A 62-year-old man with 3-month history of progressive right knee pain
A 62-year-old African-American man who presented to the orthopedic clinic reported he had a 3-month history of atraumatic, progressive right knee pain. He said he did not have any prior injuries or surgeries. He is a life-long, one pack-per-day smoker with no other pertinent medical history. On exam, a mild knee effusion was present and knee range of motion was 0° to 130°. The patient had pain at the extremes of his knee motion. Otherwise, the patient had a normal lower extremity exam. Digital clubbing was identified (Figure 1a), as were diffuse pruritic skin plaques (Figure 1b).
The imaging obtained included radiographs of the right knee (Figures 2a and 2b) and right femur (Figure 3), a whole-body bone scan (Figure 4) and MRI (Figures 5a and 5b) of the right knee.
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Hypertrophic pulmonary osteoarthropathy
The patient’s radiographic workup was non-diagnostic and a knee arthrocentesis sample yielded a white cell count of 1067 leukocytes/mm3 with no crystals, a negative gram stain and negative cultures. A diagnostic knee arthroscopy was performed, which demonstrated diffuse synovial hypertrophy, which, on tissue analysis, depicted synovium with non-specific reactive changes. A subsequent chest radiograph (Figure 6) demonstrated a large, left, lower-lobe lung mass, which was confirmed with further workup to be lung cancer. After further treatment directed at the lung cancer, the patient unfortunately succumbed to his illness.
Hypertrophic osteoarthropathy (HOA) is an uncommon syndrome consisting of periostosis, synovial effusions and digital clubbing. The clinical presentation of hypertrophic pulmonary osteoarthropathy (HPO) is classically described as a triad of arthralgia, periostitis and digital clubbing. Some case reports describe leg and knee pain as the precursor of this paraneoplastic syndrome. Although most cases of synovial effusions are described in native joints, one case report described HPO in a patient with a total knee arthroplasty. Schumacher performed aspirations in eight patients with HPO who had synovial effusions and found that all aspirations had fewer than 450 leukocytes/mm3 and evidence of synovial microvascular injury. Periostitis is described as the “radiographic hallmark of hypertrophic osteoarthropathy.” It is most commonly found in the proximal and distal diaphysis of the tibia, fibula, radius, ulna and femur. MRI reveals periosteal reaction and soft tissue edema. Symmetric deposition of radionuclide around the diaphyseal cortex of tubular long bones produces characteristic symmetric findings on bone scan.
HOA can be classified as primary or secondary. Primary HOA is a rare autosomal dominant condition in which skin conditions predominate and it is thought to comprise approximately 3% to 5% of all HOA cases; however, the precise incidence is unknown. Secondary hypertrophic osteoarthropathy is a more common subset of HOA and is associated with pulmonary and cyanotic disease processes, such as lung cancer, tuberculosis, cystic fibrosis, right-to-left cardiac shunts and other extra-thoracic miscellaneous causes. A more specific identifying term related to pulmonary etiologies is HPO.
Although HPO may be present in a myriad of pulmonary conditions, 80% of cases are related to pulmonary malignancies or associated metastases. One study in lung cancer patients reported the incidence of confirmed HPO was 0.8% and suspected HPO was 4.5%. A more recent study reported 1.87% of patients with lung cancer had HPO. Males and smokers had a greater risk of having the condition.
The exact pathophysiology behind the development of HPO remains unknown. but several possible etiologies have been postulated. One theory involves inactivation of specific growth factors within the lungs, such as prostaglandin E2 (PGE2), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Two studies found patients with HPO had increased urinary levels of PGE2. When these patients were treated with the cyclooxygenase-2 or COX-2 inhibitor rofecoxib, pain and swelling symptoms improved, but the residual clubbing remained.
Several studies have assessed the role of VEGF in the pathogenesis of HPO. VEGF is a growth factor and substantial mediator in pathological angiogenesis, which results in vascular hyperplasia, bone formation and edema. Two studies reported decreased levels of VEGF following resection of lung tumors, which resulted in significant improvement in digital clubbing and skeletal abnormalities. Histological studies of digital clubbing support the role of VEGF by demonstrating many of the downstream effects of VEGF, such as vascular hyperplasia, endothelial cell activation, edema and periosteal proliferation in the peripheral tissues.
Treatment of HPO focuses on treatment of the primary cause and therapeutic treatment of symptoms. Symptomatic treatments available that have shown promise include indomethacin, rofecoxib, bisphosphonates, such as pamidronate and zoledronic acid, and octreotide. In cases of HPO secondary to lung cancer, treating the cancer with tumor excision and chemotherapy may improve arthralgia. One patient with HPO secondary to advanced lung adenocarcinoma was successfully treated with gefitinib, which is a selective epidermal growth factor receptor tyrosine kinase inhibitor. After treatment, the primary tumor and the abnormal bone scintigraphy uptake associated with the patient’s periostitis disappeared.
HPO is an uncommon syndrome associated with pulmonary conditions, such as lung cancer. Given the musculoskeletal symptoms associated with this disease process, these patients may in some instances present to the orthopedist’s clinic first, such as in this scenario. The patient described herein exhibited many of the classic findings associated with this syndrome, which include knee arthralgia, digital clubbing and a long history of smoking, which put him at high risk for pulmonary disease. It remains unclear whether the skin condition detailed previously was also related to this condition, but we suspect that it was. In a similar patient who presents with joint pain and diffuse long bone periostitis on imaging with no other known cause, consider HPO as a potential diagnosis. Obtaining additional imaging, to include a chest radiograph, and initiating appropriate referrals can potentially expedite the successful diagnosis and treatment of this serious condition.
- Armstrong DJ, et al. Rheumatol Int. 2007;doi:10.1007/s00296-006-0224-2
- Baranowski A, et al. Unfallchirurg. 2013; doi:10.1007/s00113-012-2263-3.
- Castori M, et al. Clin Genet. 2005;doi:10.1111/j.1399-0004.2005.00533.x.
- Ferrara N. Endocr Rev. 2004;doi:10.1210/er.2003-0027 [doi].
- Greenfield GB, et al. Am J Roentgenol Radium Ther Nucl Med. 1967;101:927-931.
- Hayashi M, et al. Anticancer Res. 2005;25:2435-2438.
- Hsieh CC, et al. Knee. 2009;doi:10.1016/j.knee.2008.10.001.
- Izumi M, et al. Respirology. 2010;doi:10.1111/j.1440-1843.2010.01769.x.
- Kozak KR, et al. J Thorac Oncol. 2012;doi:10.1097/JTO.0b013e3181fc76a9.
- Kozak KR, et al. Nat Clin Pract Rheumatol. 2006;doi: ncprheum0252.
- Lange U, et al. Z Rheumatol. 2011;doi:10.1007/s00393-010-0734-x.
- Martinez-Lavin M, et al. Curr Opin Rheumatol. 2008;doi:10.1097/BOR.0b013e3282f14a5a.
- Meeker J, et al. J Bone Joint Surg Am. 2008;doi:10.2106/JBJS.G.00660.
- Narayanan S, et al. J Clin Rheumatol. 2010;doi:10.1097/RHU.0b013e3181e04d80.
- Nguyen S, et al. Clin Rheumatol. 2011;doi:10.1007/s10067-010-1563-7.
- Olan F, et al. J Rheumatol. 2004;doi:0315162X-31-614.
- Pineda C, et al. Rheumatic Disease Clin North Am. 2013;doi:10.1016/j.rdc.2013.02.008
- Qian X, et al. Oncol Lett. 2014;doi:10.3892/ol.2014.2022.
- Schumacher HR Jr. Arthritis Rheum. 1976;19:629-636.
- Silveira LH, et al. Clin Exp Rheumatol. 2000;18:57-62.
- Yao Q, et al. Semin Arthritis Rheum. 2009;doi:10.1016/j.semarthrit.2008.07.001.
- Zhang Z, et al. Front Med. 2013;doi:10.1007/s11684-013-0246-6.
- For more information:
- John Bunyasaranand can be reached at Campbell University School of Osteopathic Medicine, 4350 U.S. 421 South, Lillington, NC 27546; email: email@example.com.
- Craig D. Cameron, DO, can be reached at Eisenhower Army Medical Center, 300 E. Hospital Rd., Fort Gordon, GA 30905; email: firstname.lastname@example.org.
- CPT Sally A. Corey, DO, can be reached at Eisenhower Army Medical Center, 300 E. Hospital Rd., Fort Gordon, GA 30905; email: email@example.com.
- MAJ Jacob C. Rumley, DO, can be reached at Martin Army Community Hospital, 6600 Van Aalst Blvd., Fort Benning, GA 31905; email: firstname.lastname@example.org.
- MAJ William F. Scully, MD, can be reached at Martin Army Community Hospital, 6600 Van Aalst Blvd., Fort Benning, GA 31905; email: email@example.com.
Disclosures: Bunyasaranand, Cameron, Corey, Rumley and Scully report no relevant financial disclosures.