by Danielle R. Lazzara, DO; Sonya G. Zarkhin, DO; Samuel N. Rubenstein, BS; and Brad P. Glick, DO, MPH, FAOCD, FAAD
Dr. Lazzara is a Dermatology Resident (PGY-4) at Larkin Community Hospital Palm Springs, Lake Erie College of Osteopathic Medicine in Hialeah, Florida. Dr. Zarkhin is a Dermatology Resident (PGY-3) at Saint Barnabas Hospital, New York College of Osteopathic Medicine Educational Consortium in The Bronx, New York. Mr. Rubenstein is with The University of Texas at Austin in Austin, Texas. Dr. Glick is the Dermatology Residency Director at Larkin Community Hospital Palm Springs, Lake Erie College of Osteopathic Medicine in Hialeah, Florida, and Glick Skin Institute in Margate, Florida.
FUNDING: No funding was provided for this study.
DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article.
Melanoma is listed among the most common cancers in the United States, with new cases increasing steadily.1 Due to the aggressive nature of melanoma and its high risk of metastasis, early detection and treatment is essential. It is noted that the majority of unresectable and metastatic melanomas are BRAF V600-mutated.2 Recently, rates of papillary thyroid carcinoma have also been increasing. Studies have indicated BRAF V600-mutations are common in papillary thyroid carcinoma, second only to melanoma. The BRAF mutation in thyroid carcinoma similarly portends more aggressive behavior. The association between melanoma and thyroid disease was noted in several patients in our clinic and fueled our literature review in an attempt to better understand this clinical observation. A systematic English-language literature review was performed using PubMed Central and ScienceDirect online databases. Search parameters included articles published from January 2000 to July 2018 and key search terms were melanoma and thyroid carcinoma and BRAF mutation and thyroid cancer. The initial search yielded 2,470 and 234 articles in each respective database. Articles that lacked relevant information were excluded. The literature we reviewed supports our theory that thyroid dysfunction is disproportionately noted among patients with a history of melanoma. In order to detect disease early, it is critical for dermatologists, internists, family practitioners, endocrinologists, and oncologists to be aware of the association between these two primary malignancies when proceeding with appropriate screening examinations.
KEYWORDS: Melanoma, thyroid carcinoma, papillary thyroid carcinoma, thyroid stimulating hormone, BRAF mutation
J Clin Aesthet Dermatol. 2019;12(9):39–41
The incidence of cutaneous melanoma and papillary thyroid carcinoma (PTC) has increased steadily in the past few decades.1 As of 2017, 87,110 new cases of melanoma and 9,730 deaths related to melanoma were reported in the United States.2 Studies have observed that patients with malignant melanoma are at an increased risk for developing other primary cancers, and much interest has been directed toward the association between melanoma and thyroid carcinoma.1–3 Gretchen et al3 identified a 2.3-fold increase in the development of PTC in patients with a history of cutaneous melanoma. Conversely, those with PTC were found to have a 1.8-fold increased risk of developing melanoma.
Compared to the general population, the presence of hypothyroidism in patients with malignant melanoma is statistically significantly higher (p<0.001).4 Ellerhorst et al5 investigated whether thyroid stimulating hormone (TSH), which is characteristically elevated in patients with thyroid failure, acts as a growth factor for melanoma cells.5 TSH receptors (TSHR) are reportedly expressed by all cutaneous melanocytic nevi, with higher expression in dysplastic nevi and melanomas, respectively.4–5 This expression of TSHR in cultured melanoma cells was demonstrated by immunofluorescence, western blot, and reverse-transcriptase-PCR.5 Evidence also shows TSHR to be functional in melanoma, as TSH activates several pathways via formation of cAMP. These TSHR signaling pathways downstream of cAMP include protein kinase A, mitogen-activated protein (MAP) kinase, and phosphatidylinositol 3-kinase, which are critical in the development of melanoma.5 Thus, it has been postulated that the transformation of melanocytes into melanoma cells is influenced by the expression of TSH at a physiologically relevant concentration.5 Another postulated theory is that melanoma causes thyroid dysfunction with resultant hypothyroidism in affected patients.4
A key player in the link between melanoma and thyroid cancer is alteration of the MEK-ERK-MAP kinase pathway.3 BRAF mutations are reported in several human cancers, the most prevalent being melanoma (66%) and dysplastic nevi (82%). BRAF encodes a cytoplasmic serine-threonine kinase.2 In the last decade, BRAF mutations have been identified as the second most prevalent in thyroid carcinoma (36%–69%), particularly in aggressive subtypes of papillary thyroid cancer.1,6 BRAF missense mutations result in oncogenic activation of the MAP kinase pathway, which causes upregulation in cell division and proliferation leading to tumorigenesis. Specifically, the transversion of thymine (T) to adenine (A) at nucleotide 1799 (T1799A) BRAF mutation results in a V600E amino acid substitution (valine [V] to glutamic acid [E]) and constitutively activates BRAF kinase.2
Whole-genome sequencing studies have determined melanoma to be the most frequently mutated tumor type.2 BRAF mutations, similar to PTC, are seen in about one-half of advanced melanomas, with more than 97 percent of mutations shown to be located in codon 600. Even more so, in up to 90 percent of cases, T1799A results in the V600E mutation.2 This V600E BRAF mutation also portends a more aggressive behaving melanoma. Typical phenotypic manifestation of BRAF-mutated melanoma includes superficial spreading or nodular tumors occurring in younger individuals in areas of chronic sun damage.2,6
PTC has various histological subtypes, including conventional PTC, follicular-variant PTC, and tall-cell PTC, with the latter displaying the highest prevalence of BRAF mutation. Conventional PTC displays the second highest BRAF mutation prevalence. This order of BRAF prevalence in PTC subtypes (tall-cell>conventional>follicular) is consistent with the idea that BRAF mutation predicts aggressivity and prognosis.6
Other common genetic alterations associated with thyroid cancer that share the MAP kinase pathway include Ras and RET/PTC rearrangement mutations; however, these mutations display mutual exclusivity. BRAF mutation is not found in benign thyroid neoplasms, in contrast to Ras and RET/PTC mutations.3 It has been observed that melanoma also displays this mutual exclusivity.3 In regards to age, BRAF mutation is seen more commonly in adults, whereas RET/PTC has a higher incidence in children with PTC. Thus, old age is a predisposing factor for developing a BRAF mutation.3,6
In regards to thyroid dysfunction, T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is associated with a poor clinical-pathological outcome.2,6 Numerous studies have been performed evaluating BRAF mutation prognostic value and indicate that the mutation is associated with extrathyroidal invasion, advanced tumor stage, distant metastasis (especially to the cervical lymph nodes), and recurrence.6 Xing et al6 demonstrated these prognostic features associated with BRAF mutation PTC by multivariate analysis with adjustment for confounding factors. Similarly, BRAF mutation positive melanoma is more aggressive, with higher rates of tumor ulceration, Breslow depth, and lymphocytic infiltration.1,6 Thus, patients could present with advanced stage disease at the time of diagnosis in accordance with the American Joint Committee on Cancer TNM system; however, direct correlation between stage of melanoma and BRAF mutation has not been determined.1,2 There is also evidence to suggest that BRAF mutation influences disease progression. Sedliarou et al6 demonstrated that BRAF mutations were significantly increased in undifferentiated tumors compared to well differentiated PTC.
It has been observed that in thyroid cells, TSH up-regulates iodide-handling genes by acting on TSHR.7 The most important of the iodide handling genes is the sodium/iodide symporter (NIS), which transports iodide from the bloodstream intracellularly to synthesize thyroid hormone.7 BRAF mutation (MAP kinase activation) is associated with inhibition of thyroid iodide-handling genes and decreased radioiodine sensitivity.7 Phosphoinositide 3-kinase and Akt/Protein kinase B (PI3/Akt) pathway similarly has a role in regulating the expression of thyroid iodide-handling genes.7 Peng et al7 identified thyroid handling genes to be expressed in melanoma via inhibition of the MAP kinase and PI3/Akt pathways via dual targeting. Radioiodide uptake in melanoma cells could then theoretically be achieved by dual inhibition of pathways and used as a novel adjunct therapy to treat melanoma.7
With knowledge of the association between melanoma and thyroid cancer, physicians should consider routinely monitoring thyroid function in melanoma patients. In addition, patients with thyroid dysfunction should be informed of this association and encouraged to establish care with a dermatologist in order to be appropriately screened for melanoma through annual, full-body skin examinations. Additionally, T1799A BRAF mutation can be utilized as a specific cancer diagnostic marker, as it solely occurs in PTC, but not benign thyroid neoplasms.2–4 A positive BRAF mutation analysis on fine needle aspiration biopsy (FNAB) has perfect positive predictive value in diagnosing PTC. However, a negative mutation result is not diagnostic, as indeterminate cytology exists, in which about eight percent will reportedly be positive for BRAF mutation.2,4
In light of identifying a large percentage of melanomas with BRAF mutations, selective inhibitors of the BRAF V600-mutated kinase, vemurafenib and dabarafenib were developed, as well as the downstream MEK kinase inhibitors trametinib and cobimetinib.2 Combination of BRAF and MEK inhibitors have been shown to increase response and delay acquired resistance to therapy.2 It is now considered the standard of care to treat individuals with BRAF-mutated melanoma with combination therapy (dabrafenib+trametinib or vemurafenib+cobimetinib).2 Dual targeting of the MAP kinase and PI3/Akt pathway has also been evaluated and determined to have an antitumor effect, as opposed to single pathway suppression.7 The study by Peng et al noted dual targeting to synergistically cause cell death in melanoma. Dual pathway suppression also promotes expression of thyroid-iodide handling genes, which was found to be significantly enhanced by TSH in melanoma cells. Thus, melanoma could potentially be susceptible to radioiodine ablation, and this novel therapy could potentially be used in conjunction with other treatment modalities.7
In patients with advanced melanoma, determining BRAF mutation status has become the standard of care when selecting the most appropriate systemic therapy. Combination therapy with these drugs has tremendously improved survival rates in BRAF V600-mutant advanced melanoma.2 Furthermore, thyroid failure secondary to immunotherapy of melanoma is well noted in the literature and thought to occur as a result of cross-reactive antigens. These cross-reactive antigens might be TSHR, and could potentially be another effective therapeutic target.5 An alternative consideration includes suppression of TSH with thyroid hormone for patients with TSH-sensitive tumors and advanced disease.5 More studies evaluating these various avenues of targeted treatments need to be performed. Awareness of the association between melanoma and thyroid cancer and the respective aggressiveness of these BRAF mutation harboring malignancies highlights the critical nature of early detection. With early detection and development/utilization of targeted therapy, patient survival rates can be significantly improved.
- Oakley GM, Curtin K, Layfield L, et al. Increased melanoma risk in individuals with papillary thyroid carcinoma. JAMA Otoloaryngol Head Neck Surg. 2014;140(5):423–427.
- Cheng L, Lopez-Beltran A, Massari F, et al. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod Pathol. 2017;31(1): 24–38.
- Xu X, Quiros RM, Gattuso P, et al. High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Research. 2003;63:4561–4567.
- Kim CY, Lee SH, Oh CW. Cutaneous malignant melanoma associated with papillary thyroid cancer. Ann Dermatol. 2010;22(3):370–372.
- Ellerhorst JA, Sendi-Naderi A, Johnson MK, et al. Human melanoma cells express functional receptors for thyroid-stimulating hormone. Endocr Relat Cancer. 2006;13: 1269–1277.
- Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005;12:245–262.
- Hou P, Liu D, Ji M, et al. Induction of thyroid gene expression and radioiodine uptake in melanoma cells: novel therapeutic implications. PLoS ONE. 2009;4(7):e6200