Hemothorax is the accumulation of blood in the pleural cavity. It usually has a traumatic, coagulopathic, or iatrogenic cause. In spontaneous hemothorax (SH), blood accumulates within the pleural space in the absence of any of these causes.1 On the other hand, limited studies have reported that malignant neoplasms can induce SH development.1–3 Among patients with malignant neoplasms, hemorrhagic pleural effusion is common, whereas hemothorax leading to pleural hematoma formation is rare. The malignant neoplasms that are most frequently associated with SH include metastases of hepatocellular carcinoma or sarcoma to the lung or pleura and pulmonary angiosarcoma.2 SH resulting from a primary epithelial lung tumor is exceedingly rare. Especially, no previously reported case appears to involve an anaplastic lymphoma kinase (ALK)-rearrangement and tumor suppressor gene p53 (TP53) mutant adenocarcinoma.

ALK-rearranged cancers are known to occur more frequently in younger patients and are often characterized by extensive metastatic spread, including pleural involvement. TP53 mutations have been reported in 23.8% of cases of ALK-rearranged non-small cell lung cancer (NSCLC) and are associated with aggressive tumor biology, earlier development of treatment resistance, and poorer prognosis.4 However, TP53 co-mutation in ALK-positive NSCLC has not been established as a risk factor for hemothorax.

We herein report a patient with lung adenocarcinoma harboring both an ALK-rearrangement and a mutation of TP53, in whom hemothorax led to the development of a giant hematoma in the pleural cavity.

A 75-year-old, male patient was referred to our あhospital with dyspnea. Computed tomography (CT) revealed a nodule in the left lower lobe of the lung, mediastinal and cervical lymph node swelling, and right pleural effusion. The findings of a needle biopsy of the mediastinal and cervical lymph nodes led to the diagnosis of lung adenocarcinoma cT1cN3M1b stageIVB (Figure 1a). Analysis of a specimen using Oncomine Comprehensive Assay v3 (ThermoFisher Scientific, Waltham, Massachusetts, USA) demonstrated an ALK rearrangement and TP53 mutation.

Figure 1 Chest computed tomography demonstrated metastases to the mediastinal lymph nodes. (a) Before radiation and alectinib administration. (b) After 2 months of treatment with alectinib. (c) After 8 months of treatment with alectinib and before lorlatinib administration. Progression of the metastases to the mediastinal lymph nodes can be seen. (d) After 3 months of treatment with lorlatinib followed by one month of treatment with brigatinib.

The patient had a smoking history of 25 pack-years. At presentation, he had no comorbidity and was receiving no medication. Radiotherapy 30 Gy/10 fr was administered before systemic chemotherapy to treat bronchial compression due to enlargement of the mediastinal lymph nodes.

Alectinib, an ALK tyrosine kinase inhibitor (TKI), was administered as first-line therapy. The best overall response was a partial response (PR) on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Figure 1b). Enlargement of the mediastinal lymph nodes observed ten months after the start of alectinib therapy (Figure 1c) prompted a switch to lorlatinib as the second-line drug. Lorlatinib reduced the swelling of the mediastinal lymph nodes, but led to a Grade 2 cognitive disturbance as defined by the Common Terminology Criteria for Adverse Events (CTCAE) three months after its administration. As the patient was unwilling to continue lorlatinib therapy or switch to cytotoxic chemotherapy from fear of decreasing his quality of life, he opted for brigatinib (third-line treatment) therapy two months later. Although the mediastinal lymph nodes did not increase in size (Figure 1d), brigatinib was discontinued on day 14 after grade 1 pneumonitis developed. Corticosteroid therapy was begun when the pneumonitis worsened to grade 3, and resulted in an improvement to grade 1. Chemotherapy was paused for one month.

In the following month, the patient presented to the emergency department with acute dyspnea. Physical examination found tachypnea and diminished breath sounds on the right side. His vital signs were stable Hemoglobin had fallen from 9.8 g/dL to 6.2 g/dL within two weeks. Contrast-enhanced CT revealed encapsulated fluid retention with faint high attenuation in the right pleural cavity (Figure 2a). Magnetic resonance imaging (MRI) demonstrated a mildly high signal on T1-weighted imaging (Figure 2b) and a low signal on T2-weighted imaging (Figure 2c), suggesting the presence of a hematoma. The patient’s Eastern Cooperative Oncology Group performance status was 4, and surgical removal of the hematoma was not indicated. Enhanced CT found no active bleeding, and after discussion with the radiology team, observation was chosen over intervention. Follow-up CT four days later found no evidence of hematoma progression but revealed severe compression of the pulmonary artery. One week after admission, the patient died following respiratory failure and the deterioration of hypotension.

Figure 2 (a) Chest computed tomography demonstrated encapsulated fluid retention in the right pleural cavity with faint high attenuation. (b) Chest magnetic resonance imaging (MRI) demonstrated a mildly high signal on T1-weighted imaging. (c) Chest MRI demonstrated a low signal on T2-weighted imaging.

An autopsy confirmed the presence of the hematoma in the pleural cavity immediately above the diaphragm and metastases to the pleura surrounding the hematoma. Although no definite source vessel responsible for the hematoma was found, bleeding from the metastatic lesion was observed (Figure 3).

Figure 3 Histological features of the pleura surrounding the hematoma. Tumor cells were found in the metastases to the pleura, which also demonstrated bleeding (hematoxylin and eosin stain, (a) ×40 (b) ×100). Scale bar = 200μm.

While trauma is the chief cause of hemothorax, previous reports have also found that malignant neoplasms can also cause this condition. The most common malignant neoplasms giving rise to hemothorax are pulmonary angiosarcoma and lung or pleural metastases of hepatocellular carcinoma or sarcoma.2 Hemothorax caused by a primary epithelial tumor of the lung is extremely rare; a search of PUBMED using the terms, “hemothorax,” “lung cancer,” and “carcinoma of the lung cancer” on 26 November 2025, yielded only 12 cases (Table 1)5–15 comprising sarcomatoid carcinoma (n=4), poorly differentiated adenocarcinoma (n=3), carcinoid, undifferentiated large cell carcinoma, bronchoalveolar carcinoma, and bronchogenic carcinoma (n=1 each). The present case is the first instance of ALK-rearranged adenocarcinoma inducing hemothorax.

Table 1 Characteristics of Previous Cases of Primary Epithelial Tumor of the Lung with Hemothorax

The treatment options for hemothorax caused by tumor-related bleeding include surgery and bronchial artery embolization.10 All the documented cases of hemothorax to date, with the exception of the present case and one previous case were treated surgically.

Our patient’s poor general condition precluded surgery, and bronchial artery embolization was not performed because the imaging studies found no evidence of active bleeding. Although the hemothorax did not worsen over the following days, the patient died, from a combination of hemodynamic compromise caused by the compression of the pulmonary artery, respiratory failure related to the hemothorax and pleural effusion, and disease progression.

The putative etiology of hemothorax in lung cancer is pleural metastasis and rupture caused by the pleural infiltration of tumor cells, bleeding from the pulmonary artery following tumor cell invasions, and intratumoral bleeding.5 The absence of a definite source vessel for the hemothorax in our patient, led to the conclusion that the persistent bleeding of the pleural metastatic lesion had caused the hematoma.

From a molecular perspective, ALK-rearranged lung adenocarcinoma is usually not associated with hemorrhage. The ALK rearrangement itself has no known effect on vascular integrity. However, ALK-rearranged cancers tend to affect younger patients and often metastasize widely, including to the pleurae. Pleural involvement and/or pleural effusion has been reported in ALK-positive non-small cell lung cancer(NSCLC). In a multicenter retrospective study of 362 patients with ALK-positive NSCLC, pleural involvement and/or effusion was observed at baseline in 57 patients (15.7%).16 In addition, previous studies have suggested that ALK rearrangement is associated with a higher propensity for pleural disease compared with other molecular subtypes.17 It is noteworthy that ALK inhibitors can on rare occasions cause a pulmonary hemorrhage: one recent report described a diffuse alveolar hemorrhage five days after the start of alectinib administration.18 The patient in the study improved after receiving steroid therapy. In contrast, there are no previous reports of pleural hemorrhage (hemothorax) as a complication of ALK TKI. Our patient’s hemothorax coincided with disease progression rather than with the administration of any drug.

The present study also found that a TP53 mutation may have contributed to the aggressive course of the ALK-positive lung adenocarcinoma. TP53 encodes the p53 protein, one of the main regulators of cell division and cell death.19 A TP53 mutation is not only causes the loss of tumor-suppression but also the gain of novel, oncogenic functions that actively promote cancer progression, metastasis, and treatment resistance.20 TP53 mutations were found to be present in 23.8% of causes of ALK-rearranged NSCLC and to be associated with an aggressive biology, earlier onset of treatment resistance, and poorer prognosis.4 Recent studies have shown that ALK-positive NSCLC patients with a TP53 mutation receiving an ALK inhibitor had significantly worse progression-free and overall survival.21 While these data do not directly implicate TP53 mutations in bleeding, they underscore the more aggressive behavior of tumors harboring this anomaly. Furthermore, TP53 mutations also reported tumors are more aggressive. Also, TP53 mutations have been reportedly repress the transcription of vascular endothelial growth factor (VEGF).22 Treatments using bevacizumab, an anti-VEGF humanized monoclonal antibody, were effective against lung adenocarcinoma harboring TP53 mutation and ALK rearrangement.23 TP53-driven angiogenic factors or necrosis may have played a role in vascular rupture in the present case. While there is currently no evidence linking the status of TP53 to the hemothorax risk, our case suggests that TP53-mutant/ALK-rearranged NSCLC may behave more catastrophically.

This case report has several limitations. First, because this report describes a single patient, the findings cannot establish a causal relationship between ALK rearrangement, TP53 mutation, ALK-TKI exposure, and the development of spontaneous hemothorax. Although autopsy demonstrated pleural metastases surrounding the hematoma and bleeding from a metastatic pleural lesion, no definite responsible vessel was identified; therefore, the exact mechanism of bleeding remains inferential. Second, the diagnosis and clinical assessment of hemothorax were based on the rapid decrease in hemoglobin level, CT and MRI findings, and autopsy findings, but pleural fluid hematocrit measurement and angiographic evaluation were not performed because of the patient’s poor performance status and the absence of active extravasation on contrast-enhanced CT. Third, repeat molecular profiling of the pleural metastatic lesion at the time of disease progression was not performed; therefore, the possible contribution of acquired resistance mechanisms, clonal evolution, tumor necrosis, or angiogenic alterations to the hemorrhagic event could not be evaluated. Finally, previously reported cases of hemothorax associated with primary epithelial lung cancer are extremely limited and heterogeneous with respect to histology, disease extent, treatment, and intervention. Thus, further accumulation of similar cases is required to clarify the clinicopathological and molecular features associated with this rare but potentially fatal complication.

Importantly, the present case underscores the need for vigilance. Although cases like the present one are rare, a sudden onset or increase of pleural effusion in any cancer patient should prompt suspicion of hemothorax, especially if imaging studies demonstrate a hyperdense fluid accumulation. Early recognition is critical despite the limited options. Our report also illustrates the importance of the autopsy for confirming the etiology of the present case.

Institutional approval was not required to publish the case details.

Informed consent for the publication of the details of this case was obtained from the patient’s next-of-kin.

The authors would like to thank this patient and his family in this study.

M.Y. received honoraria (lecture fee) from AstraZeneca, Takeda, MSD, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol-Myers Squibb. Y. H. received honoraria (lecture fee) from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda, Eisai, Novartis, Pfizer and MSD. The other authors declare that they have no conflicts of interest.

1. Davide P, Nikolaos P, Jonathan P, et al. Etiology and management of spontaneous haemothorax. J Thorac Dis. 2015;7(3):520–7. doi:10.3978/j.issn.2072-1439.2014.12.50

2. Martin J, Lubomir S, Jozef K, et al. Non-traumatic and spontaneous hemothorax in the setting of forensic medical examination: a systematic literature survey. Forensic Sci Int. 2014;236:22–29. doi:10.1016/j.forsciint.2013.12.013

3. Stephen RB. Hemothorax: etiology, Diagnosis, and Management. Thorac Surg Clin. 2013;23(1):89–96. doi:10.1016/j.thorsurg.2012.10.003

4. Marco C, Alessia G, Rossella B, et al. Recent Advances on Mutant p53: unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions. Biomolecules. 2024;14(6):649. doi:10.3390/biom14060649

5. Chou SH, Cheng YJ, Kao EL, Chai CY. Spontaneous haemothorax: an unusual presentation of primary lung cancer. Thorax. 1993;48(11):1185–1186. doi:10.1136/thx.48.11.1185

6. Lim KH, Sin Fai Lam KN, Tey BH, Chew LS. Massive haemothorax as a complication of primary lung cancer-a case report. Singapore Med J. 1993;34:573–574.

7. Snaebjornsson P, Cornelis GV, Hartemink KJ, et al. Fatal Hemothorax Caused by Pseudomesotheliomatous Carcinoma of the Lung. Patholog Res Int. 2011;836054. doi:10.4061/2011/836054

8. Sangani NK, Naliath SM. Pseudomesotheliomatous Type of Sarcomatoid Squamous Cell Lung Cancer Presenting With Hemothorax. Ann Thorac Surg. 2018;106(4):e201–e203. doi:10.1016/j.athoracsur.2018.03.050

9. Liam B, Joshua G, Eric KS, Chris M. Spontaneous haemothorax as the first presentation of lung cancer. ANZ J Surg. 2021;91(3):E153–E154. doi:10.1111/ans.16225

10. Yoko K, Takuya F, Yuto K, Kentaro F, Jun H. Pulmonary spindle cell carcinoma presenting with hemothorax. Respir Med Case Rep. 2022;40:101779. doi:10.1016/j.rmcr.2022.101779

11. Burcin C, Huseyin UC, Hale KC. Spontaneous massive hemothorax as an atypical presentation of bronchial carcinoid. Turk Gogus Kalp Damar Cerrahisi Derg. 2022;30(2):289–293. doi:10.5606/tgkdc.dergisi.2022.20581

12. Reagen IK, Arief B. Pulmonary spindle cell carcinoma with hemothorax: a rare case report. Int J Surg Case Rep. 2022;94:107103. doi:10.1016/j.ijscr.2022.107103

13. Hiroe A, Kiyomitsu F, Hiroshi Y, et al. Obstructive shock due to a spontaneous haemothorax caused by primary lung cancer. Respirol Case Rep. 2023;11(2):e01082. doi:10.1002/rcr2.1082

14. Chen S, Yong W, Xiaobo Z, Junjie Z. Recurrence of pulmonary sarcomatoid carcinoma presenting as haemothorax: a case report. J Int Med Res. 2023;51(11):3000605231213533. doi:10.1177/03000605231213533

15. Celia CR, Maria JAR, Ana IPM. Spontaneous Haemothorax and Diffuse Pleural Thickening as Unusual Presentations of Undifferentiated Large Cell Carcinoma of the Lung. Arch Bronconeumol. 2023;59(4):262. doi:10.1016/j.arbres.2023.02.007

16. Güner G, Aktas BY, Basal FB, et al. Is there any prognostic significance in pleural involvement and/or effusion in patients with ALK-positive NSCLC? J Cancer Res Clin Oncol. 2023;149(14):13271–13277. doi:10.1007/s00432-023-05190-3

17. Doebele RC, Lu X, Sumey C, et al. Oncogenic status predicts patterns of metastatic spread in treatment-naïve nonsmall cell ling cancer. Cancer. 2012;118(18):4502–4511. doi:10.1002/cncr.27409

18. Yosuke F, Hironori S. Alectinib-Induced Diffuse Alveolar Hemorrhage. Arch Bronconeumol. 2023;59(6):396. doi:10.1016/j.arbres.2023.03.013

19. Konstantinos V, Nefeli G. The role of TP53 in adaptation and evolution. Cells. 2023;12(3):512. doi:10.3390/cells12030512

20. Kron A, Alidousty C, Scheffler M, et al. Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer. Ann Oncol. 2018;29(10):2068–2075. doi:10.1093/annonc/mdy333

21. Matteo C, Elisabetta P, Paola C, et al. Prognosis of ALK-rearranged non-small-cell lung cancer patients carrying TP53 mutations. Transl Oncol. 2022;23:101471. doi:10.1016/j.tranon.2022.101471

22. Morvarid FG, Steven G, Jody JH. The p53 family and VEGF regulation: “It’s complicated”. Cell Cycle. 2013;12(9):1331–1332. doi:10.4161/cc.24579

23. Hirokazu I, Akihiko M, Naohiro K, et al. Remarkable clinical response of ALK-rearranged/TP53-mutant lung adenocarcinoma with liver metastasis to atezolizumab-bevacizumab-carboplatin-paclitaxel after ALK Inhibitors: a case report. Onco Targets Ther. 2023;16:465–470. doi:10.2147/OTT.S404035