Oncocytic carcinoma of the thyroid is a rare disease, characterized by a poor prognosis and low response rate to radioiodine therapy. Crizotinib is a specific anaplastic lymphoma kinase (ALK) inhibitor, which was initially developed in non-small cell lung cancer. Other solid tumors harboring a translocation in ALK have been described, such as renal carcinoma, thyroid, colorectal, ovarian cancers, and spitzoid melanoma. The research of ALK rearrangements in thyroid tumor is a promising therapeutic track, and treatments need to be explored.

We report the case of a 76-year-old woman with a history of multinodular goiter, who was hospitalized for impairment of her general condition. She was diagnosed with metastatic oncocytic thyroid cancer. Synchrone metastases were found: Multiple mediastinal lymphadenopathies, lytic bone lesions and bilateral mammary lumps. Fluorescence in situ hybridization analysis revealed an ALK rearrangement in 61% of cells. No other mutation was found. A tumor board discussion based on molecular characteristics of the tumor suggested initiating a daily treatment by crizotinib, a specific ALK inhibitor. A positron emission tomography scan performed 4 mo after the initiation of crizotinib showed a complete metabolic response.

This case highlights an unexpected efficacy of crizotinib in an ALK-rearranged thyroid tumor, and the need of further assessments.

Since 1980, the incidence of thyroid cancer has strongly increased, despite a recent decrease in the number of female cases. Each year, around 63000 new cases of thyroid cancer are diagnosed worldwide, leading to 2820 deaths. Thanks to initial diagnoses made at an earlier stage, the overall survival (OS) of patients with thyroid cancer has recently improved. The 5-year OS rate expended from 83% to 95% in the early 2000s[1].

Oncocytic tumors of the thyroid, also known as Hürthle cell tumors, are rare. The frequency of this tumor is actually unknown[2]. Hürthle (oncocytic) cell tumors are neoplasms composed of oncocytic cells. Non-invasive cases are called Hürthle cell adenomas, and cases with capsular or vascular invasion are called Hürthle cell carcinomas[3]. Follicular neoplasms can be composed in part by Hürthle cells and considered as Hürthle cell tumors only if more than 75% of the tumor is composed of Hürthle cells[4]. Oncocytic cells are large, polygonal cells with marked eosinophilic, granular cytoplasm reflective of overly abundant mitochondria[5]. Metastatic dissemination involves both blood and lymph nodes - contrasting with follicular carcinoma. Oncocytic carcinomas are characterized by a poor prognosis when compared to other differentiated thyroid carcinomas[6-8].

Papillary thyroid carcinoma cases with Hürthle cell changes are likely to have higher rates of recurrence (28% vs 11%)[9]. A SEER database cohort study showed that 25-year OS rates reached 82.1% and 89.1% in both populations, respectively[10].

In 1994, the anaplastic lymphoma kinase (ALK) gene was discovered through the identification of its fusion with nucleophosmin-1 (NPM1) in anaplastic large cell lymphomas[11]. In 2007, Hiroyuki Mano and colleagues[12] discovered a novel ALK fusion echinoderm-microtubule-associated protein-like 4 (referred to as EML4) that was found in a small percentage of Japanese lung cancers. ALK can be activated by translocation, as well as by mutation at the ALK locus, most commonly within the kinase domain, as reported in patients with thyroid cancer[13].

Crizotinib is a specific ALK inhibitor, which was initially developed in non-small cell lung cancer (NSCLC). The phase III study PROFILE 1014 compared crizotinib with chemotherapy as a first-line treatment in patients with advanced ALK-positive non-squamous NSCLC. The median progression-free survival was significantly better with crizotinib than chemotherapy [10.9 mo vs 7.0 mo, respectively, with hazard ratio of 0.45 and 95% confidence interval (CI) of 0.35, 0.60]. The objective response rates reached 74% and 45%, respectively. As compared with chemotherapy, crizotinib was associated with a greater reduction in lung cancer-related symptoms and a greater improvement in quality of life[14,15].

Other solid tumors harboring a translocation in ALK have been described, such as renal carcinoma, thyroid, colorectal, ovarian cancers, and spitzoid melanomas[16]. The identification of ALK rearrangements in thyroid tumors is highly promising. It has been reported that administration of crizotinib led to tumor stability in 1 case of advanced aggressive papillary cancer and to a response rate of 90% in 1 case of anaplastic thyroid cancer; both tumor responses lasted more than 6 mo[17,18]. We will present herein the case of a complete tumor response in 1 case of metastatic oncocytic thyroid cancer. Informed written consent was obtained from the patient for publication of this report and any accompanying images.

Based on the molecular and anatomical features found, we made a diagnosis of oncocytic carcinoma of the thyroid with nodes, breast and bone metastasis, with a rearrangement of ALK.

A multidisciplinary tumor board discussion, based on molecular characteristics of the tumor, suggested initiating a daily treatment of crizotinib (500 mg per day, taken as 250 mg in the morning and the night). The treatment was well tolerated, and the physical condition improved. No vision disorder, nausea, diarrhea, pneumonitis, hepatotoxicity or skin toxicity was reported. The patient complained of grade 2 constipation. No dose reduction or interruption was required.

The PET scan performed 4 mo after the initiation of crizotinib showed a complete metabolic response with no thyroid, pulmonary, nodal or visceral hypermetabolic spot but with multiple condensing bone metastases on most of the skeleton without significant hypermetabolism (scar lesions) (Figure 2). The patient presented a complete response according to RECIST criteria.

Open in New Tab   Full Size Figure   Download Figure

Figure 2 Comparison between baseline positron emission tomography scans (A, left) and after 4 mo of crizotinib treatment (B, right). A: Before treatment, thyroid, pulmonary, ganglion and bone hypermetabolic spots; B: Complete metabolic response with condensing bone metastases without significant hypermetabolism.

Two months later, the patient experienced a loss of balance that caused multiple falling episodes and a frontal syndrome with logorrhea and disinhibition. The cerebral scan revealed multiple supra and infra tentorial nodules suggestive of brain metastases for which whole brain radiotherapy (WBRT) has been indicated. Crizotinib was stopped during WBRT delivering 30 Gy in 10 fractions that resulted in a stability of the cerebral lesions. However, the patient’s condition stayed fragile with remaining walking and behavioral disorders, which prevented us from starting a new line of anticancer treatment. The patient died after 3 mo of palliative care.

To the best of our knowledge, we report herein the first complete metabolic response in an ALK-rearranged oncocytic tumor of the thyroid (Figure 3).

Open in New Tab   Full Size Figure   Download Figure

Figure 3 Timeline of the case history, treatment, and clinical outcome.

This new approach is interesting, as the current recommended treatment for disseminated oncocytic tumors is radioiodine, which is associated with a lower response rate than other thyroid carcinomas[19,20]. Oncocytic carcinoma is a rare type of cancer with a higher postoperative recurrence rate (28% vs 11%, P < 0.0001) and a poorer cause-specific mortality rate than papillary thyroid carcinoma (1.7% vs 4%, P < 0.0005)[16,19]. The cumulative rate of recurrence or death within 5 years after initial diagnosis of a stage III–IV disease reaches 74% in women and 91% in men, respectively[21].

Recently, understanding of the molecular pathogenesis of thyroid cancer leads to increased interest in tyrosine kinase-targeted therapy. Mutations in several oncogenes and tumor suppressor genes have been described, including the BRAF, RAS, PIK3CA, and APC genes[22,23]. In 2014, a patient diagnosed with anaplastic thyroid cancer showing an ALK rearrangement experienced an excellent response rate to crizotinib, reaching up to a 90% reduction in tumor size across all pulmonary lesions[18]. Oncocytic tumors with an ALK rearrangement have not been described extensively in the literature. Our rationale for using crizotinib in this situation was based on the following arguments.

First, disseminated oncocytic thyroid cancers are known to have poor prognoses and are likely less avid to radioactive iodine compared to papillary thyroid cancer[10,20]. The SEER study from 1988 to 2009 identified 3311 patients with oncocytic tumors who were less likely to undergo total thyroidectomy than patients with other thyroid carcinomas (P = 0.028). Absence of surgery and an existence of metastatic disease were factors independently associated with a worse prognosis in this population (hazard ratio of > 3.0, 95%CI of 1.89-6.38)[10]. A study published in 2003 showed that radioactive iodine therapy may confer a survival benefit when it is used for adjuvant ablation therapy but not when residual or metastatic disease is present. Survival benefits for the use of extensive surgery, external beam radiation therapy, or chemotherapy by doxorubicin, cisplatin or the two drugs together could not be demonstrated[24].

Second, we followed the “AcSé crizotinib” phase II study, promoted by the French National Cancer Institute, which encouraged secure access to innovative treatments for 235 patients with malignant disease harboring a molecular target such as ALK, MET or ROS1[25].

Third, crizotinib is a specific ALK inhibitor recommended at that time as a first-line treatment in NSCLC with ALK rearrangement[14]. Finally, this targeted therapy showed unexpected responses in 2 cases of aggressive papillary and anaplastic thyroid cancers, respectively[17,18].

Despite this encouraging response, this case report presents some limitations. On this unique case, there is a lack of evidence to generalize and no possibility to establish cause-effect relationship.

Biology-driven decisions should be enhanced, especially for patients suffering from rare tumors with bad clinical prognosis who could benefit from the screening of oncogenic molecular targets. Further studies are warranted to confirm our findings, with comparison with standard of care treatment.

In this case report, the patient developed secondary cerebral lesions after 7 mo under crizotinib. A study showed that crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor-naïve and had asymptomatic brain metastases (systemic disease control: 63%, 95%CI: 54%, 72%, intracranial disease control; 56%, 95%CI: 46%, 66% at 12 wk). However, progression of pre-existing or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib. Twenty percent of the patients without baseline brain metastases and whose tumor progressed under crizotinib were finally diagnosed with brain metastases[26,27]. A new approach could be undertaken with alectinib, which recently showed better intracranial responsiveness[28], superior efficacy and lower toxicity[29,30] compared to crizotinib (central nervous system response rate for alectinib of 81% with 95%CI: 58-95 and for crizotinib of 50% with 95%CI: 28-72) in primary treatment of ALK-positive NSCLCs.

This case reports unexpected and dramatic efficacy of crizotinib in a thyroid tumor with an ALK rearrangement. A comparison of crizotinib with standard radio iodine as a first therapeutic option in this indication still needs to be assessed. More studies are required to confirm clinical treatments for this rare and aggressive disease.

We thank Mrs. Fabienne Vaillant for her help in editing the manuscript.