Wechalekar, Mihir D. MBBS, FRACP*; Kennedy, Nicholas A. MBBS†; Ahern, Michael MD*; Slavotinek, John FRANZCR‡; Smith, Malcolm D. PhD§
From the *Rheumatology Unit and †Gastroenterology Unit, Repatriation General Hospital; ‡Medical Imaging, Flinders Medical Center; and §Rheumatology, Southern Adelaide Health Service, Adelaide, South Australia, Australia.
This study has no sources of support.
The authors declare no conflict of interest.
Correspondence: Mihir D. Wechalekar, MBSB, FRACP, Rheumatology Unit, Repatriation General Hospital, Daws Rd, Daw Park, Adelaide, South Australia 5041, Australia. E-mail: firstname.lastname@example.org.
Esophageal cancer usually presents late and carries a grave prognosis. Early diagnosis dramatically improves outcomes, and hence recognition of the varied presenting features, including hypertrophic osteoarthropathy (HOA), may be important. Hypertrophic osteoarthropathy is a rare manifestation of esophageal adenocarcinoma and indeed may herald the presence of this neoplasm, as it did in the case we present. A 59-year-old man presented with signs and symptoms suggestive of inflammatory wrist, ankle, and knee arthritis, and imaging revealed changes of HOA. He reported dysphagia mainly to solids, and endoscopic biopsy showed adenocarcinoma. Cancer resection treatment led to clinical resolution of his musculoskeletal symptoms. This case highlights the importance of recognition of HOA as a feature of this increasingly common cancer.
Esophageal cancer typically becomes symptomatic late in its course and has a poor prognosis despite available therapies. Early diagnosis, preferably even before the onset of symptoms, is critical as prompt treatment can dramatically improve prognosis.1 The incidence of esophageal adenocarcinoma is increasing and has outstripped squamous cell cancer (SCC) as the most common form of esophageal cancer in the developed world.2 Although rare, one of the musculoskeletal manifestations of esophageal adenocarcinoma is hypertrophic osteoarthropathy (HOA).3,4
Hypertrophic osteoarthropathy is characterized by digital clubbing and periostitis of tubular bones.5 Tenderness and swelling especially of large joints may accompany these features, clinically manifesting as polyarthritis/polyarthralgia.5 Hypertrophic osteoarthropathy is known to present with a painful arthropathy in advance of clubbing, mimicking inflammatory arthritis.6 We report a case of esophageal adenocarcinoma presenting with HOA with subsequent imaging documenting improvement of the HOA with successful treatment of the esophageal cancer.
A 59-year-old male clerk was referred to the rheumatology unit for painful and swollen wrists, knees, and ankles. He had been healthy in the past apart from diet-controlled type 2 diabetes mellitus and mild depression.
His knee and ankle arthritis had been present for 9 months before presentation and had worsened for the last 2 months with constant pain especially upon weight bearing and walking. He did not have a family history of inflammatory arthritis, but had a positive family history of bowel cancer for which he had had a normal colonoscopy 18 months prior. He was an ex-smoker and drank a cask of wine each weekend.
His overall health had deteriorated over several months before presentation with 20 kg of weight loss, which he attributed to change in diet. He reported dysphagia to solids. Clinical examination revealed tenderness and swelling involving his wrists, knees, and ankles; his systemic examination was otherwise unremarkable.
His referring practitioner had organized rheumatoid factor and anti-cyclic citrullinated peptide, both of which were negative, and his C-reactive protein and erythrocyte sedimentation rate were only mildly elevated. Because of his dysphagia and weight loss, an endoscopy was organized, and he was commenced on prednisolone to see if this would help his joint symptoms before a definitive diagnosis.
A whole-body bone scan and radiographs of his hands (Fig. 1) revealed HOA and a periosteal reaction consistent with this, respectively. His upper gastrointestinal endoscopy demonstrated a 5-cm lower-esophageal cancer, subsequently confirmed on histopathology to be invasive adenocarcinoma. Investigations for staging of his cancer including a whole-body computed tomography scan and positron emission tomography scan did not reveal metastatic disease, and he went on to have neoadjuvant chemotherapy-radiotherapy and subsequent resection (Ivor-Lewis operation) with a feeding duodenostomy in place.
Following the esophageal cancer resection, his joint symptoms lessened in about 2 weeks, and when he was formally followed up in the rheumatology clinic 6 weeks after surgery, he had no joint symptoms. A follow-up nuclear medicine scan (Fig. 1) revealed a considerable improvement in his HOA. When last seen in the rheumatology clinic 7 months after surgery, he continued to be asymptomatic with regard to his joints.
The association of esophageal adenocarcinoma and HOA or clubbing is rare: a MEDLINE and EMBASE search retrieved only 2 case reports in the indexed English-language literature.3,4 In general, esophageal cancers are a rare cause of HOA: More cases have been reported with SCCs of the esophagus3 than adenocarcinoma, which may reflect the previously more common nature of esophageal SCC.2 The incidence of esophageal adenocarcinoma has risen dramatically and now outstrips the incidence of SCC in the Western world,2 and this may lead to a relative rise in this cancer as an etiology of HOA/clubbing.
The exact underlying pathogenesis of clubbing in relation to esophageal cancer remains incompletely elucidated. A previously published case report3 described a 71-year-woman with esophageal adenocarcinoma with elevated serum estradiol and normal gonadotrophin levels, who had thrombocytosis presumably secondary to her cancer. The authors' proposed mechanism included enhanced β-adrenergic activity in the lung secondary to high estrogen levels causing vascular smooth muscle relaxation and increasing arteriovenous connections, which may have precluded the normally effective megakaryocyte filtering effect of pulmonary capillaries leading to enhanced persistence of platelet-derived growth factor.3 One of the proposed mechanisms of clubbing and HOA (which appear to be different manifestations of the same underlying disease process) is thought to be release of platelet-derived growth factor when megakaryocyte fragments reach peripheral tissues. Localized activation of platelet-endothelial cells with subsequent release of fibroblast growth and other factors may play a role.7-9 Another proposed candidate to explain features of HOA is vascular endothelial growth factor, and 1 case report described a marked decline in vascular endothelial growth factor after resection of the underlying tumour with resolution of the skeletal manifestations.10 Dramatic relief of symptoms of HOA has been reported with truncal vagotomy, leading credence to the role of reflex vagal stimulation in the pathogenesis of HOA.11
Regardless of the cause, apart from the well-known association of HOA with cancer, it is noteworthy that one of the sites of potential underlying neoplastic disease to be considered during a rheumatologic consultation for HOA is the esophagus. Furthermore, esophageal carcinoma is relatively easily amenable to confirmation by endoscopic biopsy, which may possibly lead to earlier diagnosis and potentially a better outcome.
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2. Bollschweiler E, Wolfgarten E, Gutschow C, et al. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer
3. Polkey MI, Cook GR, Thomson AD, et al. Clubbing associated with esophageal adenocarcinoma. Postgrad Med J
4. Carroll KB, Doyle L. A common factor in hypertrophic osteoarthropathy. Thorax
5. Yao Q, Altman RD, Brahn E. Periostitis and hypertrophic pulmonary osteoarthropathy: report of 2 cases and review of the literature. Semin Arthritis Rheum
6. Segal AM, Mackenzie AH. Hypertrophic osteoarthropathy: a 10-year retrospective analysis. Semin Arthritis Rheum
7. Dickinson CJ. The aetiology of clubbing and hypertrophic osteoarthropathy. Eur J Clin Invest
8. Martinez-Lavin M. Digital clubbing and hypertrophic osteoarthropathy: a unifying hypothesis. J Rheumatol
9. Pedersen NT. Occurrence of megakaryocytes in various vessels and their retention in the pulmonary capillaries in man. Scand J Haematol
10. Olan F, Portela M, Navarro C, et al. Circulating vascular endothelial growth factor concentrations in a case of pulmonary hypertrophic osteoarthropathy. Correlation with disease activity. J Rheumatol
11. Ooi A, Saad RA, Moorjani N, et al. Effective symptomatic relief of hypertrophic pulmonary osteoarthropathy by video-assisted thoracic surgery truncal vagotomy. Ann Thorac Surg
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