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Thyroid pathology in four patients with Cowden’s disease
Pathology (August 2003) 35(4), pp. 311–314
ANATOMICAL PATHOLOGY
Thyroid pathology in four patients with Cowden’s disease CHRISTINE T. HEMMINGS Department of Anatomic Pathology, Canterbury Health Laboratories, Christchurch, New Zealand
Summary Cowden’s disease (multiple hamartoma syndrome) is a rare genodermatosis, which carries an increased risk of malignancy, especially breast and thyroid carcinoma. Thyroid disease is the most common internal manifestation of the syndrome, but the histological features in benign cases have hitherto been relatively poorly described. Thyroidectomy specimens from four patients with Cowden’s disease have been reported in our laboratory in recent years. A number of rather distinctive features were common to all, raising the possibility of a distinctive ‘Cowden’s thyroid’ phenotype. Key words: Thyroid, Cowden’s disease, multiple hamartoma syndrome, adenomatoid nodules, genodermatosis. Received 12 November 2002, revised 6 March 2003, accepted 10 March 2003
INTRODUCTION Cowden’s disease (multiple hamartoma syndrome) is a rare genodermatosis, which carries an increased risk of malignancy, especially breast and non-medullary thyroid carcinoma. However, the appearances of the thyroid in Cowden’s patients with benign disease have been poorly described. The pathological findings in the thyroids of four patients with Cowden’s disease, three of whom are siblings, are presented.
CASE REPORTS Thyroidectomy specimens from four patients with Cowden’s disease were reviewed. Three of the patients (II-1, II-2, and II-3) are brothers and are designated Family A (Fig. 1). Another brother (II-4) has Cowden’s disease, but has not yet undergone thyroidectomy; a sister (II-5) does not have the disease. II-2 has a son (III-1) who has the disease, and a daughter (III-2) who does not. The brothers were diagnosed after the death of both parents, and it is not known whether either parent manifested clinical features of the syndrome. II-2 and II-3 are also said to have ‘dysplastic naevus syndrome’, although it is not clear what diagnostic criteria have been used. However, both have undergone excision of multiple naevi, of which some have shown atypical features, and both have had invasive melanoma. Case 1 Patient II-1 is the oldest of the three brothers. Like his brothers, he is described as having poor dentition and a high arched palate, along with retrognathia and a retro-displaced tongue base. He also exhibits spinal kyphosis, facial papules and papillomatosis of the lips, gingiva, tongue and hard palate. He underwent total thyroidectomy at the age of 32, for multinodular goitre with obstructive symptoms. Other surgical specimens from this patient have included seven benign intradermal naevi, multiple
Fig. 1 Family A. Squares represent males, and circles females; open symbols indicate unaffected persons, solid symbols affected persons, and grey symbols uncertain status. A slash over the symbol denotes death. papillomatous/verruciform skin lesions, an angiokeratoma, an angioleiomyoma from the wrist and a cavernous haemangioma from the leg. He was noted to have a peripheral blood lymphopenia, and cell marker studies showed a normal CD4:CD8 ratio, with reduced absolute counts of both cell types. Case 2 Patient II-2 also has poor dentition and facial papules, and is similar in appearance to Patient II-3. He underwent thyroidectomy for ‘goitre’ aged 24, prior to the diagnosis of Cowden’s disease. Other surgical specimens from Patient II-2 have included three hamartomatous gastric polyps, three soft tissue fibromata, several papillomatous or verruciform skin lesions, an epidermoid cyst, a solar lentigo, a benign compound naevus, four dysplastic naevi, a melanoma in situ arising in a dysplastic naevus, and two malignant melanomas, both with a Breslow depth of 0.3 mm. Case 3 Patient II-3 underwent left hemithyroidectomy for a ‘toxic nodule’ at age 20. Completion thyroidectomy was performed 13 years later, and at age 39 a thyroglossal cyst was removed. Patient II-3 exhibits the facial papules, poor dentition and lingual papillomatosis that are characteristic of Cowden’s disease, together with kyphosis of the spine and a high arched palate. Other surgical specimens from this patient have included hamartomatous gastric and colonic polyps, four oesophageal papillomata, a dermatofibroma, seven benign intradermal naevi, four dysplastic naevi and a malignant melanoma, Clark’s Level II, Breslow depth 0.2 mm. Case 4 The patient from Family B is not related to the other three patients. He is one of 10 children, and was diagnosed with Cowden’s disease when he and his siblings underwent genetic testing following an older brother’s diagnosis. At 18 he underwent surgery for a left temporal lobe arteriovenous
ISSN 0031–3025 printed/ISSN 1465–3931 online/03/040311–04 # 2003 Royal College of Pathologists of Australasia DOI: 10.1080/0031302031000150533
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malformation. Thyroidectomy was performed for symptomatic thyroid enlargement at the age of 32.
PATHOLOGY Five thyroid excision specimens were reviewed, including separate right and left hemithyroidectomy specimens from II-3. The left hemi-thyroidectomy from Patient II-3 weighed 78 g and was reported in 1982 as ‘nodular hyperplasia of the thyroid’. The completion thyroidectomy in 1995 weighed 71.5 g. The diagnosis of multinodular goitre was rendered, although the original report comments on two relatively hypercellular nodules, which are described as possibly, but not definitely, representing true adenomata. On review, there are solid areas with columnar cell change, and some nodules with a microfollicular architecture show nuclear features similar to those seen in the specimens from the other three patients, and resemble the ‘adenomatoid nodules’ described by Harach et al.1 (see Discussion) (Fig. 2). In addition, there is patchy lymphoplasmacytic infiltration, but without germinal centre formation or oxyphilic metaplasia sufficient to warrant a diagnosis of Hashimoto’s thyroiditis. The total thyroidectomy from Patient II-2 was reported in 1998. The thyroid weighed 95 g and again the diagnosis was multinodular goitre. Note was made of nuclear clearing in some areas but this was considered nonneoplastic. Sampling was somewhat limited, but in retrospect, the ‘pseudo-papillary’ nuclear features are similar to those in the specimens from Patient II-1 and the patient from Family B (see below). In addition, one nodule showed features reminiscent of hyalinising trabecular tumour, although these features were less well developed than in the other cases, described below (Fig. 3). The specimens from Patient II-1 and from the patient from Family B are remarkably similar. Both show the typical appearances of multinodular goitre, but with some nodules showing unusual features. In some areas the cells show relative clearing of nuclear chromatin and have prominent nucleoli, reminiscent of papillary carcinoma. Some nodules show a predominantly microfollicular and solid architecture, whilst others are predominantly trabecular
Cowden’s disease Cowden’s disease was first described by Lloyd and Dennis in 1963,2 and was named after the propositus, who subsequently died of breast cancer at the age of 30.3 The clinical findings as first described included: adenoid facies with microstomia, mandibular and maxillary hypoplasia, high arched palate and hypoplasia of the soft palate and uvula; papillomatosis of the lips and oropharynx; ‘scrotal’
Fig. 2 Thyroid from Patient II-3. Nuclear features reminiscent of papillary carcinoma (H&E, 6400).
Fig. 4 Patient II-1. Several areas reminiscent of HTA were apparent (H&E, 6100).
Fig. 3 Patient II-2. HTA-like features were focally present, but were less well-developed than in the other cases (H&E, 6100).
and contain dense eosinophilic stromal material, reminiscent of hyalinising trabecular adenomata (HTA) (Fig. 4, 5). However, the cells do not display the characteristic membrane staining with Ki-67 described in hyalinising trabecular adenoma (see Discussion). These areas are the most striking and distinctive features in both specimens, and are remarkably similar despite the fact that these two patients are not related. In addition, the patient from Family B showed features consistent with Hashimoto’s thyroiditis.
DISCUSSION
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313
the PTEN gene in Cowden’s disease kindreds identified germline mutations in four of five families.10 A number of different germline PTEN mutations have now been identified in Cowden’s patients, including missense mutations and splice mutations causing exon skipping.11 There are several reports of melanoma occurring in Cowden’s patients,4,12,13 and there is evidence to suggest that PTEN inactivation is important in melanoma tumourigenesis.14 Somatic PTEN/MMAC1 mutations and deletions have been identified in a wide range of human cancers, including 30–40% of metastatic melanoma cell lines,19 as well as sporadic breast, brain and prostate cancers.13
Fig. 5 Patient from Family B. The appearances were strikingly similar to those of Patient II-1 (H&E, 6200).
tongue; multiple thyroid adenomata; bilateral breast hypertrophy with advanced fibrocystic disease and ‘early malignant degeneration’ (DCIS); scoliosis with pectus excavatum; and ‘abnormalities’ of the central nervous system, including low intelligence.2 Subsequent case reports broadened the spectrum of findings to include multiple facial trichilemmomata,4 multiple lipomata and angiomata, colonic ganglioneuromata;5 hamartomatous intestinal polyps; thyroid carcinoma; megencephaly, epilepsy and cerebellar dysplastic gangliocytoma.6 Genitourinary anomalies have included: vaginal septum with double cervix; endometrial and cervical carcinoma;3,7 ovarian cysts; ovarian teratoma3 and menstrual irregularities;4 and transitional cell carcinoma of the renal pelvis and urinary bladder.7 Immunological studies have demonstrated various abnormalities including decreased NK cell activity, and abnormal helper:suppressor T cell ratios.3,7 Thirty-two cases had been reported by 1979,4 including 20 women, of whom nine had developed breast cancer. Three of the 32 had developed thyroid carcinoma, two colon cancer, one melanoma and one endometrial carcinoma. It soon became apparent that Cowden’s disease displayed an autosomal dominant inheritance pattern with high penetrance.7 A variety of genetic studies were undertaken to attempt to isolate the mutation responsible (including chromosome analysis, DNA repair studies, histocompatibility antigen typing, and immunoglobulin typing). In light of the fact that some 36% of female patients with Cowden’s Disease develop breast cancer,8 Williard, et al.7 studied three important genes implicated in breast cancer genesis (HER-2, ras and pS-2), and found all three to be present in single copies without translocations or rearrangements. They recommended prophylactic bilateral mastectomy for all women with established Cowden’s disease. Nelen et al.6 analysed 40 affected individuals from 12 families in four countries, and were able to exclude several suspect genes including BRCA1, BRCA2 and RET. Linkage analysis identified a locus at 10q22–23, which harbours the PTEN gene. PTEN, also termed MMAC1 and TEP1, encodes a lipid phosphatase with tumoursuppressor properties.9 Subsequent mutational analysis of
The thyroid in Cowden’s disease Thyroid disease occurs in some 67% of Cowden’s patients,7 and is the most common internal manifestation of the disease. Colloid goitre, follicular adenoma, papillary and follicular carcinoma, oncocytoma and thyroglossal duct cyst have all been described.7 The patient may be hyper-, hypo- or euthyroid. (II-3 was originally hyperthyroid; the others in this report were clinically and biochemically euthyroid and were offered surgery for symptomatic thyroid enlargement.) Thyroiditis occurs in around 3% of patients,3 and 12% develop thyroid carcinoma.8 At least some Cowden’s patients with thyroid disease have been shown to have antithyroglobulin and antimicrosomal antibodies.3,15 One such patient also had recurrent hypercalcaemia and was found to have parathyroid adenomata.15 The presence of serum factors stimulating thyroid growth in vitro has also been demonstrated.7 Despite the importance of thyroid disease in these patients, benign thyroid histology in such cases has been poorly documented to date. The notable exception is the work of Harach et al.,1 who examined the thyroids from six females and five males, ranging in age from 9 to 43 years, with Cowden’s disease. These workers found multicentric follicular adenomata and adenomatous nodules showing a wide range of cytoarchitectural patterns. Specific lesions composed of oxyphil (three cases) or clear cells (two cases), an adenolipoma, and a tumour with features of hyalinising trabecular adenoma were also identified. In another case, a follicular adenoma contained a small area with hyalinising trabecular adenoma-like features. These features are also present (and are very striking) in the specimens from Patient II-1 and the patient from Family B. ‘Significant’ thyroiditis (including two or more of: germinal centres, follicular cell destruction, oxyphilic metaplasia and squamous metaplasia) was observed in three women and one man, whilst two others showed ‘mild interstitial lymphoid infiltrates’. (In the current series, the patient from Family B had Hashimoto’s thyroiditis, and the specimens from Patient II-3 showed patchy lymphoid infiltrates.) A 3-mm papillary microcarcinoma was also found. Eight of the 11 cases studied showed PTEN germline point mutations. PTEN mutations have been described in some sporadic follicular carcinomas,1,16 whilst follicular adenomata and oxyphil cell tumours more often show heterozygous deletions of the PTEN gene.1 What is hyalinising trabecular adenoma? Hyalinising trabecular adenoma (HTA) of the thyroid was first described by Carney et al. in 1987.17 It was noted
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that the tumour cell nuclei showed features reminiscent of papillary carcinoma, and that the hyaline fibrosis mimicked amyloid but was Congo red-negative. Subsequent studies concluded that the distinctive hyaline material characteristic of the lesion is due to overproduction of basement membrane-like material by the neoplastic follicular cells.18 Five of Carney’s original 11 cases17 also showed Hashimoto’s thyroiditis. Chetty et al.19 also noted the cytomorphological overlap between HTA and papillary carcinoma, and found features of Hashimoto’s thyroiditis in all six cases examined. Papillary carcinoma may be found in one-third of thyroids containing HTA, and both lesions are associated with thyroiditis, fuelling speculation that the two lesions may be related. This appeared to be supported by the finding that high molecular weight cytokeratins, and especially CK19 (normally restricted in the thyroid to papillary carcinoma), were demonstrated in all six cases of HTA examined by Fonseca et al.20 Cytoplasmic immunoreactivity was diffuse and strong. In contrast, Hirokawa et al.21 found no or minimal CK19 or HMWCK expression in their 12 cases. Despite this contradiction, several authors22,23 now advocate the term ‘hyalinising trabecular tumour’ to reflect the uncertain nature of the lesion. There is some evidence against a relationship between HTA and papillary carcinoma. MIB-1 antibody reacts with the nuclei of cells in the late G1, S, G2 and M phases of the cell cycle. But all 15 cases of HTA studied by Hirokawa and Carney24 showed cell membrane and cytoplasmic positivity in 90% or more of the tumour cells. In contrast, none of 10 papillary carcinomas showed this staining pattern. The authors concluded that this unusual immunoreactivity is a characteristic of HTA, and could be useful in differentiating HTA from papillary carcinoma. This staining pattern was not seen in the current cases.
CONCLUSION This report describes the pathological findings in thyroids from four patients with Cowden’s disease, three of whom are brothers. The disease carries an increased risk of thyroid malignancy, but is also associated with benign thyroid disease. All cases described herein showed multinodularity with adenomatoid nodules, and one also showed features of Hashimoto’s thyroiditis. In three of my cases and some others in the literature, thyroids from Cowden’s patients contain HTA-like nodules, but in none of my cases did the pattern of MIB-1 staining support that diagnosis. The exact nature of these lesions remains unclear, but the appearances are strikingly similar in these cases, and may be characteristic of benign thyroid disease arising in the context of Cowden’s disease. Further study including longterm follow-up is needed to further define the nature and behaviour of these rare lesions. Address for correspondence: Dr C. Hemmings, Department of Anatomic Pathology, The Canberra Hospital, PO Box 11, Woden, ACT 2606, Australia. E-mail: [email protected]
References 1. Harach H, Soubeyran I, Brown A, Bonneau D, Longy M. Thyroid pathologic findings in patients with Cowden Disease. Ann Diagn Pathol 1999; 3(6): 331–40. 2. Lloyd K, Dennis M. Cowden’s Disease: a possible new symptom complex with multiple system involvement. Ann Int Med 1963; 58(1): 136–42. 3. Guerin V, Bene M, Judlin P, Beurey J, Landes P, Faure G. Cowden Disease in a young girl: gynecologic and immunologic overview in a case and in the literature. Obstet Gynecol 1989; 73(5): 890–3. 4. Wade T. Cowden’s Disease. Cutis 1979; 24(5): 537–41. 5. Weary P, Gorlin R, Gentry W, Comer J, Greer J. Multiple hamartoma syndrome (Cowden’s syndrome). Arch Dermatol 1972; 106: 682–90. 6. Nelen M, Padberg G, Peeters E, et al. Localization of the gene for Cowden Disease to chromosome 10q22–23. Nat Genet 1996; 13: 114–6 [letter]. 7. Williard W, Borgen P, Bol R, Tiwari R, Osborne M. Cowden’s Disease: a case report with analyses at the molecular level. Cancer 1992; 69(12): 2969–74. 8. Haggitt R, Reid B. Hereditary gastrointestinal polyposis syndromes. Am J Surg Pathol 1986; 10(12): 871–87. 9. Birck A, Ahrenkiel V, Zeuthen J, Hou-Jensen K, Guldberg P. Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J Invest Dermatol 2000; 114(2): 277–80. 10. Liaw D, Marsh D, Li J, et al. Germline mutations of the PTEN gene in Cowden Disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997; 16: 64–7 [letter]. 11. Tsou H, Xie X, Gruener A, et al. The genetic basis of Cowden’s Syndrome: three novel mutations in PTEN/MMAC1/TEP1. Hum Genet 1998; 102(4): 467–73. 12. Hildenbrand C, Burgdorf W, Lautenschlager S. Cowden Syndrome— diagnostic skin signs. Dermatology 2001; 202(4): 362–6. 13. Boni R, Vortmeyer A, Burg G, Hofbauer G, Zhuang Z. The PTEN tumour suppressor gene and malignant melanoma. Melanoma Res 1998; 8(4): 300–2. 14. Zhou X, Gimm O, Hampel H, Niemann T, Walker M, Eng C. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am J Pathol 2000; 157(4): 1123–8. 15. Velez-Torres R, Popham T, Redinger R, Callen J. Facial papules and nodules, thyroid goiter, and acral keratoses. Arch Dermatol 1987; 123(11): 1557–8. 16. Dahia P, Marsh D, Zheng Z, et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res 1997; 57: 4710–3. 17. Carney J, Ryan J, Goellner J. Hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Pathol 1987; 11(8): 583–91. 18. Katoh R, Jasani B, Williams E. Hyalinizing Trabecular adenoma of the thyroid: a report of three cases with immunohistochemical and ultrastructural studies. Histopathology 1989; 15(3): 211–24. 19. Chetty R, Beydoun R, Li Volsi V. Paraganglioma-like (hyalinizing trabecular) adenoma of the thyroid revisited. Pathology 1994; 26(4): 429–31. 20. Fonseca E, Nesland J, Sobrinho-Simoes M. Expression of stratified epithelial-type cytokeratins in hyalinizing trabecular adenomas supports their relationship with papillary carcinomas of the thyroid. Histopathology 1997; 31: 330–5. 21. Hirokawa M, Carney J, Ohtsuki Y. Hyalinizing trabecular adenoma and papillary carcinoma of the thyroid gland express different cytokeratin patterns. Am J Surg Pathol 2000; 24(6): 877–81. 22. Papotti M, Volante M, Giuliano A, et al. RET/PTC activation in hyalinizing trabecular tumors of the thyroid. Am J Surg Pathol 2000; 24(12): 1615–21. 23. Cheung C, Boerner S, MacMillan C, Ramyar L, Asa S. Hyalinizing trabecular tumor of the thryoid: a variant of papillary carcinoma proved by molecular genetics. Am J Surg Pathol 2000; 24(12): 1622–6. 24. Hirokawa M, Carney J. Cell membrane and cytoplasmic staining for MIB-1 in hyalinizing trabecular adenoma of the thryoid gland. Am J Surg Pathol 2000; 24(4): 575–8.
ANATOMICAL PATHOLOGY
Thyroid pathology in four patients with Cowden’s disease CHRISTINE T. HEMMINGS Department of Anatomic Pathology, Canterbury Health Laboratories, Christchurch, New Zealand
Summary Cowden’s disease (multiple hamartoma syndrome) is a rare genodermatosis, which carries an increased risk of malignancy, especially breast and thyroid carcinoma. Thyroid disease is the most common internal manifestation of the syndrome, but the histological features in benign cases have hitherto been relatively poorly described. Thyroidectomy specimens from four patients with Cowden’s disease have been reported in our laboratory in recent years. A number of rather distinctive features were common to all, raising the possibility of a distinctive ‘Cowden’s thyroid’ phenotype. Key words: Thyroid, Cowden’s disease, multiple hamartoma syndrome, adenomatoid nodules, genodermatosis. Received 12 November 2002, revised 6 March 2003, accepted 10 March 2003
INTRODUCTION Cowden’s disease (multiple hamartoma syndrome) is a rare genodermatosis, which carries an increased risk of malignancy, especially breast and non-medullary thyroid carcinoma. However, the appearances of the thyroid in Cowden’s patients with benign disease have been poorly described. The pathological findings in the thyroids of four patients with Cowden’s disease, three of whom are siblings, are presented.
CASE REPORTS Thyroidectomy specimens from four patients with Cowden’s disease were reviewed. Three of the patients (II-1, II-2, and II-3) are brothers and are designated Family A (Fig. 1). Another brother (II-4) has Cowden’s disease, but has not yet undergone thyroidectomy; a sister (II-5) does not have the disease. II-2 has a son (III-1) who has the disease, and a daughter (III-2) who does not. The brothers were diagnosed after the death of both parents, and it is not known whether either parent manifested clinical features of the syndrome. II-2 and II-3 are also said to have ‘dysplastic naevus syndrome’, although it is not clear what diagnostic criteria have been used. However, both have undergone excision of multiple naevi, of which some have shown atypical features, and both have had invasive melanoma. Case 1 Patient II-1 is the oldest of the three brothers. Like his brothers, he is described as having poor dentition and a high arched palate, along with retrognathia and a retro-displaced tongue base. He also exhibits spinal kyphosis, facial papules and papillomatosis of the lips, gingiva, tongue and hard palate. He underwent total thyroidectomy at the age of 32, for multinodular goitre with obstructive symptoms. Other surgical specimens from this patient have included seven benign intradermal naevi, multiple
Fig. 1 Family A. Squares represent males, and circles females; open symbols indicate unaffected persons, solid symbols affected persons, and grey symbols uncertain status. A slash over the symbol denotes death. papillomatous/verruciform skin lesions, an angiokeratoma, an angioleiomyoma from the wrist and a cavernous haemangioma from the leg. He was noted to have a peripheral blood lymphopenia, and cell marker studies showed a normal CD4:CD8 ratio, with reduced absolute counts of both cell types. Case 2 Patient II-2 also has poor dentition and facial papules, and is similar in appearance to Patient II-3. He underwent thyroidectomy for ‘goitre’ aged 24, prior to the diagnosis of Cowden’s disease. Other surgical specimens from Patient II-2 have included three hamartomatous gastric polyps, three soft tissue fibromata, several papillomatous or verruciform skin lesions, an epidermoid cyst, a solar lentigo, a benign compound naevus, four dysplastic naevi, a melanoma in situ arising in a dysplastic naevus, and two malignant melanomas, both with a Breslow depth of 0.3 mm. Case 3 Patient II-3 underwent left hemithyroidectomy for a ‘toxic nodule’ at age 20. Completion thyroidectomy was performed 13 years later, and at age 39 a thyroglossal cyst was removed. Patient II-3 exhibits the facial papules, poor dentition and lingual papillomatosis that are characteristic of Cowden’s disease, together with kyphosis of the spine and a high arched palate. Other surgical specimens from this patient have included hamartomatous gastric and colonic polyps, four oesophageal papillomata, a dermatofibroma, seven benign intradermal naevi, four dysplastic naevi and a malignant melanoma, Clark’s Level II, Breslow depth 0.2 mm. Case 4 The patient from Family B is not related to the other three patients. He is one of 10 children, and was diagnosed with Cowden’s disease when he and his siblings underwent genetic testing following an older brother’s diagnosis. At 18 he underwent surgery for a left temporal lobe arteriovenous
ISSN 0031–3025 printed/ISSN 1465–3931 online/03/040311–04 # 2003 Royal College of Pathologists of Australasia DOI: 10.1080/0031302031000150533
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malformation. Thyroidectomy was performed for symptomatic thyroid enlargement at the age of 32.
PATHOLOGY Five thyroid excision specimens were reviewed, including separate right and left hemithyroidectomy specimens from II-3. The left hemi-thyroidectomy from Patient II-3 weighed 78 g and was reported in 1982 as ‘nodular hyperplasia of the thyroid’. The completion thyroidectomy in 1995 weighed 71.5 g. The diagnosis of multinodular goitre was rendered, although the original report comments on two relatively hypercellular nodules, which are described as possibly, but not definitely, representing true adenomata. On review, there are solid areas with columnar cell change, and some nodules with a microfollicular architecture show nuclear features similar to those seen in the specimens from the other three patients, and resemble the ‘adenomatoid nodules’ described by Harach et al.1 (see Discussion) (Fig. 2). In addition, there is patchy lymphoplasmacytic infiltration, but without germinal centre formation or oxyphilic metaplasia sufficient to warrant a diagnosis of Hashimoto’s thyroiditis. The total thyroidectomy from Patient II-2 was reported in 1998. The thyroid weighed 95 g and again the diagnosis was multinodular goitre. Note was made of nuclear clearing in some areas but this was considered nonneoplastic. Sampling was somewhat limited, but in retrospect, the ‘pseudo-papillary’ nuclear features are similar to those in the specimens from Patient II-1 and the patient from Family B (see below). In addition, one nodule showed features reminiscent of hyalinising trabecular tumour, although these features were less well developed than in the other cases, described below (Fig. 3). The specimens from Patient II-1 and from the patient from Family B are remarkably similar. Both show the typical appearances of multinodular goitre, but with some nodules showing unusual features. In some areas the cells show relative clearing of nuclear chromatin and have prominent nucleoli, reminiscent of papillary carcinoma. Some nodules show a predominantly microfollicular and solid architecture, whilst others are predominantly trabecular
Cowden’s disease Cowden’s disease was first described by Lloyd and Dennis in 1963,2 and was named after the propositus, who subsequently died of breast cancer at the age of 30.3 The clinical findings as first described included: adenoid facies with microstomia, mandibular and maxillary hypoplasia, high arched palate and hypoplasia of the soft palate and uvula; papillomatosis of the lips and oropharynx; ‘scrotal’
Fig. 2 Thyroid from Patient II-3. Nuclear features reminiscent of papillary carcinoma (H&E, 6400).
Fig. 4 Patient II-1. Several areas reminiscent of HTA were apparent (H&E, 6100).
Fig. 3 Patient II-2. HTA-like features were focally present, but were less well-developed than in the other cases (H&E, 6100).
and contain dense eosinophilic stromal material, reminiscent of hyalinising trabecular adenomata (HTA) (Fig. 4, 5). However, the cells do not display the characteristic membrane staining with Ki-67 described in hyalinising trabecular adenoma (see Discussion). These areas are the most striking and distinctive features in both specimens, and are remarkably similar despite the fact that these two patients are not related. In addition, the patient from Family B showed features consistent with Hashimoto’s thyroiditis.
DISCUSSION
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the PTEN gene in Cowden’s disease kindreds identified germline mutations in four of five families.10 A number of different germline PTEN mutations have now been identified in Cowden’s patients, including missense mutations and splice mutations causing exon skipping.11 There are several reports of melanoma occurring in Cowden’s patients,4,12,13 and there is evidence to suggest that PTEN inactivation is important in melanoma tumourigenesis.14 Somatic PTEN/MMAC1 mutations and deletions have been identified in a wide range of human cancers, including 30–40% of metastatic melanoma cell lines,19 as well as sporadic breast, brain and prostate cancers.13
Fig. 5 Patient from Family B. The appearances were strikingly similar to those of Patient II-1 (H&E, 6200).
tongue; multiple thyroid adenomata; bilateral breast hypertrophy with advanced fibrocystic disease and ‘early malignant degeneration’ (DCIS); scoliosis with pectus excavatum; and ‘abnormalities’ of the central nervous system, including low intelligence.2 Subsequent case reports broadened the spectrum of findings to include multiple facial trichilemmomata,4 multiple lipomata and angiomata, colonic ganglioneuromata;5 hamartomatous intestinal polyps; thyroid carcinoma; megencephaly, epilepsy and cerebellar dysplastic gangliocytoma.6 Genitourinary anomalies have included: vaginal septum with double cervix; endometrial and cervical carcinoma;3,7 ovarian cysts; ovarian teratoma3 and menstrual irregularities;4 and transitional cell carcinoma of the renal pelvis and urinary bladder.7 Immunological studies have demonstrated various abnormalities including decreased NK cell activity, and abnormal helper:suppressor T cell ratios.3,7 Thirty-two cases had been reported by 1979,4 including 20 women, of whom nine had developed breast cancer. Three of the 32 had developed thyroid carcinoma, two colon cancer, one melanoma and one endometrial carcinoma. It soon became apparent that Cowden’s disease displayed an autosomal dominant inheritance pattern with high penetrance.7 A variety of genetic studies were undertaken to attempt to isolate the mutation responsible (including chromosome analysis, DNA repair studies, histocompatibility antigen typing, and immunoglobulin typing). In light of the fact that some 36% of female patients with Cowden’s Disease develop breast cancer,8 Williard, et al.7 studied three important genes implicated in breast cancer genesis (HER-2, ras and pS-2), and found all three to be present in single copies without translocations or rearrangements. They recommended prophylactic bilateral mastectomy for all women with established Cowden’s disease. Nelen et al.6 analysed 40 affected individuals from 12 families in four countries, and were able to exclude several suspect genes including BRCA1, BRCA2 and RET. Linkage analysis identified a locus at 10q22–23, which harbours the PTEN gene. PTEN, also termed MMAC1 and TEP1, encodes a lipid phosphatase with tumoursuppressor properties.9 Subsequent mutational analysis of
The thyroid in Cowden’s disease Thyroid disease occurs in some 67% of Cowden’s patients,7 and is the most common internal manifestation of the disease. Colloid goitre, follicular adenoma, papillary and follicular carcinoma, oncocytoma and thyroglossal duct cyst have all been described.7 The patient may be hyper-, hypo- or euthyroid. (II-3 was originally hyperthyroid; the others in this report were clinically and biochemically euthyroid and were offered surgery for symptomatic thyroid enlargement.) Thyroiditis occurs in around 3% of patients,3 and 12% develop thyroid carcinoma.8 At least some Cowden’s patients with thyroid disease have been shown to have antithyroglobulin and antimicrosomal antibodies.3,15 One such patient also had recurrent hypercalcaemia and was found to have parathyroid adenomata.15 The presence of serum factors stimulating thyroid growth in vitro has also been demonstrated.7 Despite the importance of thyroid disease in these patients, benign thyroid histology in such cases has been poorly documented to date. The notable exception is the work of Harach et al.,1 who examined the thyroids from six females and five males, ranging in age from 9 to 43 years, with Cowden’s disease. These workers found multicentric follicular adenomata and adenomatous nodules showing a wide range of cytoarchitectural patterns. Specific lesions composed of oxyphil (three cases) or clear cells (two cases), an adenolipoma, and a tumour with features of hyalinising trabecular adenoma were also identified. In another case, a follicular adenoma contained a small area with hyalinising trabecular adenoma-like features. These features are also present (and are very striking) in the specimens from Patient II-1 and the patient from Family B. ‘Significant’ thyroiditis (including two or more of: germinal centres, follicular cell destruction, oxyphilic metaplasia and squamous metaplasia) was observed in three women and one man, whilst two others showed ‘mild interstitial lymphoid infiltrates’. (In the current series, the patient from Family B had Hashimoto’s thyroiditis, and the specimens from Patient II-3 showed patchy lymphoid infiltrates.) A 3-mm papillary microcarcinoma was also found. Eight of the 11 cases studied showed PTEN germline point mutations. PTEN mutations have been described in some sporadic follicular carcinomas,1,16 whilst follicular adenomata and oxyphil cell tumours more often show heterozygous deletions of the PTEN gene.1 What is hyalinising trabecular adenoma? Hyalinising trabecular adenoma (HTA) of the thyroid was first described by Carney et al. in 1987.17 It was noted
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HEMMINGS
that the tumour cell nuclei showed features reminiscent of papillary carcinoma, and that the hyaline fibrosis mimicked amyloid but was Congo red-negative. Subsequent studies concluded that the distinctive hyaline material characteristic of the lesion is due to overproduction of basement membrane-like material by the neoplastic follicular cells.18 Five of Carney’s original 11 cases17 also showed Hashimoto’s thyroiditis. Chetty et al.19 also noted the cytomorphological overlap between HTA and papillary carcinoma, and found features of Hashimoto’s thyroiditis in all six cases examined. Papillary carcinoma may be found in one-third of thyroids containing HTA, and both lesions are associated with thyroiditis, fuelling speculation that the two lesions may be related. This appeared to be supported by the finding that high molecular weight cytokeratins, and especially CK19 (normally restricted in the thyroid to papillary carcinoma), were demonstrated in all six cases of HTA examined by Fonseca et al.20 Cytoplasmic immunoreactivity was diffuse and strong. In contrast, Hirokawa et al.21 found no or minimal CK19 or HMWCK expression in their 12 cases. Despite this contradiction, several authors22,23 now advocate the term ‘hyalinising trabecular tumour’ to reflect the uncertain nature of the lesion. There is some evidence against a relationship between HTA and papillary carcinoma. MIB-1 antibody reacts with the nuclei of cells in the late G1, S, G2 and M phases of the cell cycle. But all 15 cases of HTA studied by Hirokawa and Carney24 showed cell membrane and cytoplasmic positivity in 90% or more of the tumour cells. In contrast, none of 10 papillary carcinomas showed this staining pattern. The authors concluded that this unusual immunoreactivity is a characteristic of HTA, and could be useful in differentiating HTA from papillary carcinoma. This staining pattern was not seen in the current cases.
CONCLUSION This report describes the pathological findings in thyroids from four patients with Cowden’s disease, three of whom are brothers. The disease carries an increased risk of thyroid malignancy, but is also associated with benign thyroid disease. All cases described herein showed multinodularity with adenomatoid nodules, and one also showed features of Hashimoto’s thyroiditis. In three of my cases and some others in the literature, thyroids from Cowden’s patients contain HTA-like nodules, but in none of my cases did the pattern of MIB-1 staining support that diagnosis. The exact nature of these lesions remains unclear, but the appearances are strikingly similar in these cases, and may be characteristic of benign thyroid disease arising in the context of Cowden’s disease. Further study including longterm follow-up is needed to further define the nature and behaviour of these rare lesions. Address for correspondence: Dr C. Hemmings, Department of Anatomic Pathology, The Canberra Hospital, PO Box 11, Woden, ACT 2606, Australia. E-mail: [email protected]
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