Development of Symptomatic Bone Marrow Metastasis After Complete Response to Immunochemotherapy in Squamous Cell Lung Carcinoma.

1
Introduction
Symptomatic bone marrow metastasis can occur in nonhematological malignancies and is associated with poor prognosis [1, 2]. The most common primary nonhematological malignancies associated with bone marrow metastasis in adults are breast, stomach, prostate, and lung cancers [1, 2, 3, 4, 5, 6, 7, 8, 9]. Compared with small cell lung cancer [1, 2, 3, 10], symptomatic bone marrow metastasis is rare in non‐small cell lung cancer (NSCLC) [1, 2, 4, 5, 6, 7, 8, 9]. In addition, lung adenocarcinoma is the predominant histological type and bone marrow metastases from squamous cell lung cancer are further rare.
We present a case of squamous cell lung cancer that developed symptomatic bone marrow metastases, presenting with anemia, thrombocytopenia, and leukoerythroblastosis during pembrolizumab maintenance therapy. Although the patient initially had multiple bone metastases, he achieved a complete response (CR) to carboplatin/Nab‐paclitaxel and pembrolizumab.

2
Case Presentation
A 63‐year‐old Japanese man who had a history of gastrectomy for gastric cancer 7 years previously had been followed up at Nagano Prefectural Kiso Hospital without recurrence. Whole‐body computed tomography (CT) performed in July 2023 revealed left main bronchial wall thickening and left hilar lymph node swelling (Figure 1A). Positron emission tomography with fluorodeoxyglucose‐computed tomography (FDG‐PET/CT) showed uptake in these areas (Figure 1B) and revealed multiple bone lesions, including the spine and the bilateral humerus and femur (Figure 1C). Endobronchial ultrasound‐guided transbronchial needle biopsy confirmed squamous cell carcinoma (Figure 2). The patient received 6 cycles of carboplatin (AUC 5), Nab‐paclitaxel (100 mg/m2), and pembrolizumab (400 mg), with no hematological toxicity or immune‐related adverse events. Chest CT showed resolution of left main bronchial thickening and disappearance of left hilar lymphadenopathy (Figure 3A). FDG‐PET/CT demonstrated complete resolution of FDG uptake in all previously identified lesions, indicating CR (Figure 3B,C). He continued pembrolizumab maintenance therapy for over 1 year, but was admitted to Nagano Prefectural Kiso Hospital because of general fatigue, appetite loss, and rapid progression of anemia and thrombocytopenia. The hemoglobin and platelet count declined from 11.7 g/dL (normal range: 13.7–16.6 g/dL) and 13.2 × 104 μL (normal range 15.8–34.8 × 104 μL) to 9.8 g/dL and 2.8 × 104 μL for 1 month, respectively. Other laboratory findings were: white blood cells, 4000/μL (normal range 3300–8600/μL); lactate dehydrogenase, 560 IU/L (normal range: 124–222 IU/L); alkaline phosphatase, 183 IU/L (normal range 38–113 IU/L); and leukoerythroblastosis. Tumor markers were also elevated: SCC antigen, 4.8 ng/mL (normal range < 2.5 ng/mL) and CYFRA, 7.9 ng/mL (normal range < 3.5 ng/mL), both of which were within the normal limits at the time of the initial diagnosis of squamous cell carcinoma (1.2 and 2.3 ng/mL, respectively). Bone marrow aspiration yielded a dry tap, so bone marrow biopsy was performed. Histopathological examination revealed malignant cells surrounding fibrotic tissue with myxomatous changes (Figure 4A,B). Immunohistochemistry showed positivity for pan‐cytokeratin (AE1/AE3; Figure 4C) and p40 (Figure 4D), confirming bone marrow metastases from squamous cell lung carcinoma. The rate of programmed death‐1 (PD‐L1) expression was high in tumor cells (95%) using IHC 22C3 pharm Dx antibody. Few hematopoietic cell nests were observed in the bone marrow. The patient received multiple blood transfusions but died of aspiration pneumonia 1 month after admission.

3
Discussion
Previous clinical studies indicated that most bone marrow metastases occur in cases with adenocarcinoma histology, including cancers of the breast, stomach, prostate, and NSCLC [1, 2, 3, 4, 5, 6, 7, 8, 9]. Regarding squamous cell lung cancer, to our best knowledge, there were two case reports showing symptomatic bone marrow metastasis [11, 12]. Thus, bone marrow metastases originating from squamous cell lung cancer were extremely rare. In addition, it was also noteworthy in the present case that bone marrow metastasis eventually developed after a prolonged CR to immunochemotherapy. The clinical manifestation adds to the knowledge of a new clinical aspect of recurrence type during management in patients with lung cancer.
FDG‐PET/CT has high sensitivity for detecting bone marrow involvement in patients with malignancies [13]. In our case, FDG‐PET/CT 6 months after initiation of immunochemotherapy showed no abnormal FDG uptake in any systemic organs, including bone marrow. Therefore, the therapeutic response was assessed as CR to immunochemotherapy. Although the tumor cells demonstrated a high PD‐L1 expression (95%), pembrolizumab failed to control metastatic tumor cells in the bone marrow. Pathological examination revealed extensive fibrotic stromal changes surrounding scattered tumor cells, as reported previously in other cases of bone marrow metastasis [1, 2, 3, 4], which may have contributed to impaired microcirculation and led to inadequate drug delivery. Taken together, these observations suggest that residual tumor cells resistant to immunochemotherapy or undetectable by FDG‐PET/CT may have persisted during pembrolizumab maintenance therapy and subsequently contributed to the development of fibrotic stroma and tumor cell infiltration within the bone marrow space.
Several previous case series reported that most patients with bone marrow metastases also had concurrent bone metastases [1, 2, 3, 4, 5, 7]. This suggests that bone metastases could be a prevision for bone marrow involvement [3, 4, 7], because malignant cells in metastatic bone lesions could extravasate, disseminate, and infiltrate the bone marrow compartment.
In a meta‐analysis on molecular detection of tumor cells in bone marrow micrometastases in patients with early‐stage NSCLC after surgery, Deng et al. [14] reported no significant differences in the rate of bone marrow involvement between adenocarcinoma and squamous cell carcinoma. However, clinically documented symptomatic bone marrow metastasis has been reported predominantly in adenocarcinoma [1, 2, 3, 4, 5, 6, 7, 8, 9]. The mechanisms underlying symptomatic bone marrow metastasis development and progression are complex, and the reasons for the observed histological differences remain unclear.
The prognosis of NSCLC with symptomatic bone marrow metastasis is very poor [1, 4, 5, 6, 7, 8, 9], with reported survival ranging from only a few days or weeks to several months. Chemotherapy remains the only treatment option available. However, its use is dependent on the patient's physical condition and the extent of peripheral blood impairment. However, prolonged survival has been reported in patients with symptomatic bone marrow metastasis from EGFR‐ [9], ERBB2‐ mutated [15] or ALK fusion—positive [16] adenocarcinoma treated with tyrosine kinase inhibitors. These findings highlight the importance of comprehensive cancer multigene panel testing, even in cases of bone marrow metastasis in NSCLC. Unfortunately, our patient was not eligible for targeted molecular therapy and died 4 weeks after the diagnosis of bone marrow metastasis.
Anemia and thrombocytopenia are the most common clinical manifestations of bone marrow metastases. When these hematological abnormalities are unexplained, bone marrow metastasis should be considered in patients with NSCLC, particularly those with existing bone metastases.

4
Conclusion
We reported the first case of bone marrow metastasis originating from squamous cell lung cancer after a prolonged complete response to immunochemotherapy. This case highlights the importance of considering bone marrow involvement even in patients with NSCLC showing an excellent therapeutic response, particularly those with bone metastases.

Author Contributions
A.M., T.K., R.T., Y.W., H.M., N.K., F.K., and H.H. contributed to treatment, data collection, and drafted the manuscript. M.O. contributed to the pathological diagnosis. T.K. is the corresponding author. All authors contributed to the article and approved the submitted version.

Funding
The authors received no specific funding for this work.

Ethics Statement
Ethics approval was not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient's family for the publication of this case report and any accompanying images.

Conflicts of Interest
The authors declare no conflicts of interest.