Primary Pulmonary Osteosarcoma Presenting as a 1.7-cm Subpleural Nodule in a 61-Year-Old Man: A Case Report

Introduction

Primary pulmonary osteosarcoma (PPOS) is an exceedingly rare malignant neoplasm, constituting approximately 0.01% of all primary pulmonary tumors [1,2]. The rarity is compounded by diagnostic complexities, as PPOS often mimics metastatic lesions or benign pulmonary nodules, leading to significant clinical challenges [1]. Historically, in patients with PPOS, the size of tumors at the first visit mostly exceeded 5 cm, and tumors larger than 5 cm were usually associated with a poor prognosis [2,3].

Clinically, PPOS presents with nonspecific symptoms, such as chest pain, cough, and hemoptysis. These features overlap with common pulmonary diseases, complicating diagnosis [1,2]. Differential diagnosis is particularly arduous, requiring exclusion of metastatic osteosarcoma, primary lung carcinomas, and benign osseous lesions [3,4]. Key diagnostic steps include whole-body imaging, such as with positron emission tomography/computed tomography (PET/CT) and bone scintigraphy, to rule out extrapulmonary primary sites and immunohistochemistry (IHC) to confirm osteoblastic differentiation, such as special AT-rich sequence-binding protein 2 (SATB2) positivity [2,5,6]. The coexistence of comorbid malignancies, such as hepatocellular carcinoma (HCC) in this case, further complicates the interpretation of imaging findings, necessitating integrated multimodal approaches. These challenges highlight the critical role of multidisciplinary collaboration-combining radiological, pathological, and clinical expertise-to avoid misclassification and facilitate timely intervention. Complete resection is the mainstay of management, while evidence for adjuvant chemotherapy remains limited due to the rarity of PPOS [1,3]. This report describes the case of a 61-year-old man with a 1.7-cm PPOS in the right upper lobe, highlighting the diagnostic challenges and management approach.

Case Report

A 61-year-old man with a history of poorly differentiated HCC, treated with left lateral lobectomy and transarterial chemoembolization in February 2020, was under regular surveillance. In August 2024, a computed tomography (CT) scan incidentally detected a 0.7-cm, well-circumscribed, smooth-edged subpleural nodule in the posterior segment of the right upper lobe (Figure 1A). The lesion was considered radiologically benign, and follow-up was recommended.

In January 2025, a follow-up CT scan showed that the nodule had enlarged to 1.7 cm (Figure 1B). Subsequently, PET/CT was performed, revealing increased metabolic activity within the nodule, with a maximum standardized uptake value (SUVmax) of 5.2 (Figure 1C). Whole-body bone scintigraphy showed no evidence of skeletal uptake or other extrapulmonary lesions (Figure 1D).

The patient underwent uniportal video-assisted thoracoscopic wedge resection of the right upper lobe with lymph node sampling. The surgical margins were negative. Gross examination revealed a well-circumscribed, gray-white solid nodule measuring 1.8×1.6×1.5 cm.

Histologic examination revealed a hypercellular spindle-cell sarcoma producing irregular, lace-like malignant osteoid directly rimmed and permeated by atypical cells; focal chondroid differentiation was also present (Figure 2A, 2B). IHC was performed to confirm the diagnosis and rule out other malignancies. The tumor cells showed strong diffuse nuclear positivity for SATB2, supporting osteoblastic differentiation. The Ki-67 proliferation index was approximately 30%. Tumor suppressor protein (p53) showed a diffuse strong nuclear staining pattern, suggestive of a mutant phenotype. Epithelial markers (low-molecular-weight cytokeratin antibody CK8/18 [CAM5.2], epithelial membrane antigen, pan-cytokeratin antibody) were largely negative. Markers for vascular tumors (CD34) and solitary fibrous tumor (signal transducer and activator of transcription 6 [STAT6]) were negative. Smooth muscle actin (SMA) and S100 showed focal positivity, while desmin was negative. B-cell lymphoma 2 (BCL-2) showed partial positivity (Figure 3A–3K). Although IHC for hepatocellular markers (eg, HepPar-1 and arginase-1) were not performed, the diagnosis of metastatic HCC was considered unlikely based on the following evidence: (1) serum alpha-fetoprotein levels remained within normal limits; (2) follow-up imaging showed no evidence of intrahepatic recurrence or extrahepatic metastasis; and (3) the histomorphology showed definitive malignant osteoid formation, which is not a feature of HCC. Correlation of morphology, immunophenotype, and whole-body imaging excluded an extrathoracic osteogenic primary and established a final diagnosis of PPOS.

To diagnose a lung mass as PPOS, the following criteria must be met: (1) the tumor must be composed entirely of homogeneous osteosarcoma tissue; (2) the tumor must be capable of producing osteoid or bone matrix; and (3) the tumor must originate from the lung and exclude the possibility of other primary osteogenic tumors [6]. The patient received 6 cycles of adjuvant therapy with liposomal doxorubicin combined with cisplatin, with no recurrence or metastasis observed during 9 months of follow-up. This regimen is consistent with contemporary sarcoma protocols; however, evidence specific to PPOS remains limited [1,3].

Discussion

This case highlights that PPOS can present as a small, well-circumscribed subpleural nodule, even in patients with a history of malignancy, and underscores the critical importance of a structured imaging-pathology workup to distinguish it from metastatic disease. In our patient with prior HCC, the initial clinical suspicion was pulmonary metastasis. However, the combination of normal serum alpha-fetoprotein level, absence of hepatic or extrahepatic recurrence on imaging, an IHC profile negative for epithelial, vascular, and solitary fibrous tumor markers, and the definitive histologic finding of malignant lace-like osteoid with SATB2 positivity collectively supported a diagnosis of PPOS.

PPOS is an extremely rare malignancy, which can be diagnosed in patients with a history of other cancers [1,3,7]. The differential diagnosis includes metastasis from osteosarcoma, primary lung carcinoma, and benign pulmonary lesions, such as hamartomas [3]. In this context, PET/CT and whole-body bone scintigraphy are invaluable tools for excluding an occult primary skeletal osteosarcoma [3,8], while IHC for SATB2 serves as a highly specific marker for confirming osteoblastic differentiation [9,10].

In our case, the tumor size of 1.7 cm was smaller than those typically reported, which are often larger than 5 cm [1,3]. This small tumor size likely contributed to the favorable prognosis observed in our patient [1]. Surgical resection is the standard treatment, and complete resection has been shown to improve outcomes [1,3]. Adjuvant doxorubicin-cisplatin regimens have been used in PPOS, although their benefit remains uncertain, given limited data [1,3]. Further research is needed to establish standardized diagnostic and therapeutic guidelines for PPOS and to validate the diagnostic and potential prognostic utility of markers like SATB2 [1,10].

Conclusions

This case illustrates the diagnostic complexity of PPOS in a patient with prior HCC. Small, well-circumscribed pulmonary nodules can harbor histologically malignant lesions, such as PPOS. Early surgical intervention within a structured imaging-pathology workup can achieve favorable short-term outcomes in selected patients with PPOS.