Hypertrophic pulmonary osteoarthropathy (HPO), also known as the Pierre Marie-Bamberger syndrome, was first described by Bamberger in 1889 (1), and is distinguished by painful, swollen joints, digital clubbing and periostitis (2,3). HPO is an uncommon clinical syndrome that may be associated with various pulmonary and non-pulmonary diseases, including the hepatopulmonary syndrome of advanced liver or cirrhosis cyanotic heart diseases (4). HPO may be an indicator of malignant disease and various types of cancer also induce HPO, including primary malignancies or metastasis carcinomas (5–7). As a gold standard for detecting bone metastases of malignancies, bone scintigraphy is a highly sensitive method for the diagnosis of HPO (8). The typical scintigraphic presentation is a diffuse, symmetrically increased uptake in the diaphysis and metaphysis of tubular bones, with a distinctive double stripe or parallel track sign (7). According to previous studies, the incidence of HPO ranges from 0.7 to 17% (9–13). To the best of our knowledge, few studies have investigated the incidence of HPO in a large series of lung cancer patients.

The present study investigated the incidence of HPO and the clinical characteristics of patients with lung cancer and HPO based on a large population of lung cancer patients from China.

Between January 1996 and December 2008, 6,151 patients with lung cancer underwent bone scintigraphy at the Zhejiang Cancer Hospital (Hangzhou, China). A total of 115 consecutive, unselected patients with lung cancer were included in the present study. The study was approved by the ethics committee of the Zhejiang Cancer Hospital (Hangzhou, China). The clinical characteristics were investigated based on available clinical and pathological records. Lung cancer staging was performed for all patients according to the seventh tumor-node-metastasis classification (14). The patient selection criteria were as follows: i) Pathologically proven primary lung cancer. The patients who had other disorders (for example, multiple bone metastases, arthropathy with known causes, such as rheumatoid arthritis or heart disease, abnormal venous stasis in the lower extremities, or thyroid and pituitary dysfunction) that may have led to an incorrect diagnosis of HPO were excluded. HPO was diagnosed based on bone scintigraphy findings at the time of lung cancer diagnosis. ii) All the patients received bone scintigraphy; the bone scintigrams were performed with 740 MBq ^99mTc-methylene diphosphonate (Shanghai Syncor Pharmaceutical Co., Ltd., Shanghai, China) and static imaging was performed within 3–6 h. iii) HPO was diagnosed by experienced radiologists based on a diffuse, symmetric pattern of bilateral increased uptake in the long tubular bones on the bone scintigrams. Each image was independently examined by two specialists. iv) All the patients had digital clubbing in the extremities as well as joint pain.

Of the studies included in the present report, incidences of HPO ranged from 0.7 to 17% in lung cancer patients (Table II) (16). In the current study, HPO was presented with an incidence of 0.64%, which is lower compared with that of previous studies. To the best of our knowledge, this is one of the largest studies concerning HPO secondary to lung cancer.

The proportion of males is high and comprises 70–90% of the HPO population (17,18). A total of 105 (91.3%) patients with HPO in the present study were male. Histopathologically, adenocarcinoma predominated (47.8%), squamous cell carcinoma was second (23.5%) and there were only two cases of small cell carcinoma (1.7% of all lung cancer patients with HPO) in the present study. In previous studies, adenocarcinoma accounted for 11–53% of patients with lung cancer and HPO (Table II), whereas squamous cell carcinoma accounted for ~25–50%. The patients with clinical stage IIIB or IV (56%) disease predominated in the present study, and the patients treated with surgery accounted for 49% (Table I). Numerous studies have described that surgical resection frequently leads to immediate marked remission of joint symptoms and abnormal bone scintigram findings of HPO secondary to lung cancer (19,20). In the present study, the HPO symptoms promptly improved following surgical resection in 91.1% (51/56) of the patients with lung cancer. The improvement rate was 77.4% in non-resected patients, which was lower compared with the resected patients (P=0.049). The majority of symptoms were eliminated in patients following surgical resection, with a higher proportion than non-resected patients. Therefore, we suspect that the the existance of the tumor may influence HPO. This may be attributed to the affect of the lesion on HPO.

Despite numerous years of clinical diagnoses of HPO, the pathogenesis remains poorly understood. The predominantly investigated factor is biochemical; the biochemical hypothesis states that biochemical compounds are produced and released by the lung cancer itself. Elevated levels of serum growth hormone, growth hormone-releasing hormone, vascular endothelial growth factor and platelet-derived growth factor have been reported in certain patients with lung cancer and HPO (21–23). In 1987, Dickenson and Martin (24) hypothesized that pathological shunting around the pulmonary vasculature permits numerous circulating factors, which are normally inactivated by the lungs, to directly enter the systemic vasculature. This hypothesis may partly elucidate the proportional difference in symptom improvement between advanced and early-stage lung cancer patients. Uppal et al (25) mapped HPO to chromosome 4q33–q34 using autozygosity methods and revealed mutations in 15-hydroxyprostaglandin dehydrogenase, which is the primary enzyme of prostaglandin degradation. Homozygous individuals develop HPO secondary to chronically elevated prostaglandin E2 levels. These findings indicate that a mechanism operates at the gene level. Additional debatable hypotheses include mechanical and neurogenic reasoning (26). As the incidence of HPO is rare, future investigations are required to detect the true mechanism.

The standard treatment for HPO is resection of the primary lesion. In the case of advanced lung cancer, however, surgical excision of the tumor can be complicated if the underlying primary disease is not controlled by chemotherapy or radiation therapy. Administration of adrenocortical hormone is known to be a useful adjuvant treatment. Furthermore, radiofrequency ablation and epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been reported and achieved favorable results (27,28).

As a retrospective observation, the present study has certain limitations. The patients that were included are cases who exhibited apparent clinical symptoms. Therefore, the sample size of HPO in the study may be less than the true incidence of such lesions. In addition, the mechanisms that predispose lung cancer to give rise to HPO were not detected.

In conclusion, this retrospective study of lung cancer patients that were treated at one cancer center, indicated that 1.87% of the 6,151 patients had symptoms of HPO. Males, adenocarcinoma patients, smokers and those with advanced disease contributed to the majority of cases of HPO in primary lung cancer patients. The symptoms and bone scintigram of HPO improved in the patients who received treatment, particularly in the patients that underwent surgery. Despite recent advances in recognizing and treating HPO, further investigations are required to elucidate its pathogenesis.