Hypertrophic Osteoarthropathy and Follicular Thyroid Cancer: A Rare Paraneoplastic Syndrome

What Is Known about This Topic?

• Reported cases of hypertrophic osteoarthropathy (HOA) as a paraneoplastic syndrome associated with thyroid cancer are very rare. We report the first case of an unusual presentation of HOA and follicular thyroid cancer.

What Does This Case Report Add?

• The pathogenesis of HOA still remains unclear. Vascular endothelial growth factor seems to play a key role; platelet-derived growth factor and prostaglandin E₂ could also be implicated but in our case they were all normal. We hypothesized the production of one or more unknown soluble circulating factors responsible for HOA and persistent hemoptysis.

Introduction

Hypertrophic osteoarthropathy (HOA) is a condition characterized by digital clubbing and periostitis often associated with joint disease. Periosteal appositions are mostly observed on tibial bones. The joint disease consists of noninflammatory arthritis of the large joints, especially knees, ankles, wrists and elbows.

HOA can be primary, also called pachydermoperiostosis, a hereditary disorder caused by a mutation in HPGD encoding 15-hydroxyprostaglandin dehydrogenase, the enzyme responsible for prostaglandin degradation, or SLCO2A1 which encodes solute carrier organic anion transporter family member 2A1, a prostaglandin transporter that leads to a marked elevation in the levels of circulating prostaglandin E₂ [1,2]. The secondary form of HOA is associated with various diseases. In 80-90% of the cases, the syndrome is observed in patients with bronchopulmonary diseases or congenital cardiopathies. It has been found in around 1% of patients with lung cancer [3]. We report the first case of HOA associated with a differentiated, infiltrative and radioiodine refractory follicular thyroid cancer.

Case Report

In March 2007, a 40-year-old female patient presented with a 4-cm firm right thyroid lobe nodule. She underwent surgery twice. First, an explorative cervicotomy with biopsy revealed a largely invasive follicular carcinoma. Computerized tomography (CT) and 18-fluorodeoxyglucose positron emission tomography documented the large and invasive tumor without any distant metastases. Then a total thyroidectomy was carried out in September 2007 confirming a largely invasive follicular well-differentiated cancer classified as pT3NxMx.

Subsequently, radioiodine therapy with 100 mCi ¹³¹I after LT4 withdrawal was performed in October 2007, showing an intense unique cervical fixation with no distant metastases. The thyroglobulin level was 11 ng/ml under LT4 withdrawal.

Neck ultrasound and CT performed just before radioiodine showed a rapid, invasive and local recurrence in the right thyroid bed (about 37 mm); because of the fast onset of recurrence, radiotherapy (70 Gy in the thyroid bed and 40 Gy in the neck compartment) and chemotherapy with cisplatinum were performed just after radioiodine therapy. The patient complained a great deal about the side effects of this treatment and an esophageal stenosis occurred.

In March 2008 a second radioiodine treatment with 100 mCi ¹³¹I showed no fixation. The tumor was thus considered as refractory to radioiodine. The thyroglobulin level was 0.1 ng/ml under LT4 withdrawal.

A new surgical procedure was performed in April 2008 to remove local tumoral tissue causing tracheal compression and dysphagia. This time, the histologic report found a poorly differentiated follicular thyroid cancer with extension to the periesophageal smooth muscle tissue classified as pT4NxMx.

Then, 12 cycles of GEMOX (gemcitabine-oxaliplatin) chemotherapy were performed from June to December 2008.

During the follow-up (8 years), the cervical disease was stable with no metastatic localizations and without thyroglobulin secretion, but six severe hemoptysis episodes occurred. The patient was hospitalized several times and required multiple embolizations of the bronchial and tracheal arteries (fig. 1). Lung cancer and infective causes were excluded as well as a restrictive lung disease as a consequence of the chemo- and radiotherapy. After embolization, bleeding persisted but less abundantly. Furthermore, the patient complained of the progressive appearance of clubbing (fig. 2) and painful joints with articular effusion evoking arthritis. Pain increased pressing on the arms and the anterior side of the legs. Osteoarticular symptoms worsened her quality of life. X-rays (fig. 3a, b) and magnetic resonance highlighted periosteal osseous proliferation. Bone scintigraphy (fig. 4a, b) excluded bone metastasis and confirmed HOA in the arms, elbows, hip, legs, knees and feet.

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Superselective arteriography of the thyrocervical trunk shows pathological vascularization of the neck.

Citation: European Thyroid Journal 4, 4; 10.1159/000437052

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Digital clubbing with the typical increase in the angle of the hyponychium to over 180°, periungual edema and softening of the nail bed.

Citation: European Thyroid Journal 4, 4; 10.1159/000437052

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a, b X-rays of ankles show periosteal apposition.

Citation: European Thyroid Journal 4, 4; 10.1159/000437052

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a Bone scintigraphy showing the typical hyperfixation of HOA images in the humerus, elbows, ulna and radius, thigh, knees, tibia and tarsus. b Detail of accumulation of the tracer on knees and tibias.

Citation: European Thyroid Journal 4, 4; 10.1159/000437052

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There was no familial history of pachydermoperiostosis, the genetic variant of the disease. Antineutrophil cytoplasmic antibodies, anti-CCP (cyclic citrullinated peptide) and anti-DNA antibodies were negative. C3, rheumatoid factor and β₂-microglobulin were normal. Aregenerative anemia and polyclonal increase in IgG at immunofixation electrophoresis were also present. Vascular endothelial growth factor (VEGF) dosage was normal. A diagnosis of HOA secondary to a paraneoplastic syndrome was made.

The patient started therapy with colchicine, nonsteroidal anti-inflammatory drugs and opioids with no pain control obtained. She then tried corticosteroids with no success and began methotrexate 10-20 mg/week. Methotrexate was helpful almost exclusively for periosteal pain, but not for knee arthritis. After 6 months, the combination of hydroxychloroquine 400 mg/day permitted her to stop opioids. Local infiltrations in the knees with steroids were also performed, with an improvement in the painful symptoms.

Discussion

To our knowledge, reported cases of HOA as a paraneoplastic syndrome associated with thyroid cancer are very rare. Only 2 cases are present in the literature. The first was described in 1984 by Dexemple et al. [4]: a young woman with HOA associated with an undifferentiated fusiform cell thyroid cancer with mediastinal extension. Indeed, thyroid sarcoma could not be excluded. HOA regressed somewhat after surgery and treatment with indomethacin, but persisted. The second case was found by Vico et al. [5] in 1992: a 42-year-old man with anaplastic thyroid carcinoma and extensive metastatic dissemination in the lung, brain and adrenals. He developed symmetrical arthritis, arthralgia and digital clubbing, and imaging showed the typical periosteal apposition of HOA. The rheumatological disease was unresponsive to treatment. In both cases the authors hypothesized the presence of a circulating factor to explicate the pathogenesis of HOA.

These 2 cases are very different from our patient; they were both undifferentiated thyroid cancers from the outset and the second patient had distant metastases. In our patient, the typical finding of X-rays, magnetic resonance, bone scintigraphy and the negativity of all rheumatological markers confirmed the diagnosis of paraneoplastic syndrome. We excluded the primary form because her familial history was negative. In addition, VEGF, which is today the best candidate in the pathogenesis of HOA, was in the normal range. Therefore, we assumed that the very fast dedifferentiation of thyroid cancer could have created the production of one or more soluble circulating factors responsible for HOA.

The pathogenesis of HOA, in fact, still remains unclear. To date, VEGF seems to play a key role [6]. It produces vascular hyperplasia, edema and fibroblast/osteoblast proliferation which are all clubbing histologic characteristics.

The role of platelet-derived growth factor was suggested [7], but its implication was not confirmed in earlier studies. The release of platelet-derived growth factor in response to an accumulation of megakaryocyte fragments or platelet aggregates in the lung capillary network could increase vascularity, permeability and mesenchymal cell growth, and promote new bone formation and clubbing [8].

The role of prostaglandins is still under study, too. Prostaglandin E₂ is a potent stimulus of VEGF-mediated osteoblast activation and bone formation, and could explicate the proliferative periostitis. It is likely that all these factors act simultaneously on HOA pathogenesis [4,9].

The role of hemoptysis remains unclear. The origin of bleeding and HOA could be the same: a not clearly identified factor responsible for the increased vascularity and blood vessel permeability causing both of the clinical manifestations. On the other hand, hemoptysis might be a side effect of radiotherapy or be caused by microscopic tumor invasion. After various treatment regimens, we were able to reduce the patient's pain. The management of secondary HOA consists of cancer-directed therapy associated with standard pain treatments. In patients with refractory disease, bisphosphonates (zoledronic acid) and localized palliative radiation have been reported to be effective [10]. A well-standardized treatment is lacking because paraneoplastic HOA is rare; however, rheumatological paraneoplastic syndromes are of major clinical importance because they have a significant impact on the quality of life and morbidity of affected patients. In addition, as the number of patients with cancer grows, and as these patients live longer, the incidence of paraneoplastic syndromes will most likely increase.

Acknowledgments

We thank L. Chami and V. Magnano San Lio for the help in the interpretation of radiological images.

Disclosure Statement

All authors declare they have no conflicts of interest.