・ワルデンシュトレームマクログロブリン血症に対してチラブルチニブが奏効した高齢患者の一例
2025 年 28 巻 1 号 p. 54-58
詳細
2025 年 28 巻 1 号 p. 54-58
Contrast-enhanced CT images of the chest before and 4 months after the start of tirabrutinib, showing size reduction of the right lung hilar tumor and mediastinal LNs (white arrows) with treatment. LN indicated by the yellow arrow was considered to correspond to station #4R LN targeted by EBUS-TBNA (Figure 2). The infiltrate in the right S7 segment also disappeared (blue arrows). Note that the superior vena cava, azygos vein, and pulmonary artery passing through the tumor were patent.
An 81-year-old man was referred to the Department of Respiratory Medicine due to a tumor in the right pulmonary hilum. Chest X-ray and computed tomography (CT) confirmed the right hilar tumor as well as mediastinal lymphadenopathy (Key Figure), and 18F-fluorodeoxyglucose-positron emission tomography combined with CT revealed tracer accumulation in these lesions with a maximum standardized uptake value of 10.1, suggesting hilar-type lung cancer associated with lymph node (LN) metastasis. The patient was aware of mild fatigue and loss of appetite, and had lost 4 kilograms in body weight.
Eleven years earlier, the patient had presented to the Department of Hematology with IgM/κ monoclonal gammopathy. The bone marrow (BM) showed an increased number of lymphoplasmacytic cells, leading to the diagnosis of Waldenström macroglobulinemia (WM).1 One year after the initial presentation, as the level of M protein steadily increased, the patient was treated with 3 cycles of rituximab, fludarabine, and cyclophosphamide (RFC regimen).2 In response to the treatment, M protein decreased to undetectable levels, and the patient was lost to follow-up.
Laboratory test values at this visit were: hemoglobin level, 10.3 g/dL; white blood cell count, 4.88 × 103/µL with normal differential; platelet count, 241 × 103/µL; lactate dehydrogenase, 166 U/L; aspartate aminotransferase, 17 U/L; alkaline phosphatase, 87 U/L; C-reactive protein, 0.17 mg/dL; CEA, 4.5 ng/mL; CYFRA, 3.8 ng/mL (reference value, ≤3.5 ng/mL); proGRP, 38.9 pg/mL (reference value, ≤74.7 pg/mL); β2 microglobulin, 2.11 µg/mL (reference range, 0.8 to 1.9 µg/mL); soluble interleukin-2 receptor (sIL-2R), 782 U/mL (reference range, 156.6 to 474.5 U/mL). Electrophoresis of serum proteins failed to detect an M peak, but immunoelectrophoresis detected IgM/κ-type M protein (Figure 1). Other immunoglobulin-related values were: serum IgG, 1,092 mg/dL; IgA, 166 mg/dL; IgM, 218 mg/dL (reference range, 33 to 183 mg/dL); free light-chain κ, 36.3 (reference range, 3.3 to 19.4 mg/dL); λ, 24.9 mg/dL; κ/λ ratio, 1.46 (reference range, 0.26 to 1.65).
Immunofixation test of serum proteins at relapse of LPL/WM. Small IgM/κ monoclonal proteins are indicated by arrows.
Diagnostic endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed (Figure 2). The specimen obtained from a right lower paratracheal LN (LN station #4R) contained aggregates of medium to large lymphoid cells (Figure 3A). The cells were positive for CD20 and BCL2 (Figure 3B and C), focally positive for BCL6, and weakly positive for CD10 by immunohistochemistry (IHC). CD3 and CD138 were negative. The Ki-67 labeling index was 20% (Figure 3D). Flow cytometry (FCM) identified two overlapping clonal B-cell populations expressing IgM/κ immunoglobulins: the major population, accounting for 50% of B cells, was consisted of small to medium-sized cells, being CD19+, CD20+, CD5−, CD10−, CD38dim+/+, CD45RO+, and HLA-DR+/dim+; the minor population, accounting for 10% of B cells, was consisted of small cells, being CD19+, CD20bright+, CD5−, CD10+, CD38bright+, CD45RO−, and HLA-DRbright+. BM showed hypocellularity with normal hematopoietic precursors.
EBUS-TBNA. (A) An endobronchial image of the distal trachea at the carina level. LN stations #4R and #4L can be assessed through the lateral wall of the lower trachea, and LN station #7 through the medial wall of either the left or right main bronchus. (B) Endobronchial ultrasound image demonstrating an enlarged LN of station #4R, with well-defined borders and a heterogenous echotexture. (C and D) Endobronchial ultrasound images demonstrating the dedicated 21-gauge needle within LN during TBNA.
Histopathology of EBUS-TBNA specimens. A, hematoxylin & eosin staining (original magnification of objective lens, 20×); B, anti-CD20 immunostaining (20×); C, anti-BCL2 (20×); and D, anti-Ki67 (20×).
BIOMED-2 multiplex polymerase chain reaction (PCR) detected clonal rearrangements of IGK and IGH in DNA from the LN.3 The entire IGHV-D-J sequences were composed of V3-23*01/V3-23D*01, D4-23*01, and J4*02, and IGHV sequence identity with germline sequences was 89.58% according to IMGT/V-QUEST analysis. MYD88 p.L265P mutation was detected by both allele-specific (AS-) PCR and PCR-restriction fragment length polymorphism (RFLP) tests (Figure 4).4 Fluorescence in situ hybridization of interphase nuclei revealed 3 copies of BCL6 at 3q27 and loss of one copy of MYB at 6q23. BM was negative for IGH/IGK rearrangements and MYD88 mutation (Figure 4).
Ethidium bromide-stained gel electrophoresis of PCR products showing MYD88 p.L265P mutation. In AS-PCR (top), PCR products of 298 bp representing the wild-type (wt) and mutated (mut) alleles were run side-by-side, and in PCR-RFLP (bottom), BsiEI-undigested and -digested PCR products were run side-by-side. Arrows indicate the presence of the mutation in LN but not in BM.
We diagnosed the patient with lymphoplasmacytic lymphoma (LPL)/WM that recurred 10 years after RFC treatment, which was one of the first-line treatments for LPL/WM at that time,5 and initiated administration of a Bruton’s tyrosine kinase (BTK) inhibitor, tirabrutinib.6,7 The effect was significant: one month after the start of treatment, chest X-ray showed a reduction of the hilar tumor, and a blood test revealed decreases of IgM and sIL-2R levels to within their normal ranges. Constitutional symptoms such as general fatigue and loss of appetite also improved. No significant adverse events were observed except for mild pruritus. CT after 4 months of treatment showed seize decreases of the hilar tumor and mediastinal LNs, being presented in Key Figure for comparison with pre-treatment pictures.
LPL/WM is an uncommon mature B-cell neoplasm characterized by lymphoplasmacytic cell infiltration in BM and the presence of IgM monoclonal protein in serum.1,8,9 The latter laboratory abnormality may cause hyperviscosity, neuropathy, funduscopic abnormalities, cryoglobulinemia, and bleeding diathesis, and specific managements for such manifestations may be required.1 Despite these diverse clinical characteristics, 93 to 97% of patients with LPL/WM carry the MYD88 p.L265P driver mutation that leads to constitutive activation of the NF-κB pathway, and BTK inhibitors have been shown to be effective for both treatment-naïve and recurrent patients.5,6,8 The present patient was unique in that recurrent disease occurred in LNs, which are less frequent sites of involvement of LPL/WM than BM,8,9 and the level of monoclonal IgM in serum was low. Nevertheless, we were able to make a correct diagnosis of LPL/WM by applying IHC, FCM, and molecular tests to the small specimens obtained by EBUS-TBNA. Considering the efficacy of BTK inhibitors,5 any available diagnostic modalities should be performed for the diagnosis of LPL/WM.
