Hypertrophic Pulmonary Osteoarthropathy

Hypertrophic pulmonary osteoarthropathy (HPOA) syndrome is a condition characterized by proliferative periostitis of the long bones, especially in the distal and periarticular regions. HOA can result in proliferation of the synovial membranes, which causes painful and swollen joints; it is often accompanied by clubbing of the digits. Although clubbing was first described by Hippocrates in the 5th century BC, the association of clubbing, arthralgia, and ossifying periostitis as a distinct clinical syndrome was not recognized until 1889 and 1890 by Bamberger and Marie, respectively. HOA is also known as the Pierre Marie-Bamberger syndrome.

This syndrome is classified into primary and secondary HPOA. Primary HPOA is not associated with any other medical disorders; however, secondary HPOA (which is more common) is generally associated with lung cancer, tuberculosis, pulmonary abscess, bronchiectasis, emphysema, cystic fibrosis, interstitial lung disease, right-to-left cardiac shunts, and, less often, other disorders (eg, Hodgkin lymphoma and cirrhosis). Primary or idiopathic HPOA (also called pachydermoperiostosis and Touraine-Solente-Gole syndrome) is a hereditary disorder that presents in childhood and clinically mimics secondary HPOA. It may be associated with bilateral eyelid ptosis, leonine facies, and thickened skin. The genetic abnormality in primary HPOA involves a mutation in the hydroxyprostaglandin dehydrogenase (HPGD) gene that encodes 15-hydroxyprostaglandin dehydrogenase, which is the primary enzyme responsible for prostaglandin degradation.

The incidence of secondary HPOA in patients diagnosed with lung cancer, either primary or metastatic, is approximately 4-5%. Approximately 80% of pulmonary lesions associated with HPOA are lung cancers; pleural tumors account for 10%, and a miscellaneous group of intrathoracic malignancies account for 5%. Among patients with lung cancer, HPOA is associated with all cell types, most frequently with adenocarcinoma and less frequently with small cell carcinoma. This secondary form of HPOA is also known as hypertrophic pulmonary osteoarthropathy (HPOA).

While the etiology of HPOA is still poorly understood, both neurogenic and humoral mechanisms may play a role. Clubbing and HPOA appear to be different manifestations of the same disease process. It is thought that localized activation of platelet-endothelial cells, with the subsequent release of fibroblast growth factors (eg, platelet-derived growth factor, PDGF) play an important role in the pathogenesis of HPOA. The frequent association of HOA with lung disease raises the possibility that circulatory bypass of the lungs may be responsible. One hypothesis regarding the etiology of HPOA theorizes that megakaryocytes escape their normal fragmentation to platelets in the lung and reach the distal extremities, where they release growth factors.

Another hypothesis involves tumor production and the release of factors into the circulation (eg, vascular endothelial growth factor [VEGF]) that promote features of HPOA , such as vascular proliferation, edema formation, and new bone formation. Two case reports of patients with lung cancer and HOA reported elevated circulating concentrations of VEGF. In one case, a marked decline in VEGF followed resection of tumor and was temporally correlated with the disappearance of the skeletal abnormalities. Elevated levels of PDGF, endothelin-1 (ET-1), β-thromboglobulin (β-TG), and VEGF have all been reported in patients with HPOA. Estrogen and growth hormone (GH) produced by pulmonary tumors has also been implicated in the development of HPOA. In one case report, previously high levels of GH were noted to return to normal after resection of tumor, along with relief of clinical symptoms. Finally, the central abnormality in primary HPOA, prostaglandin E2, may also play a pathogenetic role in secondary HPOA.

The clinical features of HPOA include digital clubbing and periostitis or periosteal new bone formation of tubular bones (particularly the long bones of the distal extremities). Periostitis causes severe burning pain in the distal extremities that is aggravated by dependency and weight bearing. It is usually accompanied by tenderness to palpation of the involved areas. Some patients present with a painful, symmetric, arthritis-like changes in the large joints and periarticular tissues (ankles, knees, wrists, metacarpopharyngeal joints, and elbows). HPOA mimics rheumatoid arthritis clinically; however, synovial fluids have been reported to be typically noninflammatory, with leukocyte counts less than 0.5 × 103/µL (0.5 × 109/L). The synovial membrane in cases of HPOA demonstrates vascular congestion with mild lymphocytic infiltration. Increased thickness of the subcutaneous soft tissues may be noted in the distal one-third of the arms and legs and, sometimes, of the facial tissues, which may simulate acromegaly. Neurovascular changes of the hands and feet, including chronic erythema, paresthesia, and increased sweating, may occur. In primary HPOA, bone and joint pain tends to be less severe, whereas furrowing of the face and scalp tends to be more severe. Patients with full-blown HPOA may in fact initially present to rheumatologists with severe arthritic symptoms, or they may even see a cardiologist with bilateral ankle swelling presumed to be caused by congestive heart failure.

When HPOA is suspected, diagnostic tests should be directed at the chest because the most frequent cause of acute-onset HPOA is a primary or secondary lung neoplasm. In one-third of patients with lung cancer, clinical HPOA predates the onset of respiratory symptoms, whereas in another third, patients present with respiratory symptoms simultaneously. In the remaining patients, signs and symptoms of HPOA may appear after the diagnosis of malignancy is established. Removal of lung cancer or the treatment of other causes of HPOA results in regression of the clinical manifestations of HPOA. In mild-to-moderate cases, symptom control may be attempted with analgesics such as nonsteroidal anti-inflammatory medications, steroids, or narcotics; however, many patients find the associated pain to be disabling and their symptoms are often resistant to these treatments. A single dose of 4 mg of zoledronic acid has been effectively used to alleviate symptoms. In refractory cases, subcutaneous octreotide may be used to relieve symptoms.

Laboratory testing is not particularly useful in evaluating HPOA; however, an elevated ESR of more than 50 mm/h and, in advanced cases, an elevated alkaline phosphatase level may be found.

Imaging studies are important in evaluating HPOA. Radionuclide studies are more sensitive than radiography in the detection of HPOA. The appearance of HPOA on radionuclide studies can range from an increased "bracelet-like" appearance to more diffuse, symmetrically increased uptake along the cortical margins of the diaphyses of the long, tubular bones (sometimes referred to as the "tram track" or "double stripe sign"). Although uncommon, there may be asymmetric and irregular involvement of the long bones (as seen in this case). Increased uptake in the distal phalanges is associated with marked clubbing. Although usually located in the peripheral skeleton, HPOA can also affect the skull, clavicles, ribs, and scapulae. The disease is typically more active in the lower extremities than in the upper ones, and it is usually greater in the long bones distal to the knees and elbows than those proximal to these joints.

The scintigraphic abnormalities found in the peripheral skeleton of patients with HPOA are not easily mistaken for diffuse skeletal metastasis. Metastatic tumor almost always involves the central skeleton in an irregular, focal, asymmetric pattern. When long bones are involved in cases of metastasis, it is the medullary cavity which is primarily affected, as opposed to the cortical involvement seen in HPOA. The radiographic and radionuclide image findings may diminish or even disappear following appropriate therapy of the associated disease process.

HPOA has no prognostic significance and early detection may lead to the discovery of a potentially resectable lung carcinoma. Subclinical cases may be diagnosed by radiographs or by skeletal scintigraphy (which is more sensitive than plain radiographs), with an incidence of lung cancer of approximately 20%. HPOA should be considered in the differential diagnosis of bone and joint pains in patients with cancer in addition to bone metastasis or inflammatory arthritis.

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