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High prevalence of hypothyroidism in male patients with cutaneous melanoma

  • Author(s): Shah, Monica;
  • Orengo, Ida F;
  • Rosen, Ted
  • et al.
Main Content

High prevalence of hypothyroidism in male patients with cutaneous melanoma
Monica Shah MD, Ida F Orengo MD, and Ted Rosen MD
Dermatology Online Journal 12 (2): 1

Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas. vampireted@aol.com

Abstract

A recent study reported a higher than expected prevalence of hypothyroidism among patients with cutaneous melanoma. To further characterize and validate those findings, we conducted a retrospective review of the prevalence of hypothyroidism among all consecutive patients diagnosed with cutaneous melanoma in the dermatology clinic at the Michael E. DeBakey VA Medical Center (VAMC) in Houston, Texas. To accomplish this task, the electronic medical records of all patients diagnosed with cutaneous melanoma at the VAMC from January 2001 through October 2004 were examined for signs of hypothyroidism. Data regarding the site of melanoma and age at diagnosis were obtained for these hypothyroid cases and for age- and gender-matched euthyroid controls from the same melanoma cohort. Among 156 cutaneous melanoma patients (151 male and 5 female), 8 (5.1 %) showed a history of hypothyroidism [7 of 151 male (4.6 %) and 1 of 5 female (20 %)]. The prevalence of hypothyroidism among the male melanoma patients was significantly higher than that reported for the general population. The prevalence data concerning hypothyroidism among our female patients was not considered evaluable due to the primarily male distribution of our study population. We conclude that hypothyroidism (excluding iatrogenic etiologies) is frequent among male patients with cutaneous melanoma. Our results further suggest that a subset of melanoma tumors may respond to hormones of the hypothalamus-pituitary-thyroid axis, raising many questions that could influence the diagnosis, care, and treatment of a subset of melanoma patients.



Introduction

The lifetime probability for developing an invasive melanoma in the United States is currently 1 in 55 for males and 1 in 82 for females [1]. Approximately 55,100 new cases of invasive melanoma were diagnosed in the United States in 2004, with an overall 5-year survival rate for patients diagnosed with localized melanoma estimated to be about 97 percent [1]. Surgical excision of localized cutaneous melanoma can lead to a cure in many patients, however, there is currently no uniformly satisfactory therapy for patients presenting with melanoma metastatic to distant sites. These patients have a 14 percent 5-year survival rate with a median survival of about 6-9 months following diagnosis [1]. The pathogenesis of this disease depends on a multitude of factors including cytokines, growth factors, and tumor suppressors [2]. Despite an expanding body of knowledge regarding this malignancy, few novel, clinically useful nonsurgical therapies have been developed. Therefore, identifying groups of melanoma patients with biologically distinct tumors might offer insights into disease pathogenesis, diagnostic testing, or development of therapeutic options for patients afflicted with advanced disease.

Ellerhorst et al. recently reported a high prevalence of hypothyroidism among patients with cutaneous melanoma; among the 1,580 patients studied, the authors observed a 7 percent prevalence of hypothyroidism, with 2.4 percent of males and 13.9 percent of females so affected [2]. With an overall 4.6 percent prevalence of hypothyroidism in the general population, their results proved to be highly significant, leading one to question whether a pathophysiologic molecular interaction exists between melanoma and thyroid-related compounds. This pioneering work supported previous findings by the same group with regards to uveal melanoma [3]. The cumulative effect of these studies suggests the following line of questioning: if there is an interaction, how do the altered levels of hormones within the hypothalamic-pituitary-thyroid loop affect the growth of melanoma tumors?

To further characterize and validate these findings, we conducted a retrospective study of the prevalence of hypothyroidism among patients diagnosed with cutaneous melanoma at the Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas. We report a similar positive association, further suggesting that a subgroup of cutaneous melanoma patients with tumors exhibiting identifiable hormonal properties may well exist.


Methods

The study population consisted of all patients registered in the dermatology clinic at the MEDVAMC with the diagnosis of cutaneous melanoma during the 46-month period of January 2001 through October 2004. From this cohort, we identified patients with a history of clinically overt hypothyroidism (defined as a requirement for thyroid hormone replacement) and no other iatrogenic cause of hypothyroidism such as surgery or thyroid irradiation. Detailed review of the electronic medical records for each patient in the group identified these hypothyroid case subjects. In particular, each patient's problem list, medication list, and laboratory result for thyroid function tests were reviewed for signs of hypothyroidism. In select cases, several notes by the patient's primary care provider were also reviewed to verify the information obtained from the medical record. A control group was then selected from the same study population, consisting of individuals who were not receiving thyroid hormone replacement and who had no history of thyroid disease. Controls were frequency matched to cases at a 3:1 ratio, based on gender and within 2-year age groups at diagnosis. The medical records of all cases and controls were also examined for information regarding type of primary tumor, depth of invasion, location of tumor, and age at diagnosis.


Results


Study population

During the period from January 2001 through October 2004, there were 156 patients diagnosed with cutaneous melanoma in the Dermatology Clinic at MEDVAMC. This group, consisting of 151 males and 5 females, included all those patients referred to the dermatology service for evaluation and treatment of cutaneous melanoma.


Prevalence of hypothyroidism among the cutaneous melanoma population

A history of hypothyroidism, defined as a requirement for thyroid hormone replacement without a history of an iatrogenic etiology, was given by eight patients (5.1 %), including 20 percent of females and 4.6 percent of males. These numbers were compared to those reported in a large population-based study designed to examine the prevalence of overt and subclinical thyroid disease [4]. The overall prevalence of hypothyroidism in our melanoma patient population, as well as the prevalence in male and female subsets, was greater then expected with statistical significance (p < .001).

Table 1. Prevalence of hypothyroidism in the cutaneous melanoma population and comparison to the general population.
Melanoma &
Hypothyroid
NHANES III
Cases%%p-value
Total 8/156 5.1 4.6<0.001
Male 7/151 4.6 1.6<0.001
Female 1/5 20 7.4<0.001

Diagnosis dates of both hypothyroidism and melanoma were available for six patients. For four patients, the two conditions were diagnosed within a year of each other, and for two patients, the diagnosis of hypothyroidism preceded the melanoma diagnosis by more than 1 year.


Disease presentation

A case-control analysis was performed to determine if melanoma patients with a history of hypothyroidism differed from euthyroid melanoma patients in terms of site of disease. Age and gender matched controls were chosen at a 3:1 ratio for each hypothyroid case, except for the one female case because no controls could be identified for that patient. Hence, a total of 21 control subjects were selected for the eight cases. The cases and control populations are described in Table 2. A comparison of the two groups in terms of site of primary cutaneous tumor is described in Table 3. The calculated χ² for that data was 10.8 while the critical value (χ²0.05[3]) was 7.815, demonstrating that a difference did exist between the two groups in terms of site of primary cutaneous tumor. In this regard, hypothyroidism appeared to be more common among those with melanoma located on the head and neck as compared to other anatomical sites. However, because of the small number of cases and controls, we do not consider this conclusion to be reliably significant, but merely suggestive.

Table 2. Case and control populations
CaseControl
      n      (%)       n      (%)
No.      8       21
Gender
      Male      7      (87.5)      21      (100)
      Female      1      (12.5)       0       (0)
Dx age (years)
      Median           68.5            70
      Range            61-80            63-81

Table 3. Location of melanoma in case and control subjects.

Cases (n=8) Controls (n=21)

      n      (%)       n      (%)
Limb      2      (25.0)      8      (38.1)
Trunk      3      (37.5)      11      (52.4)
Head/Neck      3      (37.5)      2      (9.5)
Acral      0      (0.0)      0      (0.0)
      Calculated χ²=10.8, Critical Value of χ²0.05[3]=7.815


Discussion

This retrospective review was undertaken to explore if an increased prevalence of hypothyroidism was noted in patients diagnosed with cutaneous melanoma over a longer period of time than has been previously studied. Our results show that, amongst a predominantly male patient population seen at the MEDVAMC, cutaneous melanoma patients reporting to dermatologists for care demonstrate an overall prevalence rate of hypothyroidism greater than expected based upon statistics relating to the general population as reported by the NHANES III study, a large population-based investigation of various medical conditions, including thyroid disease. This study was the most appropriate reference population demographically because it assessed clinical and subclinical thyroid disease in 17,353 American adults [4]. Among this group, there were 820 individuals (4.6 % of study population) who reported a need for thyroid hormone replacement, a history of goiter or other thyroid disease leading to hypothyroidism [4]. We reported a 5.1% prevalence of hypothyroidism in our study group which is slightly higher than our reference population, and slightly less than that described in the study by Ellerhorst and co-workers [2]. We attribute this result to the fact that our case group was mostly male and only included patients currently on thyroid hormone replacement therapy and who do not have a history of iatrogenic hypothyroidism. The Ellerhorst study [2] included all patients on thyroid hormone replacement therapy regardless of the etiology of hypothyroidism, and therefore would be expected to demonstrate a higher prevalence of hypothyroidism. Nevertheless, when compared to the more broadly defined study groups noted in the NHANES III and Ellerhorst studies, our findings still show significance. Furthermore, we observed that the prevalence of hypothyroidism among our male patients is almost twice as high as noted in the prior study.

The limitations of this investigation include a smaller overall subject population in comparison to the Ellerhorst et al. study [2] and the primarily male distribution of the patients in our cohort. Consequently, we do not consider the 20 percent prevalence of hypothyroidism that we reported among females in our group to be significant, as our cohort included only five female patients. Furthermore, we were unable to identify any controls that were gender- and age-matched for the one female case of hypothyroidism in our study group, limiting our ability to gain any valuable information from the case-control analysis. The information obtained about site of primary cutaneous tumor was not reliably useful because of the small number of cases and controls. Additionally, we chose not to include any information regarding staging and disease presentation in the case-control analysis, as it was difficult to obtain accurate data for a majority of the patients.

The question evoked by these data involves the nature of interaction between cutaneous melanoma and hypothyroidism. There are two possible ways to look at this situation. Does the melanoma induce thyroid dysfunction leading to hypothyroidism, possibly through an autoimmune mechanism, or does the abnormal hormone environment in the setting of hypothyroidism predispose patients to the development of melanoma? Low circulating thyroid hormone levels and concomitantly elevated TSH levels are the diagnostic criteria of hypothyroidism. In this setting, elevated TSH could possibly drive the growth of transformed melanocytes; recent studies have shown that cultured melanoma cells express transcript mRNA for the TSH receptor [5]. The significance of thyrotropin releasing hormone (TRH), produced by the hypothalamus in response to low thyroid hormone levels, is also of interest because studies show that this tripeptide has affinity for the melanocortin 1 (MC1) receptor found on melanocytes [6]. Generally α-MSH, a product of the adrenal axis that shares no homology with TRH, binds to the MC1 receptor, where it is involved in pigmentation by stimulating melanocytes. However, TRH is generally found only in the hypothalamic-pituitary portal circulation, so to find significant amounts of TRH in systemic circulation on the level that could possibly stimulate melanocytes appears unlikely. However, if melanoma cells have the ability to produce TRH, it could function as an autocrine growth factor by binding to the MC1 receptor on melanoma cells. This supposition is supported by the recent discovery of the presence of immunoreactive TRH in preserved human melanoma tissue as well as demonstration of an in-vitro proliferative response of four of five melanoma cell lines (but not melanocyte cell lines) following exposure to low concentrations of exogenous TRH [7]. Another intriguing possibility is that immunostaining of pigmented lesions for TRH might help distinguish benign nevocellular nevi from dysplastic nevi and frankly malignant melanocytic tumors [7].

The potential clinical implications of the findings of this study, as well as prior similar investigations, are numerous. First of all, patients with hypothyroidism may have a greater risk of developing melanomas and consequently should be followed carefully with a higher level of suspicion for worrisome skin lesions. Secondly, it can be assumed that with this higher prevalence of overt hypothyroidism in melanoma patients, it is likely that the prevalence of subclinical hypothyroidism is also increased in these patients, possibly warranting the need for more aggressive thyroid screening for this subset of patients.


Conclusion

In conclusion, we report additional evidence that suggests an association between cutaneous melanoma and hypothyroidism in a select group of patients. Future studies might focus on how the presence or absence of hypothyroidism in melanoma patients affects overall survival rates to determine whether the association is detrimental or beneficial for patients.

Acknowledgments: The authors would like to thank Marian C. Gibson for her assistance in data collection.

References

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