Pulmonary adenocarcinoma with osseous metaplasia: a rare occurrence possibly associated with early stage?

Adenocarcinoma is the most common type of malignant pulmonary tumor, but osseous metaplasia of this tumor is extremely rare. To date, only 21 cases have been reported in the literature worldwide. Here, we report a case of primary pulmonary adenocarcinoma with benign osseous stromal metaplasia in a 60-year-old woman and discuss the pathogenesis of intratumoral ossification and review the relevant literature. We found that pulmonary adenocarcinoma with osseous metaplasia may be more likely to occur in early tumor stages.

Introduction

Metaplasia is a process in which a differentiated cell type is replaced by another mature differentiated cell type. Although rare, osseous stromal metaplasia has been described in the literature for both benign and malignant neoplasms. Here, we report a unique case of primary pulmonary carcinoma with osseous metaplasia. We believe that this is a case of minimum bone formation (approximately 1.25 mm × 0.85 mm) in a primary pulmonary carcinoma.

Case report

A 60-year-old Chinese woman presented with the symptom of bloody sputum, which she had noticed for 2 weeks. Enhanced computed tomography (CT) showed an irregular abnormal soft tissue mass located in the left upper lobe that was approximately 1.7 cm× 0.8 cm in size and obviously enhanced with contrast medium (Figure 1). The CT value in the enhanced arterial phase was approximately 40–60 Hounsfield units, while the venous phase CT value was approximately 72 Hounsfield units. Minimal calcification was not apparent in the tumor. The patient denied any history of gastric carcinoma or digestive symptoms. On the basis of her history and imaging studies, the patient was diagnosed with a malignant pulmonary tumor and underwent lobectomy. The tumor had a heterogeneous off-white appearance and was solid with unclear boundaries. No depressions or varicose veins were found in the pleura.

Figure 1

Computed tomography scan showed an irregular abnormal soft tissue mass located in the left upper lobe.

Hematoxylin and eosin-stained sections showed that the alveolar structure had disappeared within the tumor and that the tumor cells were distributed into round or oval glands with a central lumen. There was no mucin in the tumor cell cytoplasm or glandular cavity. The tumor cell nuclei were ovoid and dark-stained, with prominent nucleoli. The mitotic activity was approximately two mitoses per ten high-powered fields. New bone formation was observed at the center of the tumor (approximately 1.25 mm × 0.85 mm, Figure 2A). The bone island consisted of mature bone tissue and was surrounded by osteoblast cells that were accompanied by proliferating fibroblasts (Figure 2B). No bone marrow cells were present in the bone tissue. Immunohistochemical staining showed that the tumor cells were positive for cytokeratin-7 (Figure 3A) and thyroid transcription factor-1 (Figure 3B), but the metaplastic bone tissue was negative for these factors. However, the tumor cells were negative for caudal-related homeodomain protein 2, which ruled out the possibility of gastrointestinal adenocarcinoma metastasis to the lung, and the Ki-67 labeling index was approximately 35%. An epidermal growth factor receptor exon 19 deletion mutation was found in this patient, but the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase rearrangement was not found. On the basis of histologic and immunohistochemical findings, this tumor was diagnosed as an invasive pulmonary adenocarcinoma with a predominant acinar pattern, accompanied by osseous metaplasia in tiny lesions and without lymphatic metastasis. This diagnosis was based on the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification system for standard lung adenocarcinoma.1

Figure 2

(A) Tumor showing the moderately differentiated adenocarcinoma growing with a born formation. Hematoxylin and eosin staining, original magnification ×50. Scale bar 1 mm. (B) Mature bony trabeculae in the abundant fibroblastic stroma were surrounded by osteoblasts. Hematoxylin and eosin staining, original magnification ×100. Scale bar 600 μm.

Figure 3

(A) On immunohistochemical analysis, tumor cells were positive for cytokeratin 7. (B) TTF-1 immunohistochemistry shows strong nucleus staining in the tumor cells, original magnification ×100. Scale bar 400 μm.

Abbreviation: TTF-1, thyroid transcription factor-1.

Discussion

Malignant neoplasms accompanied by osseous metaplasia have been sporadically reported in the kidney,2 gastrointestinal tract,3,4 thyroid,5 soft tissue,6 endometrium,7 bladder,8 brain,9 and urachus;10 however, heterotopic ossification within a primary pulmonary carcinoma is extremely rare. Only 21 cases of pulmonary adenocarcinoma with heterotopic ossification have been previously reported11–22 in patients whose ages ranged from 46 to 76 (mean 62.4) years. The male to female ratio in these patients was 11:10, and the tumor sizes ranged from 1.5 cm to 7 cm (mean 3.59 cm). One patient received radiotherapy. Two patients also presented with osteoplastic metastasis. Follow-up information was available for 14 patients and indicated that one patient died after 33 months, while one patient developed a recurrence after 60 months of follow-up. In contrast with patients having conventional lung adenocarcinoma, which usually presents as an advanced cancer,23 lung adenocarcinoma with osseous metaplasia seems to be more frequent in early-stage disease, given that patients with stage I, II, III, and IV disease accounted for 57.1% (n=12), 14.3% (n=3), 19.0% (n=4), and 4.8% (n=1) of the cases, respectively; staging information was not available for one patient. The stage of the patient presented in this paper was IA, which is consistent with this phenomenon (Table 1).

Table 1

Summary of previously reported cases of heterotopic mesenteric ossification

Reference	Sex/age	Size (cm)	Histological type	P stage	TNM	Operation	CT/RT	Follow-up
McLendon et al11	M/62	3	Adeno/mod	IIIA	T1N2M0	Lob	NA	NA
Yoshida et al13	M/49	3.5	Adeno/mod	IIB	T2N1M0	Lob	NA	Recur, 60 months
Miyata et al12	F/62	3.3	Adeno/well	IB	T2N0M0	Lob	NA	NA
Fukuse et al14	M/61	4.5	Adeno/mod	IB	T2N0M0	Lob	NA	NA
Hayakawa et al15	M/53	NA	Adeno/mod	IV	T?N2M1	Autopsy	RT	Dead, 33 months
Tsuchiya et al18	F/70	NA	NA	IA	T1N0M0	Lob	NA	NA
Hara et al16	F/70	3.2	Adeno/mod	IIIB	T4N2M0	Lob	NA	Alive, 6 months
Hosoda et al17	M/66	3	Adeno/mod	IA	T1N0M0	Lob	NA	NA
Usami et al20	M/46	4.5	Adeno/poor	IB	T2N0M0	Lob	NA	Alive, 14 months
Ueshima et al19	F/73	NA	NA	NA	NA	Lob	NA	NA
Kato et al21	M/76	1.5	NA	IA	T1N0M0	Lob	NA	NA
Kim et al22	F/65	3.2	Adeno/mod	IB	T2N0M0	Lob	NA	Alive, 52 months
Kim et al22	M/70	4	Adeno/mod	IIB	T2N1M0	Bilob	CT	Alive, 49 months
Kim et al22	M/63	3.7	Adeno/mod	IB	T2N0M0	Lob	CT	Alive, 43 months
Kim et al22	F/65	6	Adeno/mod	IB	T2N0M0	Lob	NA	Alive, 27 months
Kim et al22	M/57	4.5	Adeno/mod	IB	T2N0M0	Lob	NA	Alive, 14 months
Kim et al22	F/66	2	Adeno/poor	IIA	T1N1M0	Lob	CT	Alive, 13 months
Kim et al22	F/57	7	Adeno/mod	IIIA	T2N2M0	Lob	CT	Alive, 12 months
Kim et al22	F/57	2.5	Adeno/mod	IA	T1N0M0	Lob	NA	Alive, 10 months
Kim et al22	M/59	2.5	Adeno/mod	IIIB	T4N0M0	Lob	CT	Alive, 4 months
Kim et al22	F/64	2.8	Adeno/mod	IB	T2N0M0	Lob	NA	Alive, 4 months
Present case	F/60	1.7	Adeno/mod	IA	T1N0M0	Lob	NA	Alive, 26 months

Abbreviations: Adeno, adenocarcinoma; mod, moderately differentiated; well, well differentiated; NA, not available; Bilob, bilobectomy of right middle and lower lobe; Lob, lobectomy; CT, chemotherapy; Recur, recurrence; RT, radiation therapy.

The mechanism responsible for osseous histogenesis in malignant neoplasms remains obscure. Several studies have documented that osseous metaplasia results from osteoblast metaplasia of pulmonary fibroblasts.22 Other studies reported abnormally high serum calcium levels (hypercalcemia) in patients with malignant neoplasms; these levels were closely associated with bone formation. However, the serum calcium level was within normal limits in this patient. Most authors report that multipotent stromal stem cells are involved in the metaplastic process, resulting in bone formation.24 Some cytokines such as bone morphogenetic protein 7 promote bone formation by inducing differentiation of pluripotent cells, mesenchymal cells, or fibroblasts into osteoprogenitor cells.25 Further, some studies showed that bone formation might occur as a result of local or systemic inflammation. Inflammatory cells, including monocytes and macrophages, produce cytokines such as tumor necrosis factor-alpha and interleukin-1. Tumor necrosis factor-alpha and interleukin-1 are reported to stimulate activated cells to produce transforming growth factor beta and bone morphogenetic protein 7, which act as local cellular regulators of ectopic bone formation.26,27

Osseous histogenesis in malignant neoplasms is a rare and interesting phenomenon, but the prognostic implications of this occurrence are not very clearly described in the literature. Some studies suggest that cerebral ventricle ependymoma with ossification might exhibit more aggressive clinical behavior.9 However, ossification has been suggested to be a marker of favorable prognosis in patients with renal cell carcinoma.28 Therefore, investigations of the prognosis in patients with pulmonary adenocarcinoma and bone formation remain worthwhile. The lack of evidence of recurrence and metastasis in this patient at a 26-month follow-up indicated that ossification in pulmonary adenocarcinoma might not have adverse prognostic implications, but a longer follow-up period and more case studies are needed to illustrate this rare phenomenon.