Familial Cancer DOI 10.1007/s10689-015-9816-x
ORIGINAL ARTICLE
Follicular variant of papillary thyroid cancer in Alstro¨m syndrome M. Papadakis1 • A. Meyer1 • F. Schuster1 • N. Weyerbrock1 • C. Corinth2 • C. Dotzenrath1
Ó Springer Science+Business Media Dordrecht 2015
Abstract Alstro¨m syndrome (AS) is an autosomal recessive disorder, characterized by cone-rod dystrophy, sensorineural hearing loss, obesity, hyperinsulinemia with insulin resistance, type 2 diabetes mellitus and progressive pulmonary, hepatic and renal dysfunction. AS is caused by mutations in the ALMS1 gene, located on the short arm of chromosome 2. We report a 35-year-old woman with known history of AS, who developed a follicular variant of papillary thyroid carcinoma. To our knowledge this is the first association of AS with thyroid malignancy, among the approximately 450 cases reported since the first description of the syndrome. We conclude that papillary thyroid carcinoma should be considered in the differential diagnosis of thyroid nodules in patients with AS. Keywords Thyroid cancer Alstro¨m syndrome Follicular variant of papillary thyroid carcinoma Thyroid goitre
Introduction Alstro¨m syndrome (AS) is a rare multisystemic autosomal recessive disorder with a prevalence of 1.4 cases per million in the general population. It is characterized by cone-
& M. Papadakis [email protected] 1
Department of Endocrine Surgery, Helios Klinikum Wuppertal, University Hospital Witten-Herdecke, Heusnerstr. 40, 42283 Wuppertal, Germany
2
Department of Pathology, Helios Klinikum Wuppertal, University Hospital Witten-Herdecke, Heusnerstr. 40, 42283 Wuppertal, Germany
rod dystrophy, sensorineural hearing loss, obesity, hyperinsulinemia with insulin resistance, type 2 diabetes mellitus and progressive pulmonary, hepatic and renal dysfunction [1]. It was named after Carl-Henry Alstro¨m, a Swedish psychiatrist who first described the syndrome in 1959 [2]. AS is caused by a variety of mutations in the gene ALMS1, located on chromosome 2p13, including insertions, deletions and nonsense mutations leading to altered protein truncations. In 2007, Marshall et al. [3] suggested diagnostic criteria that still serve as the most reliable criteria for clinicians. Their diagnostic tool is based on the occurrence of ALMS1 mutations together with the presence of specific age-dependent primary and secondary clinical features, mainly vision disorders, hearing loss, obesity and/or insulin resistance. Herein, we report a 35-year-old woman with known history of AS, who developed a follicular variant of papillary thyroid carcinoma (FVPTC). AS is extremely rarely associated with malignancy. To our knowledge thyroid cancer is not previously reported in association with AS. The related literature is discussed.
Case presentation A 35-year-old woman with a history of Alstro¨m syndrome (AS) was referred to our institute with a steadily growing thyroid goitre. At the age of 9 months the patient developed nystagmus and by the age of 13 she was diagnosed with bilateral sensorineural hearing loss of unknown origin. At the age of 27 she developed type 2 diabetes mellitus and 2 years later she became completely blind. Finally, diagnosis of Alstro¨m syndrome was confirmed at the age of 32 by the identification of the c8911C[T (p.Gln2971X) mutation in exon 8 in the ALMS1 gene.
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The thyroid goitre was first observed in 2011. Thyroid ultrasound showed a 2 cm well-defined cyst in the right upper pole and a nodule, measuring 41 mm in maximum diameter, in the left lower pole. Technetium scan confirmed the presence of a cold nodule in the lower pole of the left lobe. Nodule aspiration and histological examination was negative for malignancy. Two years after the nodule aspiration, the patient presented to our department with a gradually growing cervical mass and local compression symptoms. At the time of the referral the patient was blind, deaf, and obese. She had history of type 2 diabetes mellitus, hypertension, no signs of cardiac failure and her medications included Metformin, 1000 mg twice daily and Candesartan, 8 mg twice daily. The patient did not have exposure to ionizing radiation. Physical examination revealed palpable bilateral thyroid nodules without cervical lymphadenopathy. Laboratory tests showed normal TSH (1.5 mIU/l; normal range 0.4–3.5 mIU/l), free T4 levels within normal limits (10.5 pmol/l; normal range 9–22.7 pmol/l) and free T3 levels within normal limits (6.2 pmol/l; normal range 2.8–7.2 pmol/l). Calcitonin levels were \2 pg/ml (normal range \10 pg/ml) and anti-TPO antibodies were also negative. Serum calcium, phosphorus and parathyroid hormone levels were also in normal ranges. Thyroid ultrasound showed a 3 cm hypoechogenic homogeneous nodule on the right lower lobe and an 6 cm hypoechogenic, heterogeneous mass with irregular margins on the left upper lobe, without any evidence of lymphatic invasion. Thyroid scintigraphy after intravenous injection of 76MBq Tc-99m-PTT demonstrated areas with decreased tracer uptake (‘‘cold’’ nodules), at the site of the palpable nodular structures. The patient underwent thyroidectomy. The histological examination revealed extensive fibrotic infiltration and an encapsulated follicular variant of papillary thyroid cancer (EnFVPTC, to distinguish from the diffuse FVPTC type) with surgical margins free of cancer. The disease was classified as pT2, N0, R0. The patient did not take levothyroxine for 4 weeks post-operatively. The pre-ablative TSH level was 21 mU/l (normal range 0.27–4.2 mU/l). The patient received 3.618 GBq radioactive iodine. The post-ablative serum thyreoglobulin level was 10 ng/ml (normal range\1 ng/ml), showing hypothyroidism, and a substitution therapy with levothyroxine, 150 lg once daily, was introduced. Four months later she underwent a whole body scintigraphy with 0.411 GBq radioactive iodine, which was negative. Thyreoglobulin levels also returned to normal range.
Discussion Alstro¨m syndrome is an autosomal recessive disorder caused by mutations in ALMS1 gene. Patients with AS suffer from progressive retinal dystrophy leading to
123
blindness, hearing impairment, obesity, insulin resistance, type 2 diabetes mellitus and dilated cardiomyopathy with heart failure. The syndrome was first described in 1959 and the current literature contains 450 published cases [4]. With a prevalence of 1.4 cases per million in the general population, AS ‘falls within the EU rare disease definition of a prevalence of not more than 5 affected persons per 10,000 population’ [5]. The AS causative gene, ALMS1 gene, consisting of 23 exons, encodes a protein of unknown function. The disease-cause variants are primarily clustered in exon 8, as our case, exon 10, and exon 16. Currently, 239 different ALMS1 mutations have been identified, the majority of which are nonsense and frameshift (insertions or deletions) mutations [1, 6]. Our patient was hemi-/homozygous for a mutation of the ALMS1 gene in exon 8 (c8911C[T, p.Gln2971*). To the best of our knowledge this mutation has not been reported before [6]. ALMS1 protein is located in centrosomes and ciliary basal bodies of most tissues affected in AS, explaining the wide range of phenotypical variability. Recent studies have implicated its role in ciliogenesis and cellular quiescence [7]. An underlying ciliary dysfunction, due to mutation in BBS genes, is the cause of Bardet–Biedl syndrome with similar phenotype. Current evidence suggests that deregulation of cilia and ciliary dysfunction may correlate closely with cancer through multiple signaling pathways [8]. Our patient at the time of the referral had most of the AS clinical features and developed an encapsulated follicular variant of papillary thyroid cancer [9]. The follicular variant counts for approximately 10 % of PTC [10]. The association of PTC variants with distinct genetic syndromes is not unknown in the literature. Thus, the cribriform-morular PTC variant is associated with familial adenomatosous polyposis, whereas the follicular variant is correlated with germline PTEN mutations, responsible for follicular epithelial proliferations [11]. A review of the literature revealed only two other cases of AS associated with malignancy, including a 39-year-old female patient with a well differentiated endometroid adenocarcinoma of the ovary [12] and a 11-year-old boy, younger of two siblings, who developed acute lymphoblastic leukemia, confirmed by cytochemistry and immunophenotyping findings [13]. Interestingly, our patient was diagnosed at 35 years, whereas Zidan et al., reported a median age at diagnosis of 44 years in a retrospective series of 100 patients with FVPTC [14]. Nevertheless, in our case, as well as in the above mentioned works, it is not clear that the malignancies represent a true association or a simple coincidence, since more and more individuals with AS are surviving longer. The increased risk of cancer including pancreatic, liver, breast, colorectal, urinary tract, gastric and female
Follicular variant of papillary thyroid cancer in Alstro¨m syndrome
reproductive cancers among diabetic patients is well documented in the existing literature [15]. However, the increased risk of thyroid cancer among diabetic patients remains controversial. Several mechanisms for such a possible link have been proposed, including elevated TSH, glucose, triglycerides, insulin resistance, obesity and vitamin D deficiency [16, 17]. Antidiabetic medications, especially sulfonylureas are also assumed to increase the risk of thyroid cancer in the diabetic patients. Furthermore, patients with diabetes duration \5 years seem to have a significantly lower thyroid cancer risk [18]. Our patient, at the time of referral, was already 8 years under antidiabetic treatment with Metformin (Fig. 1). Histologically, it is difficult to differentiate EnFVPTC from follicular thyroid carcinoma. The diagnosis is generally based on the presence of the typical follicular architectural pattern, along with the typical nuclear features of PTC [10]. In difficult cases, specific immunohistochemical and molecular markers can be used to prevent misdiagnosis with follicular adenomas and follicular carcinomas [9]. In our case, the identification of follicles, together with cytologic features of PTC (enlarged nuclei with nuclear clearing) and tumor capsule invasion were adequate enough to establish the diagnosis. Extensive fibrosis was also observed, as multiorgan fibrotic infiltration is common in AS patients [1]. Encapsulated follicular pattern lesions with PTC nuclear features can also be seen in benign lesions, i.e. follicular adenoma (FA) with equivocal PTC nuclear lesions. For this reason, Kakudo et al. [19] proposed the necessity for a unified nomenclature of all encapsulated follicular pattern lesions with equinoval PTC nuclear features, malignant and benign, in a distinct category of borderline malignancy,
Fig. 1 Follicular variant of papillary carcinoma in our patient with Alstro¨m syndrome: Large colloid-filled follicles, translucent nuclei with irregular outlines and inclusions
suggesting the term ‘‘well-differentiated tumor of uncertain malignant potential’’ [20]. FVPTC has a similar prognosis to PTC, but a greater risk for distant metastasis and vascular invasion, especially the diffuse type [21]. In our patient, no vascular invasion was observed and the patient is disease-free 9 months postoperatively. In conclusion, we have reported a patient with a known history of AS who developed a FVPTC. To our knowledge this is the first reported association of AS with thyroid malignancy. Therefore, PTC should be considered in the differential diagnosis of thyroid nodules in patients with AS. Conflict of interest
The authors declare no conflicts of interest.
Compliance with ethical standards The manuscript complies to the Ethical Rules applicable for this journal. Informed consent Informed consent was obtained by patient concerning the present publication.
References 1. Marshall JD, Maffei P, Collin GB, Naggert JK (2011) Alstrom syndrome: genetics and clinical overview. Curr Genomics 12(3):225–235. doi:10.2174/138920211795677912 2. Alstrom CH, Hallgren B, Nilsson LB, Asander H (1959) Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence–Moon–Bardet–Biedl syndrome: a clinical, endocrinological and genetic examination based on a large pedigree. Acta Neurol Scand Suppl 129:1–35 3. Marshall JD, Beck S, Maffei P, Naggert JK (2007) Alstrom syndrome. Eur J Hum Genet 15(12):1193–1202. doi:10.1038/sj. ejhg.5201933 4. Sheck L, Al-Taie R, Sharp D, Vincent A (2011) Alstrom syndrome—an uncommon cause of early childhood retinal dystrophy. BMJ Case Rep. doi:10.1136/bcr.06.2011.4388 5. Farmer A, Ayme S, de Heredia ML et al (2013) EURO-WABB: an EU rare diseases registry for Wolfram syndrome, Alstrom syndrome and Bardet–Biedl syndrome. BMC Pediatr 13:130. doi:10.1186/1471-2431-13-130 6. Marshall JD, Muller J, Collin GB et al (2015) Alstro¨m syndrome: mutation spectrum of ALMS1. Hum Mutat. doi:10.1002/humu. 22796 7. Li G, Vega R, Nelms K et al (2007) A role for Alstro¨m syndrome protein, Alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet 3(1):e8. doi:10.1371/journal.pgen.0030008 8. Seeger-Nukpezah T, Little JL, Serzhanova V, Golemis EA (2013) Cilia and cilia-associated proteins in cancer. Drug Discov Today Dis Mech 10(3):e135–e142 9. Lloyd RV, Buehler D, Khanafshar E (2011) Papillary thyroid carcinoma variants. Head Neck Pathol 5(1):51–56. doi:10.1007/ s12105-010-0236-9 10. Becker KL (2001) Principles and practice of endocrinology and metabolism. Lippincott Williams and Wilkins, Philadelphia, p 385 11. Winer DA, Winer S, Rotstein L, Asa SL, Mete O (2012) Villous papillary thyroid carcinoma: a variant associated with marfan syndrome. Endocr Pathol 23(4):254–259. doi:10.1007/s12022012-9219-6
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M. Papadakis et al. 12. Moberg E, Hjerpe E, Ehrsson R, Mo¨ller C, Angelin B (2009) Is endometroid cancer of the ovaries a late manifestation of Alstro¨m syndrome? J Intern Med 265(2):296–298 13. Chen B-H, Chiou S-S, Tsai R-K, Lin Y-F, Wu J-R (2000) Acute lymphoblastic leukemia in one of two siblings with Alstrom syndrome. J Formos Med Assoc 99(10):792–795 14. Zidan J, Karen D, Stein M, Rosenblatt E, Basher W, Kuten A (2003) Pure versus follicular variant of papillary thyroid carcinoma. Cancer 97(5):1181–1185. doi:10.1002/cncr.11175 15. Xu CX, Zhu HH, Zhu YM (2014) Diabetes and cancer: associations, mechanisms, and implications for medical practice. World J Diab 5(3):372–380. doi:10.4239/wjd.v5.i3.372 16. Shih SR, Chiu WY, Chang TC, Tseng CH (2012) Diabetes and thyroid cancer risk: literature review. Exp Diab Res 2012:578285. doi:10.1155/2012/578285
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17. Sahin M, Ucan B, Ginis Z et al (2013) Vitamin D3 levels and insulin resistance in papillary thyroid cancer patients. Med Oncol (Northwood, London, England) 30(2):589. doi:10.1007/s12032013-0589-5 18. Tseng CH (2012) Thyroid cancer risk is not increased in diabetic patients. PLoS One 7(12):e53096. doi:10.1371/journal.pone. 0053096 19. Kakudo K, Bai Y, Liu Z, Ozaki T (2012) Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer. Pathol Int 62(3):155–160. doi:10.1111/j.1440-1827.2011.02773.x 20. Kakudo K, Bai Y, Liu Z, Li Y, Ito Y, Ozaki T (2012) Classification of thyroid follicular cell tumors: with special reference to borderline lesions. Endocr J 59(1):1–12 21. Oertli D, Udelsman R (2012) Surgery of the thyroid and parathyroid glands. Springer, Berlin
ORIGINAL ARTICLE
Follicular variant of papillary thyroid cancer in Alstro¨m syndrome M. Papadakis1 • A. Meyer1 • F. Schuster1 • N. Weyerbrock1 • C. Corinth2 • C. Dotzenrath1
Ó Springer Science+Business Media Dordrecht 2015
Abstract Alstro¨m syndrome (AS) is an autosomal recessive disorder, characterized by cone-rod dystrophy, sensorineural hearing loss, obesity, hyperinsulinemia with insulin resistance, type 2 diabetes mellitus and progressive pulmonary, hepatic and renal dysfunction. AS is caused by mutations in the ALMS1 gene, located on the short arm of chromosome 2. We report a 35-year-old woman with known history of AS, who developed a follicular variant of papillary thyroid carcinoma. To our knowledge this is the first association of AS with thyroid malignancy, among the approximately 450 cases reported since the first description of the syndrome. We conclude that papillary thyroid carcinoma should be considered in the differential diagnosis of thyroid nodules in patients with AS. Keywords Thyroid cancer Alstro¨m syndrome Follicular variant of papillary thyroid carcinoma Thyroid goitre
Introduction Alstro¨m syndrome (AS) is a rare multisystemic autosomal recessive disorder with a prevalence of 1.4 cases per million in the general population. It is characterized by cone-
& M. Papadakis [email protected] 1
Department of Endocrine Surgery, Helios Klinikum Wuppertal, University Hospital Witten-Herdecke, Heusnerstr. 40, 42283 Wuppertal, Germany
2
Department of Pathology, Helios Klinikum Wuppertal, University Hospital Witten-Herdecke, Heusnerstr. 40, 42283 Wuppertal, Germany
rod dystrophy, sensorineural hearing loss, obesity, hyperinsulinemia with insulin resistance, type 2 diabetes mellitus and progressive pulmonary, hepatic and renal dysfunction [1]. It was named after Carl-Henry Alstro¨m, a Swedish psychiatrist who first described the syndrome in 1959 [2]. AS is caused by a variety of mutations in the gene ALMS1, located on chromosome 2p13, including insertions, deletions and nonsense mutations leading to altered protein truncations. In 2007, Marshall et al. [3] suggested diagnostic criteria that still serve as the most reliable criteria for clinicians. Their diagnostic tool is based on the occurrence of ALMS1 mutations together with the presence of specific age-dependent primary and secondary clinical features, mainly vision disorders, hearing loss, obesity and/or insulin resistance. Herein, we report a 35-year-old woman with known history of AS, who developed a follicular variant of papillary thyroid carcinoma (FVPTC). AS is extremely rarely associated with malignancy. To our knowledge thyroid cancer is not previously reported in association with AS. The related literature is discussed.
Case presentation A 35-year-old woman with a history of Alstro¨m syndrome (AS) was referred to our institute with a steadily growing thyroid goitre. At the age of 9 months the patient developed nystagmus and by the age of 13 she was diagnosed with bilateral sensorineural hearing loss of unknown origin. At the age of 27 she developed type 2 diabetes mellitus and 2 years later she became completely blind. Finally, diagnosis of Alstro¨m syndrome was confirmed at the age of 32 by the identification of the c8911C[T (p.Gln2971X) mutation in exon 8 in the ALMS1 gene.
123
M. Papadakis et al.
The thyroid goitre was first observed in 2011. Thyroid ultrasound showed a 2 cm well-defined cyst in the right upper pole and a nodule, measuring 41 mm in maximum diameter, in the left lower pole. Technetium scan confirmed the presence of a cold nodule in the lower pole of the left lobe. Nodule aspiration and histological examination was negative for malignancy. Two years after the nodule aspiration, the patient presented to our department with a gradually growing cervical mass and local compression symptoms. At the time of the referral the patient was blind, deaf, and obese. She had history of type 2 diabetes mellitus, hypertension, no signs of cardiac failure and her medications included Metformin, 1000 mg twice daily and Candesartan, 8 mg twice daily. The patient did not have exposure to ionizing radiation. Physical examination revealed palpable bilateral thyroid nodules without cervical lymphadenopathy. Laboratory tests showed normal TSH (1.5 mIU/l; normal range 0.4–3.5 mIU/l), free T4 levels within normal limits (10.5 pmol/l; normal range 9–22.7 pmol/l) and free T3 levels within normal limits (6.2 pmol/l; normal range 2.8–7.2 pmol/l). Calcitonin levels were \2 pg/ml (normal range \10 pg/ml) and anti-TPO antibodies were also negative. Serum calcium, phosphorus and parathyroid hormone levels were also in normal ranges. Thyroid ultrasound showed a 3 cm hypoechogenic homogeneous nodule on the right lower lobe and an 6 cm hypoechogenic, heterogeneous mass with irregular margins on the left upper lobe, without any evidence of lymphatic invasion. Thyroid scintigraphy after intravenous injection of 76MBq Tc-99m-PTT demonstrated areas with decreased tracer uptake (‘‘cold’’ nodules), at the site of the palpable nodular structures. The patient underwent thyroidectomy. The histological examination revealed extensive fibrotic infiltration and an encapsulated follicular variant of papillary thyroid cancer (EnFVPTC, to distinguish from the diffuse FVPTC type) with surgical margins free of cancer. The disease was classified as pT2, N0, R0. The patient did not take levothyroxine for 4 weeks post-operatively. The pre-ablative TSH level was 21 mU/l (normal range 0.27–4.2 mU/l). The patient received 3.618 GBq radioactive iodine. The post-ablative serum thyreoglobulin level was 10 ng/ml (normal range\1 ng/ml), showing hypothyroidism, and a substitution therapy with levothyroxine, 150 lg once daily, was introduced. Four months later she underwent a whole body scintigraphy with 0.411 GBq radioactive iodine, which was negative. Thyreoglobulin levels also returned to normal range.
Discussion Alstro¨m syndrome is an autosomal recessive disorder caused by mutations in ALMS1 gene. Patients with AS suffer from progressive retinal dystrophy leading to
123
blindness, hearing impairment, obesity, insulin resistance, type 2 diabetes mellitus and dilated cardiomyopathy with heart failure. The syndrome was first described in 1959 and the current literature contains 450 published cases [4]. With a prevalence of 1.4 cases per million in the general population, AS ‘falls within the EU rare disease definition of a prevalence of not more than 5 affected persons per 10,000 population’ [5]. The AS causative gene, ALMS1 gene, consisting of 23 exons, encodes a protein of unknown function. The disease-cause variants are primarily clustered in exon 8, as our case, exon 10, and exon 16. Currently, 239 different ALMS1 mutations have been identified, the majority of which are nonsense and frameshift (insertions or deletions) mutations [1, 6]. Our patient was hemi-/homozygous for a mutation of the ALMS1 gene in exon 8 (c8911C[T, p.Gln2971*). To the best of our knowledge this mutation has not been reported before [6]. ALMS1 protein is located in centrosomes and ciliary basal bodies of most tissues affected in AS, explaining the wide range of phenotypical variability. Recent studies have implicated its role in ciliogenesis and cellular quiescence [7]. An underlying ciliary dysfunction, due to mutation in BBS genes, is the cause of Bardet–Biedl syndrome with similar phenotype. Current evidence suggests that deregulation of cilia and ciliary dysfunction may correlate closely with cancer through multiple signaling pathways [8]. Our patient at the time of the referral had most of the AS clinical features and developed an encapsulated follicular variant of papillary thyroid cancer [9]. The follicular variant counts for approximately 10 % of PTC [10]. The association of PTC variants with distinct genetic syndromes is not unknown in the literature. Thus, the cribriform-morular PTC variant is associated with familial adenomatosous polyposis, whereas the follicular variant is correlated with germline PTEN mutations, responsible for follicular epithelial proliferations [11]. A review of the literature revealed only two other cases of AS associated with malignancy, including a 39-year-old female patient with a well differentiated endometroid adenocarcinoma of the ovary [12] and a 11-year-old boy, younger of two siblings, who developed acute lymphoblastic leukemia, confirmed by cytochemistry and immunophenotyping findings [13]. Interestingly, our patient was diagnosed at 35 years, whereas Zidan et al., reported a median age at diagnosis of 44 years in a retrospective series of 100 patients with FVPTC [14]. Nevertheless, in our case, as well as in the above mentioned works, it is not clear that the malignancies represent a true association or a simple coincidence, since more and more individuals with AS are surviving longer. The increased risk of cancer including pancreatic, liver, breast, colorectal, urinary tract, gastric and female
Follicular variant of papillary thyroid cancer in Alstro¨m syndrome
reproductive cancers among diabetic patients is well documented in the existing literature [15]. However, the increased risk of thyroid cancer among diabetic patients remains controversial. Several mechanisms for such a possible link have been proposed, including elevated TSH, glucose, triglycerides, insulin resistance, obesity and vitamin D deficiency [16, 17]. Antidiabetic medications, especially sulfonylureas are also assumed to increase the risk of thyroid cancer in the diabetic patients. Furthermore, patients with diabetes duration \5 years seem to have a significantly lower thyroid cancer risk [18]. Our patient, at the time of referral, was already 8 years under antidiabetic treatment with Metformin (Fig. 1). Histologically, it is difficult to differentiate EnFVPTC from follicular thyroid carcinoma. The diagnosis is generally based on the presence of the typical follicular architectural pattern, along with the typical nuclear features of PTC [10]. In difficult cases, specific immunohistochemical and molecular markers can be used to prevent misdiagnosis with follicular adenomas and follicular carcinomas [9]. In our case, the identification of follicles, together with cytologic features of PTC (enlarged nuclei with nuclear clearing) and tumor capsule invasion were adequate enough to establish the diagnosis. Extensive fibrosis was also observed, as multiorgan fibrotic infiltration is common in AS patients [1]. Encapsulated follicular pattern lesions with PTC nuclear features can also be seen in benign lesions, i.e. follicular adenoma (FA) with equivocal PTC nuclear lesions. For this reason, Kakudo et al. [19] proposed the necessity for a unified nomenclature of all encapsulated follicular pattern lesions with equinoval PTC nuclear features, malignant and benign, in a distinct category of borderline malignancy,
Fig. 1 Follicular variant of papillary carcinoma in our patient with Alstro¨m syndrome: Large colloid-filled follicles, translucent nuclei with irregular outlines and inclusions
suggesting the term ‘‘well-differentiated tumor of uncertain malignant potential’’ [20]. FVPTC has a similar prognosis to PTC, but a greater risk for distant metastasis and vascular invasion, especially the diffuse type [21]. In our patient, no vascular invasion was observed and the patient is disease-free 9 months postoperatively. In conclusion, we have reported a patient with a known history of AS who developed a FVPTC. To our knowledge this is the first reported association of AS with thyroid malignancy. Therefore, PTC should be considered in the differential diagnosis of thyroid nodules in patients with AS. Conflict of interest
The authors declare no conflicts of interest.
Compliance with ethical standards The manuscript complies to the Ethical Rules applicable for this journal. Informed consent Informed consent was obtained by patient concerning the present publication.
References 1. Marshall JD, Maffei P, Collin GB, Naggert JK (2011) Alstrom syndrome: genetics and clinical overview. Curr Genomics 12(3):225–235. doi:10.2174/138920211795677912 2. Alstrom CH, Hallgren B, Nilsson LB, Asander H (1959) Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence–Moon–Bardet–Biedl syndrome: a clinical, endocrinological and genetic examination based on a large pedigree. Acta Neurol Scand Suppl 129:1–35 3. Marshall JD, Beck S, Maffei P, Naggert JK (2007) Alstrom syndrome. Eur J Hum Genet 15(12):1193–1202. doi:10.1038/sj. ejhg.5201933 4. Sheck L, Al-Taie R, Sharp D, Vincent A (2011) Alstrom syndrome—an uncommon cause of early childhood retinal dystrophy. BMJ Case Rep. doi:10.1136/bcr.06.2011.4388 5. Farmer A, Ayme S, de Heredia ML et al (2013) EURO-WABB: an EU rare diseases registry for Wolfram syndrome, Alstrom syndrome and Bardet–Biedl syndrome. BMC Pediatr 13:130. doi:10.1186/1471-2431-13-130 6. Marshall JD, Muller J, Collin GB et al (2015) Alstro¨m syndrome: mutation spectrum of ALMS1. Hum Mutat. doi:10.1002/humu. 22796 7. Li G, Vega R, Nelms K et al (2007) A role for Alstro¨m syndrome protein, Alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet 3(1):e8. doi:10.1371/journal.pgen.0030008 8. Seeger-Nukpezah T, Little JL, Serzhanova V, Golemis EA (2013) Cilia and cilia-associated proteins in cancer. Drug Discov Today Dis Mech 10(3):e135–e142 9. Lloyd RV, Buehler D, Khanafshar E (2011) Papillary thyroid carcinoma variants. Head Neck Pathol 5(1):51–56. doi:10.1007/ s12105-010-0236-9 10. Becker KL (2001) Principles and practice of endocrinology and metabolism. Lippincott Williams and Wilkins, Philadelphia, p 385 11. Winer DA, Winer S, Rotstein L, Asa SL, Mete O (2012) Villous papillary thyroid carcinoma: a variant associated with marfan syndrome. Endocr Pathol 23(4):254–259. doi:10.1007/s12022012-9219-6
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M. Papadakis et al. 12. Moberg E, Hjerpe E, Ehrsson R, Mo¨ller C, Angelin B (2009) Is endometroid cancer of the ovaries a late manifestation of Alstro¨m syndrome? J Intern Med 265(2):296–298 13. Chen B-H, Chiou S-S, Tsai R-K, Lin Y-F, Wu J-R (2000) Acute lymphoblastic leukemia in one of two siblings with Alstrom syndrome. J Formos Med Assoc 99(10):792–795 14. Zidan J, Karen D, Stein M, Rosenblatt E, Basher W, Kuten A (2003) Pure versus follicular variant of papillary thyroid carcinoma. Cancer 97(5):1181–1185. doi:10.1002/cncr.11175 15. Xu CX, Zhu HH, Zhu YM (2014) Diabetes and cancer: associations, mechanisms, and implications for medical practice. World J Diab 5(3):372–380. doi:10.4239/wjd.v5.i3.372 16. Shih SR, Chiu WY, Chang TC, Tseng CH (2012) Diabetes and thyroid cancer risk: literature review. Exp Diab Res 2012:578285. doi:10.1155/2012/578285
123
17. Sahin M, Ucan B, Ginis Z et al (2013) Vitamin D3 levels and insulin resistance in papillary thyroid cancer patients. Med Oncol (Northwood, London, England) 30(2):589. doi:10.1007/s12032013-0589-5 18. Tseng CH (2012) Thyroid cancer risk is not increased in diabetic patients. PLoS One 7(12):e53096. doi:10.1371/journal.pone. 0053096 19. Kakudo K, Bai Y, Liu Z, Ozaki T (2012) Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer. Pathol Int 62(3):155–160. doi:10.1111/j.1440-1827.2011.02773.x 20. Kakudo K, Bai Y, Liu Z, Li Y, Ito Y, Ozaki T (2012) Classification of thyroid follicular cell tumors: with special reference to borderline lesions. Endocr J 59(1):1–12 21. Oertli D, Udelsman R (2012) Surgery of the thyroid and parathyroid glands. Springer, Berlin
