Three cases of thyroid cancer following the diagnosis of testicular cancer: treatment-related complication or genetics?

Abstract

Large-scale epidemiological studies have shown that the incidence of second primary thyroid cancer in subjects diagnosed and treated for testicular cancer is raised. This finding is strongly associated to treatment with radiotherapy and/or chemotherapy and it is explained by their mutagenic effect. On the other hand, inherited cancer susceptibility syndromes inducing both testicular and thyroid cancers denote that these tumours might share common genomic aberrations. We herein present our experience with three cases of metachronous development of thyroid cancer after diagnosis and treatment of testicular cancer in our tertiary cancer centre. Our case report contributes to the limited available literature on such findings and aims to raise awareness of the cancer physicians treating these particular tumour types.

Keywords

Testicular cancer thyroid cancer chemotherapy radiotherapy genetics

Introduction

Both testicular and thyroid cancers are relatively uncommon malignancies in British men, being 16th and 20th most common with regard to incidence, respectively.¹ Germ cell tumours comprise 95% of tumours arising in the testes and are divided into seminomas and non-seminomas. Non-seminomas are further sub-classified into embryonal carcinoma, choriocarcinoma, yolk sac tumour and teratoma types, though a combination of all these histologies can be found in a primary tumour.² Thyroid cancers are predominantly differentiated (papillary, follicular and Hurthle); with less common subtypes the medullary and anaplastic carcinomas.³

There is currently limited knowledge as to the aetiology of both of these cancers. Testicular cancer has been shown to be associated with cryptorchidism, subfertility and a family history of testicular cancer.⁴ The only identified exogenous risk factor for thyroid cancer, in particular papillary carcinoma, is neck radiation, particularly in childhood.⁵ Despite there being no common risk factors implicated in the development of both cancers, there has been a small number of cases reported in the literature of men presenting with both testicular and thyroid cancers.^6,7 At the Beatson West of Scotland Cancer Centre (WoSCC, a tertiary cancer centre), three similar cases were noted; herein, these will be presented and explored.

Materials and methods

The cases currently reported in the literature focus mainly on the synchronous presentation of both tumour types. We decided to take a more general approach and include patients in our records who have ever had a diagnosis of both testicular and thyroid cancer in their lifetime.

The medical records of three patients diagnosed with both testicular and thyroid cancer at the Beatson (WoSCC) between May 2001 and December 2014 were examined.

Results

Case 1

A 42-year-old male presented in August 2012 with groin discomfort and a lump in his left testis. He underwent an orchidectomy, the pathology of which showed the presence of a mixed germ-cell tumour comprising of embryonal carcinoma (malignant teratoma undifferentiated) with a single focus of seminoma. Rete testis was involved and there was prominent lymphovascular invasion. Pre- and post-operative serum alpha-fetoprotein (AFP) and beta human chorionic gonadotrophin (β-HCG) were both within normal limits, however a staging scan showed aorta-caval and para-aortic lymphadenopathy of less than 2 cm in size. Final staging was confirmed as T2 N1 M0. (Good prognosis group by International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification.)⁸

The patient’s past medical history comprised of renal calculi and a vasectomy seven years prior to diagnosis. He had completed his family with two children. He was a lifelong non-smoker and drank 6–8 units of alcohol/week. The patient’s mother died of metastatic breast cancer at the age of 46 and there was uncertainty about the prevalence of other cancers within his family.

Three cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy were completed in October 2012. Treatment was tolerated well with no delays or dose reductions, with grade one peripheral neuropathy as the only adverse event. An end-of-treatment computed tomography (CT) scan showed sub centimetre residual lymphadenopathy with para-aortic and aorto-caval lymph nodes of 4 mm and 5 mm, respectively. No further treatment was required and he was thereafter followed-up in the germ-cell clinic in accordance to the good prognosis non-seminomatous germ-cell tumours follow-up schedule.

However, five months after, in March 2013, he presented in clinic with increasing fatigue and a new nodule on the left side of his neck which on examination was found to originate from the thyroid gland. Tumour markers (a-FP and β-HCG) were normal and chest imaging (X-ray) did not reveal any sinister intrapulmonary features. Fine needle aspiration (FNA) of the mass was suspicious of a thyroid neoplasm and the patient went on to have a left hemi-thyroidectomy, which revealed a 15 mm papillary thyroid carcinoma (pT1b) with no extra-thyroid extension or malignant nodes. Following on from this, a completion thyroidectomy was performed and a 1 mm micro-papillary tumour was detected too. He thereafter underwent adjuvant treatment with radioactive iodine ablation (I¹³¹), which he tolerated well – this was completed in May 2013. He was offered a referral to the clinical genetic services on several occasions but has not accepted this to date.

The patient is currently being monitored in both germ cell and thyroid cancer clinics with no clinical or biochemical evidence of disease recurrence two years after completion of most recent treatment.

Case 2

A 27-year-old male presented in May 2001 with a swollen right testicle. Inguinal orchidectomy was performed and histological examination demonstrated a mixed germ-cell tumour with predominantly undifferentiated embryonal carcinoma (malignant undifferentiated teratoma) with a focus of yolk sac-like differentiation and two satellite foci of seminoma in association with intratubular germ-cell neoplasia. Lymphovascular invasion was also present. Radiology excluded distant metastases and final staging was T2 N0 M0. Both AFP and β-HCG were normal pre- and post-orchidectomy. On the basis of high-risk stage 1 disease, adjuvant chemotherapy with two cycles of BEP was indicated.

There was no significant past medical history. The patient was a non-smoker, drank alcohol only socially and had no children at the time. Paternal family history was unknown. His mother had no history of cancer herself, however his maternal grandfather died of pancreatic cancer in his early 60 s and his maternal uncle died of bowel cancer.

Treatment with two cycles of BEP chemotherapy was completed in June 2001 with no significant toxicities. The patient required testosterone replacement for hypogonadism but otherwise his follow-up was unremarkable for the most part.

Approximately eleven and a half years after, in January 2013, during a routine follow-up appointment the appearance of a small palpable left abdominal lesion was noted and a re-staging scan was organised to exclude disease recurrence. The abdominal lesion had features of a lipoma but surprisingly, the scan also demonstrated a 45 mm × 33 mm nodal mass arising deep within the left sternocleidomastoid muscle and extending up to the hyoid bone with associated enlarged pre-tracheal lymph nodes and a 9 mm lesion in the lower lobe of the left lung. Positron emission tomography CT (PET-CT) confirmed that all these lesions were fluorodeoxyglucose (FDG) avid and it additionally detected a metabolically active left thyroid nodule. An ultrasound-guided FNA of the mass was highly suspicious of papillary thyroid cancer and the patient went on to have a total thyroidectomy and left neck dissection with central compartment clearance. Histology showed a pT3pN1 papillary carcinoma of the thyroid; Four out of 21 nodes were involved with extracapsular spread. After surgery, the patient received radioactive iodine ablation and on his post treatment iodine scan there was no residual uptake. The previous identified lung nodule remained unchanged and sub centimetre under CT evaluation for two years and throughout treatment; thus considered to be non-metastatic.

The patient was also reviewed by the clinical geneticists. Mild macrocephaly and the presence of multiple lipomas were noted. In view of these findings, he underwent mutational analysis for Cowden syndrome and Carney complex (CNC) but no pathogenic mutation was identified. The patient has been followed-up since and has been free of recurrence of either tumour.

Case 3

A 36-year-old man presented in May 2004 to his general practitioner with a mass in his right testicle which had malignant features on ultrasound scan. Furthermore, AFP and β-HCG were both found to be raised. He underwent an orchidectomy in June 2004, the pathology of which showed a mixed germ cell tumour. A large component of this was classical seminoma though there were two separate nodules showing malignant teratoma undifferentiated. Pagetoid spread into the right testis and epididymis was noted. Tumour markers normalised post-orchidectomy and CT imaging excluded distal metastatic spread.

The patient had no significant past medical history other than mild osteoarthritis of the right knee and chronic anxiety disorder. He had a nine-year-old son. He was an ex-smoker and drank alcohol only occasionally. He had no family history of malignancy.

Two cycles of adjuvant BEP chemotherapy were administrated – as per high-risk stage 1 disease – and treatment was completed in September 2004 with no significant toxicities.

The patient remained asymptomatic for approximately five years. In August 2009 however, he complained of neck pain during his follow-up. A neck MRI demonstrated a cystic lesion in the right oropharynx, posterior to the tonsil. FNA biopsy of the lesion showed this to be a papillary carcinoma of the thyroid. It was initially unclear whether this was metastatic papillary carcinoma or ectopic malignant thyroid tissue; however the former was believed to be the most likely scenario. The patient underwent total thyroidectomy that showed multifocal papillary carcinoma, completely excised. Surgery was followed by radioactive iodine ablation (I¹³¹), which led to complete eradication of the disease.

In March 2012, while being reviewed by the Neurological team for non-epileptic seizures, it was noted that he had high prolactin levels. A subsequent MRI of the pituitary fossa showed an empty sella with asymmetry and slight enlargement of the right lobe of the hypophysis in keeping with a microadenoma, and the diagnosis of a prolactin-secreting microadenoma was established.

Following this, he was referred to clinical genetics and was investigated for germline PTEN gene (phosphatase and tensin homolog gene) mutation. Both whole gene sequencing and multiplex ligation-dependent probe amplification were negative for sequence variants and/or deletion/duplications of the PTEN gene, excluding effectively Cowden or Cowden-like syndromes. He has remained well throughout subsequent follow-up and has no disease recurrence to date.

Discussion

The key similarity between all cases presented here is that all of them pertain to young males diagnosed primarily with a non-seminomatous germ cell tumour of the testis and a metachronous papillary thyroid tumour. All men underwent orchidectomy and received chemotherapy of the same regimen albeit at different cumulative doses (3 cycles of 3 day BE₅₀₀P versus 2 cycles of 3 day BE₃₆₀P regimens). On the other hand, the diagnosis of thyroid cancer happened at different time intervals. In case one, the thyroid cancer occurred within five months of completion of chemotherapy whereas in case two and three, it occurred after approximately 12 and 5 years, respectively.

These three interesting cases unavoidably raised the question of possible association between these neoplasms. Although one would argue that the intense medical surveillance of testicular cancer survivors could falsely raise the frequency of diagnosing a second primary, we aimed to perform a literature search to investigate whether,

The mutagenic treatment for germ-cell tumours increases the risk of developing secondary thyroid neoplasia and whether.

The two neoplasms share a common genetic aberration underlying their biology.

Epidemiological studies of second cancers in survivors of testicular cancer have shown overall that the risk of thyroid cancer is elevated (Table 1). A study of almost 29,000 testicular cancer survivors – diagnosed between 1935 and 1993 – quantified the risk of developing thyroid cancer at approximately threefold (observed/expected numbers of second malignant neoplasms = 2.92, 95% CI = 1.76–4.57, two sided p < 0.05). However this was in an era of different treatment strategies when radiation played a more pivotal role in the management of non-seminomatous germ-cell tumours; the radiation fields were wider and the cytotoxic agents differed from the contemporary ones.⁹

Table 1.

Epidemiological studies on secondary cancer occurrences on long-term cancer survivors.

Authors	Year	Number of patients	Number of secondary neoplasms	Risk of secondary cancer – statistic
Travis et al.¹⁰	2005	40,576 testicular cancer patients	2285 secondary solid cancers	Relative risk at 10 years 1.9 (p value not available) Relative risk at 35 years 1.7 (p < 0.001)
Travis et al.	2007	29,000 testicular cancer patients	1406 secondary solid cancers	Observed-to-expected ratio 1.43 (95%CI 1.36–1.51)
Veiga et al.¹³	2012	12,547 patients treated with chemotherapy	119 thyroid cancers	Cumulative incidence 1.3% for females (CI 1.0–1.6) and 0.6% for males (CI 0.4–0.8)
Fung et al.¹¹	2013	12,691 testicular cancer (6013 received chemotherapy)	210 secondary solid tumours	Standardised incidence ratio 1.43 after chemotherapy (CI 1.18–1.73)

The detrimental effect of radiotherapy on thyroid tissue has been established with a statistical analysis on an even larger cohort of patients (40,576) which demonstrated a relative risk (RR) = 3.1 (95% CI 1.2–6.7) of developing thyroid cancer after radiotherapy treatment alone for testicular cancer, again during an era when germ-cell anticancer treatments were based on aggressive radiotherapy dosing and schedules.¹⁰ This, however, remains a surprising and interesting finding given that the radiation fields of the afore-mentioned treatments rarely expand above T10 vertebra.

With regard to the association of chemotherapy to secondary malignant neoplasms (SMNs), Fung et al. conducted a study in 2013. The results of this study demonstrated a high standardised incidence ratio (SIR) of second primary thyroid cancers in patients with non-seminomatous germ-cell tumours who were treated with chemotherapy only (SIR = 4.4, 95%CI 2.19–7.88, p < 0.05)¹¹ and these data pertain to patients who received Cisplatin-based chemotherapy. It is also worth mentioning that 91% of these thyroid neoplasms were papillary carcinomas, similarly to the aforementioned cases in our centre. On the other hand, patients treated with surgery only did not exhibit a statistically significant occurrence of thyroid SMNs. The well-known chronic retention of DNA-platinum adducts and their detection in multiple organs – including thyroid – even years post completion of chemotherapy should not be dismissed as a culprit in the cases presented here.¹²

Juvenile thyroid tissue is exceedingly sensitive to DNA damage secondary to radiotherapy, a lesson learned from children with leukaemia receiving prophylactic cranial irradiation. Furthermore, a study carried out on 12,000 childhood cancer survivors who were treated with various combinations of cytotoxics (alkylating agents, anthracyclines, bleomycin, epipodophyllotoxins and platinum compounds) demonstrated that even without the use of radiotherapy, treatment with particular agents confers a higher risk of future thyroid neoplasia.¹³ Interestingly, the risk adjusted for the use of bleomycin was RR = 4.6 (95% CI 1.3–15.8, p = 0.02). When risk was adjusted for bleomycin in combination with other therapeutics, such as alkylating agents, the risk was even higher at RR = 5.5 (95% CI 1.1–40.3, p = 0.03). Although this study was carried out on non-testicular cancer survivors, it may provide some rational for the increased risk of thyroid cancer after management of testicular cancer where combination of Bleomycin with various DNA damaging agents are widely used.

A few rare inherited syndromes that can cause both thyroid and testicular tumours have been recognised and described in the literature.

Carney Complex (CNC) is one such example of this and is a dominantly inherited syndrome primarily associated with inactivating mutations of the PRKAR1A gene. PRKAR1A is located on 17q22-24 chromosome and is a key regulator of the cAMP-signalling pathway owing to its tumour suppressor gene properties. The classical clinical manifestations are spotty pigmentation, cardiac myxomas and over-activation of multiple endocrine cells leading to tumours such as thyroid and testicular tumours.¹⁴ Thirty-three to fifty-six per cent of CNC patients have testicular tumours (mainly non germ cell cancers such as large-cell calcifying sertoli cell tumours) and 10–25% of them have thyroid tumours. Pathogenic sequence variants in PRKAR1A have only been found in approximately 62% of CNC patients and CNC patients with no detectable PRKAR1A mutation tend to present later in life with more variable phenotypes.¹⁵ More recently, genomic deletions encompassing PRKAR1A have been associated with CNC and a second susceptibility locus on chromosome 2 has previously been suggested by linkage.¹⁶ Mutations in two cAMP-binding phosphodiesterases, PDE11A and PDE8B have also been found in patients with CNC and micro nodular adrenocortical disease; with germline PDE11A mutation being particularly associated with testicular cancer risk.¹⁷ The identification of these new genes within the cAMP-signalling pathway supports the importance of this pathway in the development of a number of tumour types.¹⁸

Cowden syndrome belongs to a group of syndromes occurring secondary to germline mutations of the PTEN tumour suppressor gene, an important regulator of Akt-mTOR pathway, controlling cell growth and proliferation. It is characterised by mucocutaneous manifestations and breast, thyroid or endometrial neoplasias.¹⁹ Moreover, there have been case reports described in the literature of testicular tumours in patients known to have Cowden syndrome.²⁰ Macrocephaly and one of the most commonly observed neoplasms in Cowden (such as breast, thyroid and endometrial) justify genetic testing for germline PTEN mutation.

Cowden syndrome was excluded for both our case 2 and 3 patients and so was CNC for our case 2.

Studies so far have failed to show any shared environmental risk factor between both testicular and thyroid cancer. Although we acknowledge that the occurrence of both thyroid and testicular cancer in our cases may have risen due to serendipity, we believe oncologists need to have a low threshold for investigating thyroid abnormalities in testicular cancer survivors who have received either radiation or chemotherapy treatment. Clearly, more research needs to be conducted towards identifying susceptibility genes underpinning the development of testicular and thyroid cancers and syndromes such as Cowden and Carney may provide the biological niche for this research.

Conclusion

Second primary thyroid cancers are a recognised risk in patients previously diagnosed and treated for testicular cancer. Cancer physicians should be alert to this risk.

Both genetic predisposition and treatment-related mutagenic effect could be accounted responsible for this risk.

Syndromes related to the over activation of the PI3K/AkT/mTOR and c-AMP signalling pathways (Figure 1) could provide a platform to help research on the reasons underlying the link between these two neoplasms.

Figure 1.

The c-AMP signalling pathway. The activation of G-protein coupled receptor (GPCR) by an extracellular ligand leads to the release of the a subunit from the activated intracellular heterotrimeric G protein complex and the activation of the enzyme adenylyl cyclase (AC). AC catalyses the conversion of ATP into cyclic adenosine monophosphate (cAMP). Increases in concentration of the intracellular cAMP leads to the activation of the enzyme protein kinase alpha (PKA). Once PKA is activated, it phosphorylates a number of other proteins including transcription factors that upregulate expression of genes that mediate uncontrolled cell proliferation and subsequent tumorigenesis.

Footnotes

Authors’ contribution

Dr Pavlina Spiliopoulou and Dr Sarah Pauline Bowers contributed equally to the work needed for this report. Dr Jeff White and Professor Nick Reed were the senior co-authors.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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