Downloaded from on July 27, 2015 - Published by

Case report

Treatment of painful hypertrophic osteoarthropathy associated with non-small cell lung cancer with octreotide: a case report and review of the literature Elizabeth Birch, Debbie Jenkins, Simon Noble Department of Palliative Medicine, Royal Gwent Hospital, Newport, UK Correspondence to: Simon Noble, Department of Palliative Medicine, Royal Gwent Hospital, Cardiff Rd, Newport NP20 2UB, UK; [email protected] Accepted 5 July 2011 Published Online First 7 August 2011

ABSTRACT Hypertrophic osteoarthropathy (HOA) is a syndrome most commonly associated with non-small cell lung cancer and consists of periostitis, digital clubbing and painful polyarthropathy. Its symptoms may be disabling and are reportedly difficult to manage effectively with conventional analgesia. We present a case of a lung cancer patient with opioid resistant painful HOA in whom analgesia was achieved with octreotide.

CASE HISTORY A man in his seventies presented with an 8-week history of increasing bilateral ankle and wrist swelling which limited mobility to a few steps. This coincided with new onset progressive dyspnoea, cough and an episode of haemoptysis. Physical examination was unremarkable with the exception of grade 4 bilateral digital clubbing (figure 1A,B). Chest radiography revealed a 6 cm mass in the right upper lobe, on a background of emphysematous changes (figure 2A). Laboratory tests showed a microcytic anaemia (haemoglobin: 10.5 g/dl, mean corpuscular volume: 68.1), a raised platelet count (426) and elevated C reactive protein (63.9). Other blood tests including renal biochemistry, liver function tests, bone profi le and uric acid were within normal limits. Rheumatoid and ENA screening were negative, and all tumour markers were within normal range. Chest CT confi rmed the presence of a solitary lung mass in the periphery of the right upper lobe extending down to cross the oblique fi ssure with evidence of pathological lymphadenopathy at the right hilum and enlarged nodes seen in the mediastinum (figure 2B). A provisional diagnosis of lung carcinoma with hypertrophic osteoarthropathy (HOA) was made under current diagnostic criteria.1 The patient’s analgesic requirements rapidly escalated to stage 3 of the World Health Organization analgesic ladder with only minimal benefit from a combination of paracetamol, diclofenac, morphine sulphate, amitriptyline and gabapentin. No benefit was reported from trials of steroid or pamidronate infusions. X-rays at this time showed the typical periosteal thickening of the distal anterior cortex of the tibiae and fibulae (figure 3), consistent with HOA. Bronchoscopy was unable to obtain histological confi rmation of carcinoma, but a PET scan revealed a 6 cm right upper lobe spiculated mass with right hilar nodes measuring 1.5 cm, and no evidence bone metastases. A diagnosis of lung carcinoma, T2N1M0

BMJ Supportive & Palliative Care 2011;1:189–192. doi:10.1136/bmjspcare-2011-000052

(assumed to be non-small cell carcinoma) complicated by secondary hypertrophic pulmonary osteoarthropathy was made. With pain from his HOA still uncontrolled, the patient was started on subcutaneous octreotide 150 μg daily in conjunction with MST 50 mg twice daily, amitriptyline 20 mg at night and gabapentin 300 mg three times a day (limited due to side effects), and referred for resection of his tumour. Within 48 h of commencing octreotide his pain had improved from ‘excruciating’ to ‘moderate and manageable’ and within 5 days complete pain relief was achieved. Subsequently, the dose was reduced to 100 μg on alternate days, without loss of pain control. Following a right upper pulmonary lobectomy, the HPOA symptoms resolved completely. Octreotide was discontinued with no recurrence of pain. Histology confi rmed primary bronchial adenocarcinoma, positive for TTF-1. The patient was due to commence chemotherapy when he was admitted with abdominal pain and was found to have liver metastases and his stage was revised to T2N1M1. He completed five cycles of chemotherapy with gemicitabine/carboplatin but died 13 months after his initial presentation. He did not have a recurrence of the pain from HOA after his surgery.

DISCUSSION HOA is a syndrome of periostitis, digital clubbing and painful swollen joints; occasionally it also presents with gynaecomastia or, even more unusually, myxoedematous changes in the face and ears.1 The use of modern imaging such as MRI means that several early cases of HOA have been detected before the patient has developed digital clubbing; clubbing is, therefore, no longer required to confi rm the diagnosis. 2 The periostitis leads to loosely woven, subperiosteal new bone formation which is seen radiologically as a linear calcification outside the cortex of the distal diaphysis of the tibia, ulna and radius, producing a typical ‘onion skin’ or ‘candle wax’ appearance. This new bone formation is caused by neoangiogenesis and osteoblast proliferation. Although HOA is most commonly associated with lung cancer and non-small cell lung cancers (NSCLCs) account for the majority of these, a wide range of other conditions are also associated with the condition: pulmonary diseases with systemic involvement such as congenital cyanotic heart disease, 3 cystic fibrosis4 and others have been documented. Rheumatological diseases such 189

Downloaded from on July 27, 2015 - Published by

Case report

Figure 1 (A, B) Clubbing of the fingers.

as rheumatoid arthritis and ankylosing spondylitis have also been reported, 5 as have hepatic diseases6 and chronic infections such as subacute bacterial endocarditis and acquired immune deficiency syndrome.7 It may also present without an underlying condition being present – primary HOA, an autosomal-dominant genetic condition seen in a predominantly male population. The prevalence of HOA in patients with primary lung cancer is variously reported to be between 4.5%8 and 32%,9 with more recent reviews tending to have lower estimates. Overall, 90% of those presenting with new HOA symptoms will eventually be found to have a malignancy. Retrospective review of patients with NSCLC in Japan who had had radiological investigation found that 10–20% of all patients will have some features of this disorder if not classical HOA.8 Histologically, HOA is characterised by localised vascular hyperplasia associated with platelet and endothelial cell activation; oedema and excessive connective tissue deposition accompany these changes. Since the fi rst modern descriptions of HOA by Locke in 1915,10 the pathogenesis of HOA has remained unclear. A number of hypothesis have been put forward, each offering a variety of reasons for the pathology seen and for the efficacy of various therapeutic measures. These include stimulation of the vagal nerve causing the release of vasoactive intestinal polypeptides increasing blood flow to the extremities,11 peripheral impaction of megakaryocytes and platelets in the extremities resulting in the release of platelet-derived growth factor and other growth factors that would normally be inactivated in the lungs,11 12 and a hormonal mechanism, as suggested by the high level of growth hormone13 seen in some patients and the increased levels of oestrogen seen in others.14


Current theories centring on the role of tumour and peripheral platelet production of growth factors, primarily vascular endothelial growth factor (VEGF), have gained acceptance. VEGF is a potent endothelial stimulating factor15 and is the only angiogenic factor which is a specific endothelial cell mitogen.16 It has a crucial role in physiological as well as pathological angiogenesis, through its ability to induce endothelial proliferation and migration as well as permeability. It is platelet derived and has been demonstrated to be over-expressed by almost all tumours and tumour vasculature in response to hypoxia and as a mechanism for mass growth.17 Upregulation of VEGF is also seen in diabetic retinopathy as well as other conditions leading to tissue hypoxia.18 Patients with HOA often have abnormal platelet populations19; these large platelets that would normally be fragmented in the lung microvasculature enter the systemic system instead, ending up in the distal vasculature and there releasing endothelial growth factors such as VEGF. Receptors for VEGF have been found in subperiosteal bone forming cells, and high levels of VEGF have been found in virtually all the diseases associated with secondary HOA (but not seen in congenital cyanotic heart disease) and in primary HOA; these levels correlate to levels of underlying disease activity. 20 Patients with lung cancer and HOA have been shown to have significantly higher serum levels of VEGF than those who do not have HOA. 21 22 The management and prognosis of HOA is dependent on the underlying disease process. Surgical removal of the tumour or reduction in tumour bulk with chemotherapy can improve or resolve HOA in some cases.23 Lung transplantation in a patient with cystic fibrosis was also shown to resolve symptoms.24 The tyrosine kinase inhibitor (gefitinib) has also been shown to resolve symptoms as well as providing resolution of radiological fi ndings.25 The current management of the symptoms of HOA includes conventional analgesia working up the WHO analgesic ladder, as well as non-steroidal medication and practical measures such as physiotherapy. In cases where pain is refractory to conventional analgesia, several case studies have reported success with bisphosphonates including pamidronate and zolendronic acid.26–29 Octreotide has also been reported as relieving pain in HOA associated with NSCLC and with tetralogy of Fallot.30 31 Octreotide is a synthetic octapeptide analogue of somatostatin. Somatostatin is widely distributed in the central and peripheral nervous system and is pivotal in the endocrine, autocrine and paracrine functions of living organisms. The fact that all vertebrates produce immunoreactive somatostatin, despite the divergence of fish from mammals some 400 million years ago, suggests it provides a selective advantage for organisms.32 Somatostatin modulates the secretion of multiple pituitary, pancreatic and gastric hormones. It inhibits gut motility, absorption of nutrients and ions, vascular contractility and cell proliferation; it also functions as a neurotransmitter. Octreotide along with other potent somatostatin analogues were developed to give a more stable drug with a longer half-life in order to fulfi l the potential therapeutic promise of somatostatin, which itself has a very short half-life. Somatostatin analogues possess antitumour and antisecretory activity in human cancers both in vitro and in vivo.33 The action of somatostatin is mediated by G-protein coupled receptors on target cells (sst receptors) of which there are five subtypes, 34 the nearest relatives of which are the δ opioid receptors. A large variety of tumours and their metastases express a high density of sst receptors, with sst2 being the most commonly expressed.35 Somatostatin has a direct effect on tumour cells by promoting apoptosis or cytostasis by

BMJ Supportive & Palliative Care 2011;1:189–192. doi:10.1136/bmjspcare-2011-000052

Downloaded from on July 27, 2015 - Published by

Case report

Figure 2 Chest radiograph and CT scan showing mass in right upper lobe.

Figure 3 Radiographs showing periosteal thickening of distal anterior cortex of tibiae and fibulae. binding with these receptors and causing a signalling cascade (dependent on subtype) that eventually ends in negative control of cell growth. Somatostatin has also been shown to exert its antineoplastic properties indirectly by inhibiting the secretion of mitogenic hormones, growth factors and cytokines. Like somatostatin, octreotide has been shown to be a potent inhibitor of VEGF as well as decreasing microvasculature density. 36 37 It has been used successfully in the management of chronic cancer pain, 38 and in patients with uncontrolled pain due to BMJ Supportive & Palliative Care 2011;1:189–192. doi:10.1136/bmjspcare-2011-000052

HOA.39 The limited data on octreotide’s utility in the treatment of HPOA pain, especially within the clinical trial setting, make a formal health economic evaluation for this indication highly unlikely. In this case, with octreotide being used as a bridging analgesia prior to surgery (and subsequent pain control), the cost of the drug for a short period of time was felt to be justified. For patients requiring octreotide long term for HPOA pain, the costs may be prohibitive and consideration of its use should follow exploration of all other less costly options. In conclusion, treatment of HOA relies, were possible, on the treatment of the underlying condition. However, if treatment of the presumed cause (in this case infection) fails to relieve symptoms, continued investigation for an underlying malignancy is vital. Where pain is refractory to conventional analgesics, octreotide may have a role in gaining pain control. Octreotide works directly on the tumour cells themselves to prevent proliferation but also indirectly by modulating the effect of unregulated growth factors promoting angiogenesis. Somatostatin analogues are currently providing possibilities for novel strategies in the treatment of cancers as well as presenting options for symptom control. Acknowledgements The authors are grateful to the patient for granting permission to use his images in this case report. Competing interests None. Patient consent Obtained Provenance and peer review Not commissioned; externally peer reviewed


Downloaded from on July 27, 2015 - Published by

Case report REFERENCES 1.


3. 4. 5. 6.




10. 11. 12.

13. 14. 15. 16. 17.

18. 19.


Martínez-Lavín M, Matucci-Cerinic M, Jajic I, et al. Hypertrophic osteoarthropathy: consensus on its definition, classification, assessment and diagnostic criteria. J Rheumatol 1993;20:1386–1387. Clarke S, Barnsley L, Peters M, et al. Hypertrophic pulmonary osteoarthropathy without clubbing of the digits. Skeletal Radiol 2001;30:652–655. Dickinson CJ. The aetiology of clubbing and hypertrophic osteoarthropathy. Eur J Clin Invest 1993;23:330–338. Braude S, Kennedy H, Hodson M, Batten J. Hypertrophic osteoarthropathy in cystic fibrosis. Br Med J (Clin Res Ed) 1984;288(6420):822–823. Diamond S, Momeni M. Primary hypertrophic osteoarthropathy in a patient with rheumatoid arthritis. J Clin Rheumatol 2007;13:242–243. Stoller JK, Moodie D, Schiavone WA, et al. Reduction of intrapulmonary shunt and resolution of digital clubbing associated with primary biliary cirrhosis after liver transplantation. Hepatology 1990;11:54–58. Bhat S, Heurich AE, Vaquer RA, et al. Hypertrophic osteoarthropathy associated with Pneumocystis carinii pneumonia in AIDS. Chest 1989;96:1208–1209. Izumi M, Takayama K, Yabuuchi H, et al. Incidence of hypertrophic pulmonary osteoarthropathy associated with primary lung cancer. Respirology 2010;15:809–812. Suteanu S, Rohan C, Gherasim E, et al. Hypertrophic osteoarthropathy secondary to bronchopulmonary cancer (our experience). Rom J Intern Med 1992;30:281–284. Locke E. Secondary hypertrophic osteoarthropathy and its relation to simple club-fingers. Arch Intern Med 1915;15:659–713. Martinez-Lavin M. Pathogenesis of hypertrophic osteoarthropathy. Clin Exp Rheumatol 1992;10(Suppl 7):49–50. Mito K, Maruyama R, Uenishi Y, et al. Hypertrophic pulmonary osteoarthropathy associated with non-small cell lung cancer demonstrated growth hormone-releasing hormone by immunohistochemical analysis. Intern Med 2001;40:532–535. Gosney MA, Gosney JR, Lye M. Plasma growth hormone and digital clubbing in carcinoma of the bronchus. Thorax 1990;45:545–547. Ginsburg J, Brown JB. Increased oestrogen excretion in hypertrophic pulmonary osteoarthropathy. Lancet 1961;2:1274–1276. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003;3:401–410. Silveri F, De Angelis R, Argentati F, et al. Hypertrophic osteoarthropathy: endothelium and platelet function. Clin Rheumatol 1996;15:435–439. Matsuyama W, Hashiguchi T, Mizoguchi A, et al. Serum levels of vascular endothelial growth factor dependent on the stage progression of lung cancer. Chest 2000;118:948–951. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–676. Silveira LH, Martínez-Lavín M, Pineda C, et al. Vascular endothelial growth factor and hypertrophic osteoarthropathy. Clin Exp Rheumatol 2000;18:57–62.





24. 25.

26. 27.

28. 29. 30. 31.

32. 33. 34. 35.

36. 37. 38. 39.

Tamura M, Ohta Y. Serum vascular endothelial growth factor-C level in patients with primary nonsmall cell lung carcinoma: a possible diagnostic tool for lymph node metastasis. Cancer 2003;98:1217–1222. Olán 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 2004;31:614–616. Abe Y, Kurita S, Ohkubo Y, et al. A case of pulmonary adenocarcinoma associated with hypertrophic osteoarthropathy due to vascular endothelial growth factor. Anticancer Res 2002;22:3485–3488. Fietz T, Schneider P, Knauf WU, et al. Clubbed fingers and arthralgia as a reversible paraneoplastic syndrome (Pierre-Marie-Bamberger syndrome) in a nonsmall-cell bronchial carcinoma. Pneumologie 1990;44:1306–1311. Sansores RH, Villalba-Caloca J, Ramirez-Venegas A, et al. Reversal of digital clubbing after lung transplantation. Chest 1995;107:283–285. Hayashi M, Sekikawa A, Saijo A, et al. Successful treatment of hypertrophic osteoarthropathy by gefi tinib in a case with lung adenocarcinoma. Anticancer Res 2005;25:2435–2438. Garske LA, Bell SC. Pamidronate results in symptom control of hypertrophic pulmonary osteoarthropathy in cystic fibrosis. Chest 2002;121:1363–1364. Amital H, Applbaum YH, Vasiliev L, et al. Hypertrophic pulmonary osteoarthropathy: control of pain and symptoms with pamidronate. Clin Rheumatol 2004;23:330–332. Santini D, Fratto M, Vincenzi B, et al. Bisphosphonate effects in cancer and inflammatory diseases. Biodrugs 2004;18:269–278. Luke A, Bell G, Bell SC. Pamidronate results in symptom control of hypertrophic pulmonary oseoarthropathy in cystic fibrosis. Chest 2002;121:1363–1364. Penson RT, Rudd RM. Commentary: octreotide and hypertrophic pulmonary osteoarthropathy. Thorax 1997;52:297–298. Johnson SA, Spiller PA, Faull CM. Treatment of resistant pain in hypertrophic pulmonary osteoarthropathy with subcutaneous octreotide. Thorax 1997;52:298–299. Reichlin S. Somatostatin. N Engl J Med 1983;309:1495–1501. Pyronnet S, Bousquet C, Najib S, et al. Antitumor effects of somatostatin. Mol Cell Endocrinol 2008;286:230–237. O’Carroll AM, Raynor K, Lolait SJ, et al. Characterization of cloned human somatostatin receptor SSTR5. Mol Pharmacol 1994;46:291–298. Reubi JC, Waser B, Schaer JC, et al. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 2001;28:836–846. Dasgupta P. Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis. Pharmacol Ther 2004;102:61–85. Garcia de la Torre N, Wass JAH, Turner HE. Antiangiogenic effects of somatostatin analogues. Clin Endocrinology 2002;57:425–441. Chrubasik J, Meynadier J, Blond S, et al. Somatostatin, a potent analgesic. Lancet 1984;2:1208–1209. Angel-Moreno Maroto A, Martínez-Quintana E, Suárez-Castellano L, et al. Painful hypertrophic osteoarthropathy successfully treated with octreotide. The pathogenetic role of vascular endothelial growth factor (VEGF). Rheumatology (Oxford) 2005;44:1326–1327.

BMJ Supportive & Palliative Care 2011;1:189–192. doi:10.1136/bmjspcare-2011-000052

Downloaded from on July 27, 2015 - Published by

Treatment of painful hypertrophic osteoarthropathy associated with non-small cell lung cancer with octreotide: a case report and review of the literature Elizabeth Birch, Debbie Jenkins and Simon Noble BMJ Support Palliat Care 2011 1: 189-192 originally published online August 7, 2011

doi: 10.1136/bmjspcare-2011-000052 Updated information and services can be found at:

These include:

References Email alerting service

This article cites 39 articles, 4 of which you can access for free at: Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.


To request permissions go to: To order reprints go to: To subscribe to BMJ go to:

Treatment of painful hypertrophic osteoarthropathy associated with non-small cell lung cancer with octreotide: a case report and review of the literature.

Hypertrophic osteoarthropathy (HOA) is a syndrome most commonly associated with non-small cell lung cancer and consists of periostitis, digital clubbi...
302KB Sizes 2 Downloads 3 Views

Recommend Documents

Primary hypertrophic osteoarthropathy with myelofibrosis and anemia: a case report and review of literature.
Primary hypertrophic osteoarthropathy (PHO) is a rare and usually benign disorder of bone and connective tissue growth. Here we present a 28-year-old male patient presenting to our hospital with PHO and symptomatic anemia. Bone marrow biopsy suggeste

The Use of Apatinib in Treating Nonsmall-Cell Lung Cancer: Case Report and Review of Literature.
Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which has been proved to be effective and safe in treating heavily pretreated patients with gastric cancer.The aim of the study was to explore the

Hypertrophic pulmonary osteoarthropathy with primary lung cancer.
Hypertrophic pulmonary osteoarthropathy (HPO) is a rare paraneoplastic syndrome that is frequently associated with lung cancer; however, the incidence of clinically apparent HPO is not well known. The clinical data of 6,151 patients with advanced lun

Hypertrophic osteoarthropathy in patient with Crohn's disease: a case report.
Numerous causes of hypertrophic osteoarthropathy (HOA) have been reported. Commonly, secondary osteoarthropathy accompanies pulmonary diseases such as carcinoma of the lung, pleural tumors, lung abscesses, and bronchiectasis. However, HOA in inflamma

Painful Ejaculation with Cyclobenzaprine: A Case Report and Literature Review.
Sexual dysfunction is a well-known side effect of antidepressants. Painful ejaculation is a rare side effect that has been reported with the use of some psychiatric drugs such as triclyclic antidepressants. Cyclobenzaprine is a muscle relaxant that i

New Combined Medical Treatment With Etilefrine and Octreotide for Chylothorax After Esophagectomy: A Case Report and Review of the Literature.
Postoperative chylothorax is a rare but well-known complication of general thoracic surgery. Medical treatment of chylothorax was reported in the past, but there is still considerable controversy on the appropriate management strategies.Two patients

Horseshoe Lung Associated with Left Lung Hypoplasia: Case Report and Systematic Review of the Literature.
Horseshoe lung (HL) is often associated with cardiovascular malformations such as scimitar syndrome and unilateral lung hypoplasia. In patients with HL, the hypoplastic lung is almost always located on the right side. Cases of HL with a hypoplastic l

Eyelash trichomegaly following treatment with erlotinib in a non-small cell lung cancer patient: A case report and literature review.
Inhibitors of epidermal growth factor receptor (EGFR), including tyrosine kinase inhibitors (TKIs), present significant clinical benefits in the treatment of non-small cell lung cancer (NSCLC), particularly in patients with an EGFR mutation. However,