Diseases of Thyroid 36 Sérgio Ivan Torres Dornelles, Carlos Alberto Werutsky, Ana Eliza Antunes Bomﬁm, Camila Boff, and Renan Rangel Bonamigo

Home , Postpartum thyroiditis, Thyroglossal cyst

Key Points Summary • Thyroid hormone deficiency causes • Hyperthyroidism and hypothyroidism thickening, hyperkeratosis, diffuse loss are disorders with important interaction of scalp hair, and nail atrophy with the skin • Generalized myxedema is a severe • Iodine intake levels below and above the disease that may occur in hypothyroid- recommended level are associated with ism, when mucin is deposited in the skin the occurrence of thyroid disorders and other organs resulting in a series of dermatologic and systemic outcomes • Pretibial myxedema is less frequent, S.I.T. Dornelles (*) being present in only 5% of cases of Sanitary Dermatology Service of Health Department of Rio Graves’ disease. About 90% of pretibial Grande do Sul State (ADS-SES), Porto Alegre, Brazil e-mail: [email protected] myxedema patients have hyperthyroidism • Thyroid acropachy is a rare manifesta- C.A. Werutsky Nutrology and Endocrinology, Hospital 9 de Julho, tion of thyroid autoimmune disease and São Paulo, Brazil can display finger or toe clubbing and A.E.A. Bomfim edema Sanitary Dermatology Service of Health Department • Thyroglossal cyst and cutaneous metas- of Rio Grande do Sul State (ADS-SES), Porto tases of thyroid cancer are other dis- Alegre, Brazil eases associated with the thyroid gland Department of Dermatology, Clinica Duarte, Pelotas, RS, Brazil C. Boff Sanitary Dermatology Service of the Department of Health of Rio Grande do Sul State, Porto Alegre, Brazil Epidemiology R.R. Bonamigo Dermatology Service, Hospital de Clínicas de Porto Thyroid diseases are considered very frequent dis- Alegre (HCPA), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil eases. Estimates report that hyperthyroidism affects about 2% of the general population, with a 15% Sanitary Dermatology Service of the Department of Health of Rio Grande do Sul State (ADS-SES), increase among the elderly, occurring predomi- Porto Alegre, Brazil nantly in females and in iodine ingestion–deficient Graduate Pathology Program of Federal University of regions [1]. Congenital hypothyroidism (cretinism) Health Sciences of Porto Alegre, Porto Alegre, Brazil has an incidence of 1 case per 4000 births; 19% are

© Springer International Publishing Switzerland 2018 739 R.R. Bonamigo, S.I.T. Dornelles (eds.), Dermatology in Public Health Environments, https://doi.org/10.1007/978-3-319-33919-1_36 740 S.I.T. Dornelles et al. sporadic and 5% are genetic. Hashimoto’s thyroid- A sudden increase in iodine intake in an itis mainly affects women between the ages of 30 iodine-deficient population may induce thyroid and 50 years, with a female-to-male ratio of 7:1. autoimmunity. It is well established that indi- Postpartum thyroiditis occurs in about 8–10% of vidual patients with autoimmune thyroiditis women [2]. Hyperthyroidism has a lower preva- may develop hypothyroidism when exposed to lence (2% in women and 0.2% in men (English excess iodine. Considering the very frequent data)) [1]. Regarding Graves’ ophthalmopathy in occurrence of thyroid autoimmunity in the the general population, there are incidence reports population, it would be expected that a high of 16 women and 3 men in every 100,000 popula- iodine intake would be associated with a high tion per year [3]. frequency of subclinical (with elevated serum Among many dermatologic manifestations, thyroid- stimulating hormone (TSH) but a free pruritus sine materia seems to be a significant T4 estimate within the reference range) and manifestation of thyroidopathies (Artantas et al. overt (elevated TSH and a low estimate of free [4] report a pruritus prevalence of 2.7% in T4) hypothyroidism, and this has indeed been patients with thyroid disturbances). convincingly demonstrated [4, 5]. Four methods are generally recommended to assess iodine intake: urinary iodine concentra- The Thyroid and the Environment tion, goiter rate, serum TSH, and serum thyroglobulin [4]. The spectrum of disorders that Iodine (as iodide) is widely but unevenly distributed somehow depend on the iodine intake level of the in the earth’s environment. Most iodide is found in population can be based on the median or range the oceans (about 50 μg/L), and iodide ions in the of urinary iodine concentrations, or both. High seawater oxidize to form elemental iodine, which is intake of iodine results in a urinary iodine con- volatile and evaporates into the atmosphere and centration of 100–200 μg/L. Below these concen- returns to the soil through rain, completing the trations (50–25 μg/L) insufficient iodine intake cycle. However, the cycle of iodine in many regions occurs, resulting in diseases ranging from cretin- is slow and incomplete, and soils and groundwater ism and low IQ to goiter with hypothyroidism or become deficient in iodine. Crops grown in these hyperthyroidism. High urinary concentrations of soils will contain low iodine concentrations, and iodine (>300 μg/L) may result in early Graves’ humans and animals consuming food grown in disease (GD) [2]. these soils become deficient in iodine [2]. Thus, the thyroid gland contains an advanced Iodine consists of 65% and 59% of the weights set of processes that may enhance or block the of thyroxine (T4) and tri-iodothyronine (T3), use of iodine for thyroid hormone production. respectively. Thyroid function is crucial for the Because the processes activated with low and metabolism of almost all tissues and for the high iodine intakes are different, the type of dis- development of the central nervous system in ease that dominates thyroid pathology in popula- fetuses and children. tions may be different depending on the level of Iodine deficiency is the result of insufficient iodine intake. dietary iodine intake, and the physiologic consequence is abnormal thyroid function, hypothyroidism, and goiter [3]. In nearly all regions affected Skin Manifestations by iodine deficiency, the most effective way to of Hyperthyroidism control iodine deficiency is through salt iodization. The World Health Organization / United Nations Hyperthyroidism, or excess circulating thyroid Children’s Fund / International Council for the hormone, results from a disturbance in any por- Control of the Iodine Deficiency Disorders (WHO/ tion of the hypothalamic-pituitary-thyroid axis. UNICEF/ICCIDD) recommends that iodine be In normal subjects, TSH is made by the pitu- added at a concentration of 20–40 mg iodine/kg of itary gland and stimulates the thyroid gland salt, depending on local salt intake [3]. to generate and secrete T4 (thyroxine) and T3 36 Diseases of Thyroid 741

( triiodothyronine). In the periphery, T4 is con- Etiopathogenesis verted into T3 by enzymes mainly in the liver and kidney. T3 (and to some extent T4) then binds GD results from stimulation of the TSH recep- to specific nuclear receptors in the tissues (e.g., tor through receptor-binding antibodies. Thus, heart, brain, muscle, and perhaps skin) and medi- the usual negative report promoted by the ates the thyroid hormone action [6]. T3 and T4 levels of TSH production by the Furthermore, the amount of T4 and T3 hypophysis is interrupted. The outcome of secreted by the thyroid gland is regulated by a this abnormal mechanism is excessive T3 and negative feedback system of the pituitary T4 in the peripheral circulation, which entails gland. Specifically, when the body recognizes the clinical manifestations of hyperthyroid- it has excess thyroid hormone levels, T3 (and ism. High levels of T3 and T4 promote the T4) binds to the TSH gene regulatory elements usually seen clinical symptoms of the disease, in the pituitary gland and inhibits TSH such as nervousness, anxiety, weight loss, heat production [7]. intolerance, fatigue, muscle weakness, and Hyperthyroidism is more commonly seen in palpitations [12]. women than in men (5:1 ratio). The most charac- The dermatologic and ophthalmologic mani- teristic (although rare) skin finding in GD is festations specific to the thyroid diseases result pretibial myxedema, although other more com- from the autoimmune effects of antibodies of the mon cutaneous manifestations of hyperthyroid- TSH, rather than being related to the circulating ism include warm, flushed, moist skin, with thyroid hormone levels. In the dermatologic dis- generalized increased sweating [7, 8]. eases nonspecific to the cutaneous thyroid, altera- The skin changes, and the hair may become tions are directly related to the circulating levels thin and soft; loss of scalp, eyebrow, axillary, of T3 and T4 [12]. pubic, or body hair is common. Hair loss without scarring (alopecia areata) is most often associated with autoimmune disease (GD) [9]. Clinical Presentation Up to 25% of patients with GD have clinically obvious Graves’ ophthalmopathy at the time of Dermatologic manifestations of hyperthyroidism the diagnosis of hyperthyroidism [9]. vary. The skin is warm, soft, humid, blushed, and The nails may become soft and friable, and tender, and an association with cutaneous pruri- separation of the distal nail plate from the nail tus is frequent. Hyperhidrosis may be noticed bed may occur, producing Plummer’s nails [10]. mainly in the hand palms and feet soles [4]. A definitive treatment of hyperthyroidism var- The hair may become thinner and soft, and ies depending on the etiology of the disorder, but hair loss in the scalp, eyebrows, axillae, pubic usually involves rendering the patient euthyroid area, or throughout the body is common. with antithyroid drugs (i.e., methimazole or propylthiouracil). These antithyroid agents can cause pruritic Complementary Examinations erythematous skin rash, hepatotoxicity, arthral- gias, or bone marrow suppression [11]. The blood dosage of free TSH, T3, and T4 levels The implementation of a definitive therapy added to the clinical signs and symptoms of may include long-term antithyroid agents, radio- hyperthyroidism seal the diagnosis. active iodine therapy, or thyroidectomy. It requires radioactive iodine from 2 to 3 months to cause hypothyroidism [6]. Therapeutic Approach The skin manifestations associated with hyperthyroidism are classically cleared with Treatment includes normalizing the thyroid func- treatment of the underlying cause of the hyper- tion, either through medication or the thyroid thyroidism state as described below [10]. function ablation [12, 13]. 742 S.I.T. Dornelles et al.

Special Considerations cle hypertrophy translated into visual loss that results from corneal ulceration, secondary to pro- Graves Ophthalmopathy ptosis and optical neuropathy by compression of Thyroid ophthalmopathy is an autoimmune orbit the optic nerve [17, 19]. Exophthalmos is almost disease closely associated with GD, although always bilateral and symmetric. The lower rectus both conditions may exist separately [13]. muscle is the most often involved muscle fol- Around 20–25% of GD patients have ophthal- lowed by the medial rectus, the upper rectus, and mopathy [14]. The ophthalmopathy develops before the lateral rectus muscles (Figs. 36.1 and 36.2). the hyperthyroidism presentation in around 20% of patients; concomitantly in 40%; and in 40% of the Complementary Examinations cases 6 months after the diagnosis [15]. It is worth The diagnosis is clinical, and imaging methods are bearing in mind that the ocular disease may become indicated when the diagnosis is difficult or an opti- evident after hyperthyroidism treatment, usually in cal neuropathy is suspected [17, 18]. Computed patients treated with radioiodine [16]. tomography (CT) and magnetic resonance imaging (MRI) are useful to confirm the diagnosis Etiopathogenesis through visualization of the muscle hypertrophy The most often accepted theory to explain the and the orbital fat, and also to assess the critical association between thyroid ophthalmopathy and area of the orbital apex. Often the only finding is autoimmune thyroid disease is a possible cross- increased orbital fat, with resulting proptosis [20]. relationship of sensitized T lymphocytes and/or antibodies against the thyroid and the orbit com- Therapeutic Approach mon antigens [17]. Patients are treated according to the degree of dis- The volume of retro-orbital connective and adi- ease impairment, always having in mind that most pose tissue and the volume of extraocular muscles are increased by cell proliferation, inflammation, and glycosaminoglycan accumulation, mainly hyaluronic acid. Glycosaminoglycan secretion by the fibroblasts is activated by the T-cell cytokines (tumor necrosis factor, interferon-γ), thus showing that T- and B-cell activation is important for the immunopathogenesis of Graves’ ophthalmopathy. Glycosaminoglycan accumulation brings about changes in the osmotic pressure which lead to liquid accumulation, muscular edema, and increased pressure inside the orbit. These changes, with the addition of retro-orbital Fig. 36.1 Thyroid ophthalmopathy adipogenesis, move the eyeball outside, possibly also interfering in the function of the extraocular muscles and the orbit’s venous drainage [12, 13].

Clinical Presentation The extraocular muscles are the main impaired targets and show increased volume, and together with other important clinical signs determined by inflammatory changes and/or vascular conges- tion include upper and lower eyelid retraction, conjunctival hyperemia, and preorbital edema [17, 18], as well as sequelae of extraocular mus- Fig. 36.2 Another aspect of thyroid ophthalmopathy 36 Diseases of Thyroid 743 patients display a mild disease with no progres- of the pretibial myxedema cases occur after the sion during the follow-up. Graves’ ophthalmop- patient undergoes treatment for thyroidopathy athy patients display hyperthyroidism reversal either with radioactive iodine or thyroidectomy (when present), symptom relief, and decreased [32]. The ophthalmopathy is associated with periorbital tissue inflammation [13, 21]. most of the cases, usually coming before pretibial Symptom treatment comprises the use of arti- myxedema occurring within 1–2 years [31]. Its ficial tears, raised head during sleeping hours, incidence has decreased possibly due to the early facial support when sleeping, and use of blinders diagnosis and treatment implementation for that are often enough for symptom relief. GD. Contrary to what is prompted by its name, it Photophobia and sensitivity to wind or cold air is not limited to the pretibial area, and can reach can be reduced with sunglasses [13, 22]. Some the ankles and the feet dorsa, and be present in studies suggest that use of selenium (100 μg 2×/ the elbows, knees, upper portion of the trunk and day, over 6 months) may improve soft tissue neck [33]. edema, besides the implementation of quality-of- life measures, although such results require con- Etiopathogenesis firmation [23]. Pretibial myxedema results from glycosamino- For patients with eye inflammation (red glycan accumulation, specifically hyaluronic eyes) and increased diplopia and proptosis, acid secreted by cytokine-stimulated fibroblasts. a corticosteroid (prednisone 30 mg/day for By showing the expression of the TSH receptor 4 weeks) course should be started. If large proteins by the dermis fibroblasts, the possibility doses are necessary they are intravenously arises that antibodies and/or T-cell-specific anti- administered. Cases whereby vision is lost, gens start an inflammatory reaction that stimu- usually preceded by color vision loss, require lates glycosaminoglycan production; excessive the patient to immediately undergo corticoste- glycosaminoglycans are deposited in the dermis roid therapy (intramuscular dexamethasone and the subcutaneous tissue [34–37]. 4 mg, or prednisone 100 mg orally) and hospital admission for probable surgical decom- Clinical Presentation pression. Rituximab, radiation, and surgical Pretibial myxedema is characterized by a bilat- decompression can be also used in select cases eral asymmetric cutaneous thickening, usually [13, 22, 24–26]. with one or more less delimited papules or nodules that can display different diameters [37]. Pretibial Myxedema There is color variation from yellowish chest- The cutaneous manifestations of GD may result nut to violet, and an “orange skin” aspect due from excessive thyroid circulating hormone or to the cutaneous thickening associated with from the autoimmune nature of GD [27, 28]. the follicular prominence is frequently noticed The most common clinical findings are oph- [31, 37]. Lesions are usually asymptomatic thalmopathy, acropachy, and pretibial myx- although they can be pruritic or even painful edema; the presence of the three findings make [37]. Hyperpigmentation, hyperkeratosis, and up the classic triad of GD, present in only 1% hyperhidrosis may also be present. The most of cases [29]. frequent sites include the medium and lower Pretibial myxedema is a less often seen mani- third of the pretibial region and, occasion- festation, present in only 5% of GD cases and in ally, the feet dorsa (Fig. 36.3). Other impaired 15% of cases of patients with GD and ophthal- regions are seldom noticed, although there are mopathy [30]. About 90% of the patients with reports of atypical location, such as the fingers, pretibial myxedema have hyperthyroidism and hands, upper limbs, torso, shoulder, and face, 10% are hypothyroid or euthyroid patients, albeit that in most of those reports there was although all of them display laboratory evidence history of trauma, vaccination, local scar, or of autoimmune thyroid disease [31]. About 50% surgery [31, 32, 37]. 744 S.I.T. Dornelles et al.

occlusion, are indicated; no improvement after 4–12 weeks of treatment leads to the use of intra- lesional corticosteroid, mainly for a presentation such as plaques and nodules [38]. Some authors support the use of compression stockings (20–30 mmHg) for lymphedema improvement [33, 37]. There are reports of pentoxifylline used in resistant cases [39]. Other reports mention rituximab and plasmapheresis in severely affected patients [40–43]. Immunoglobulin was effective in a series of noncontrolled cases [44]. When trauma is a precipitating factor of disease recurrence, surgical treatments must be avoided. Fig. 36.3 Pretibial myxedema Thyroid Acropachy The lesions usually develop along many The exact incidence of acropachy is not known, months and then stabilize, or, in some cases, although estimates refer to 0.1–1% of GD spontaneously recede [37]. Rarely the lesions patients [45]. evolve and reach the feet, hands, or legs, in such cases showing a more elephantiasis format Etiopathogenesis [31, 32]. Acropachy pathogenesis is similar to that of der- The differential diagnosis can be made with mopathy. A research study investigated whether stasis dermatitis, cutaneous mucinosis (in lupus fibroblast activation in the periosteum and mucin erythematosus, dermatomyositis, scleroderma), deposition may be a triggering factor [46]. amyloidosis, hypertrophic lichen planus, and lipoid necrobiosis [33]. Clinical Presentation Thyroid acropachy is a rare manifestation of thy- Complementary Examinations roid autoimmune disease, present in extreme The diagnosis of pretibial myxedema is based on forms of dermopathy, and possibly showing fin- the GD history and clinical characteristics of the ger or toe edema and clubbing. More seldom lesion (location, nonpitting nature, and badly seen is acropachy together with distal arthritis delimited margins). A biopsy is seldom neces- [46]. It is part of the acropachy, pretibial myx- sary for the diagnosis, although it can be required edema, and ophthalmopathy triad [45]. when patients display disease-suggestive lesions Three manifestations of acropachy are but with no history of thyroid disease. noticed: finger and toe clubbing (88%); edema, and hardening of the skin of fingers and toes Therapeutic Approach (20%); and presentation of arthritis and periosti- Most of the cases do not require treatment, with tis (10%) [46]. resolution occurring some years later. Treatment The most ordinary form of acropachy is digital indications include pruritus, local discomfort, or clubbing, which occurs in 20% of dermatopathic aesthetic reasons. It is wise, nevertheless, to treat patients. Digital edema and periosteal reaction in all new lesions so that they do not undergo a chronic adjacent bone is the total clinical presentation, process. Treatment encompasses minimization of though less often seen. Thyroid acropachy always the risk factors: quitting smoking, weight loss, and occurs in association with Graves’ ophthalmopa- treatment of the disturbed thyroid. Improvement thy and thyroid dermopathy. Involvement of joints in thyroid function does not necessarily improve is unusual. Acropachy is not usually painful, the myxedema [33]. As initial therapy, medium- although some patients have pain and function to high-potency corticosteroids, with or without loss due to severe edema [45, 47]. 36 Diseases of Thyroid 745

Complementary Examinations alopecia, melasma, onycholysis, and vitil- Skin biopsy shows typical pretibial myxedema igo, among others [49]. findings, including fibroblast activation and gly- The assessment of a hypothyroid patient cosaminoglycan deposits [48]. The diagnosis is requires a detailed history and physical exami- made with a combination of the thyroid disease nation. Many clinicians will also obtain a thy- history, clinical characteristics typical of ophthal- roid sonogram if there is a suspicion for mopathy and pretibial myxedema, and radio- nodules. Serum tests will include TSH initially graphic features of the hands and feet [45]. (with T4 and T3 added if TSH is abnormal or if Fusiform edema of the soft tissues both in the there is suspicion of central hypothyroidism), patient’s fingers and toes, and subperiosteal bone as well as measurement of thyroid peroxidase formation are radiographic findings. Subperiosteal antibodies. reaction is uncommon in long bones [45–47]. Once the diagnosis is made, the process involves levothyroxine administration, although Therapeutic Approach it will not directly help the autoimmune- mediated There is no specific treatment available besides aspects of the disease, such as pretibial myx- the basal immunologic treatment and manage- edema and ophthalmopathy [50]. ment of the associated dermopathy. Painful acropachy periostitis requires use of anti-inflammatory agents [47]. General Skin Manifestations and Generalized Myxedema

Skin Manifestations Endemic cretinism can result from iodine defi- of Hypothyroidism ciency in the uterus, although it may result from the transplacental passage of substances that Hypothyroidism, or a deficiency of thyroid hor- inhibit the production of thyroid hormones by mone, is most often caused by a chronic autoim- interfering with iodine absorption in the thyroid mune disease (Hashimoto’s thyroiditis), but may gland (goitrogens). In 33% of children with con- also result from pituitary tumor or failure, iatro- genital hypothyroidism, signs or symptoms of genic thyroid ablation, goiter, or iodine defi- cutaneous abnormality are not found [51]. ciency [46]. In Brazil, the bloodspot test (“Teste do Relatively common causes of primary hypo- Pezinho”) is carried out up to the 30th day of life; thyroidism also include a prior history of therapy it is now part of the Sistema Único de Saúde for hyperthyroidism, or a thyroidectomy (partial (SUS) (the publicly funded healthcare system) or total). External radiation given to the head, incorporated in 1992 (Portaria GM/MS no. 22, de neck, or chest areas for lymphoma, for example, 15 de Janeiro de 1992), with a legislation that may also result in hypothyroidism [47]. made the test mandatory for all live newborns; it Patients with hypothyroidism typically have also includes assessment for phenylketonuria and cold, pale skin that is rough, dry, and scaly [10]. congenital hypothyroidism [52]. The skin may appear yellow because of caroten- Adult hypothyroidism develops insidiously, emia. The most characteristic skin change of thus possibly persisting for many years. Adult hypothyroidism is myxedema, the accumulation hypothyroidism is a common type, more fre- of mucopolysaccharides in the skin. Patients quently occurring in women from 40 to 60 years seem to have puffiness around the eyes and swell- old [51]. ing of the hands. There is often loss of the lateral Generalized myxedema is a severe manifesta- third of the eyebrows, coarse brittle hair and tion that may be seen in hypothyroidism, when nails, and generalized hair loss [48]. mucin is deposited in the skin and other organs Cutaneous manifestations of Hashimoto’s leading to a series of dermatologic and systemic thyroiditis include acanthosis nigricans, changes [51]. 746 S.I.T. Dornelles et al.

Etiopathogenesis hair. The eyebrows exhibit a characteristic loss of There are no exact causes to determine the dis- the lateral third bilaterally. Hair growth is slow. ease besides its association with low levels of Patients with spontaneous or iatrogenic myxedema thyroid hormones, associated with relevant may also show a greater amount of hair in the telo- dermal accumulations of mucopolysaccha- gen phase. This may indicate that the hypothyroid- rides, mainly hyaluronic acid and chondroitin ism alopecia is being mediated by hormonal sulfate [51]. effects [51–54]. The nails show a slow growth and a fragile Clinical Presentation structure. Patients often display early tiredness, a feeling of In the myxedematous state wound scarring fatigue, weakness, cramps mainly in the legs, and can be impaired, thus determining such a slow severe discomfort on cold days. The myxedema process. Purpura may sometimes be noticed as a is characterized by typical periorbital swelling, consequence of the decrease in clotting factor, or thick lips, acral swelling, and widened tongue. loss of vascular support resulting from the pres- Macroglossia may display a smooth and red ence of mucin in the dermis may be seen [53, 54]. aspect. The yellowish skin is explained by caro- Some reported uncommon observations in tene accumulation in the stratum corneum (as the literature can be deduced as actual manifes- result of the lesser hepatic conversion of tations of the hyperthyroid state. A manifesta- β-carotene to vitamin A), and anemia [51, 53]. tion similar to ectodermal dysplasia, possibly The carotenemia may be seen in hand palms and inherited in a recessive autosomal manner, was soles of feet, and nasolabial folds. Clavicular fat reported by the acronym ANOTHER (alope- accumulation may be often noticed. The skin is cia, ungual dystrophy, ophthalmologic compli- dry, cold, and pale, mainly in the extension areas. cations, dysfunctional thyroid, hypohidrosis, Xerosis can be so severe that it may be consid- ephelides and enteropathy, and respiratory tract ered a form of acquired ichthyosis. It becomes infections) [51]. pale because of the higher levels of water and The systemic manifestations of hypothyroid- mucopolysaccharides in the dermis, which ism are numerous and are not covered in this change the light refraction. It also shows a periph- chapter. It is important to know that mucin depo- eral vasoconstriction that may determine features sition also occurs in many organs other than the of cutis marmorata. Hypohidrosis is also noticed. skin, such as the heart, intestines, and the kid- The palms may become significantly drier, pos- neys, resulting in functional outcomes. sibly mimicking an acquired keratoderma. The skin is diffusely swollen and becomes sturdy Complementary Examinations when touched. Despite the edematous aspect, the The diagnosis is clinically suspected and con- skin is not depressed if pressure is applied upon firmed by the low levels of free circulating T4. it. The presence of cutaneous edema may be par- The TSH serum level is high in primary hypothy- tially explained by the hygroscopic characteris- roidism and low in secondary hypothyroidism. tics of the mucopolysaccharides, although an Myxedema is not seen in secondary hypothyroid- increase in the transcapillary escape of albumin ism [53, 54]. was shown, possibly resulting in its extravascular The anatomopathologic examination shows a accumulation, thus playing a part in this edema. mild epidermal hyperkeratosis and development In addition, inappropriate lymphatic drainage can of corneal plugging in the pilous follicles, and account for the development of exudates in the small dermal deposits of mucopolysaccharides. serous cavities that become visible in the myx- In the most noticeable cases edema is seen with edematous state [51–54]. separated collagen bundles. In some cases pre- Body and head hair may be dry and brittle. Hair eminent amounts of dermal mucin can be noticed, loss results in partial alopecia. Irregular alopecia mainly perivascular and perifollicular. The num- plaques can be noticed with persistent lanuginous ber of elastic fibers is decreased [53]. 36 Diseases of Thyroid 747

Therapeutic Approach If the impairment happens in newborns, immedi- ate treatment is crucial for their appropriate mental development. This important treatment begins before the 4th month of life [53, 54]. Whatever the situation, symptoms recede when the therapy employs thyroxine.

Skin Manifestations Related to the Thyroid Gland and Not to Its Function

Thyroglossal Duct Cyst

Thyroglossal duct cyst results from a failed oblit- Fig. 36.4 Thyroglossal duct cyst eration of the duct developed in the embryogen- esis during thyroid migration, and represents the most common median line cyst. Ectopic neopla- Clinical Presentation sias of the thyroid tissues are rare, and rarer if The clinical presentation shows a nodular lesion associated with this duct [55]. of cystic consistency at the medium line of the neck at the level of the thyroid membrane. Cyst Etiopathogenesis infection may happen simultaneously with epi- In the fourth week of fetal development the thy- sodes of airway infection, and signs of local roid tissue is located in the pharyngeal floor, and inflammation can be seen (Fig. 36.4). A fistula through the thyroglossal duct this tissue migrates secondary to the cyst infection may also be into its usual position in the thyroid. During the apparent [58]. thyroid descent, the gland keeps its connection to the base of the tongue through the thyroglossal Complementary Examinations duct, and when migration is concluded the duct is Ultrasonography of the cervical region is the obliterated at around the 8th gestational week. method used to identify the cyst, with an accu- This channel persistence is called remnant thyro- racy of 90% [58]. When facing a doubtful diag- glossal duct [56]. nosis, an aspiration puncture can be conducted to This congenital remnant is usually noticed confirm the presence of thyroid tissue. as a cyst coated with a secretory epithelium. Both men and women can show this condition, Therapeutic Approach which can be located anywhere in the thyro- The treatment of choice is cyst removal per- glossal duct, found in 60% of the cases between formed using the Sistrunk technique, comprising the hyoid bone and the thyroid cartilage; 24% removal of the central part of the hyoid bone. If suprahyoid; 13% substernal; and 2% intralin- infection is ascertained, the use of systemic anti- gual [57]. biotics may be necessary [36]. The diagnosis is made up to 10 years of age in about 30% of the cases; from 10 to 20 years of age in 20%; from 20 to 30 years of age in Thyroid Cancer and Cutaneous 15%, and after 30 years of age in 35% of cases. Metastases Ectopic thyroid tissue is seen in 62% of cases and is subject to the same pathology of the thy- Thyroid papillary carcinoma accounts for most roid itself [56]. of the cases of cancers of this type in children, 748 S.I.T. Dornelles et al. usually occurring as metastases in regional lymph nodes. Papillary carcinoma is made up of Hürthle cells, usually noticed in middle-aged and elderly persons. Among the elderly population, the most common metastases are distant metastases. On the other hand, tumors of undifferentiated cells are characteristic of older people, and may pre- dispose distant metastases besides involvement of regional lymph nodes [56]. Cutaneous metastasis is a rare event [60]. In a series of 724 patients, thyroid metastatic carcinoma accounted for less than 1% of the cutaneous metastases [61], and no thyroid metastasis Fig. 36.5 Thyroid papilliferous carcinoma was noted in a series of 4020 individuals with cutaneous metastases [62]. cutaneous malignant neoplasias (basal cell carcinoma and keratoacanthoma) [63–65]. Etiopathogenesis Cutaneous manifestations common to the thy- Thyroid follicular carcinoma displays meta- roid papilliferous carcinoma are nodules in the static dissemination mainly through hematog- scalp and neck [63, 66, 67], and lesions in the enous spread, which occurs in 10–15% of cases scar of thyroidectomy [68]. A metastatic tumor at of more advanced tumors. The most often the site of thin-needle aspiration biopsy was also affected sites include the bones and the lungs, noticed by Tamiolakis et al. [67]. Cutaneous and less frequently the brain, liver, bladder, metastases of thyroid papillary carcinoma have and skin. also been described on the abdominal wall, arms, In 2005 Quinn et al. described four patients buttocks, thoracic wall, face, shoulders, and with thyroid cutaneous metastasis, three men and thighs [60] (Fig. 36.5). one woman, with a medium age range of 64 Cutaneous thyroid metastases can occur years, all of whom had invasive thyroid follicular after an early diagnosis of thyroid cancer, thus carcinoma [60]. Two of these patients displayed making the cutaneous lesion diagnosis easier, scalp metastases: one in the neck, and another in as well as being the first identified manifesta- the sacral skin. In three cases the specific mor- tion of the pathology. Since cutaneous lesions phology and immunohistochemistry were con- are accessible to clinical examination and ducted, revealing that one of these patients patient visualization, they may easily trigger showed primarily spinal metastasis of character- the investigation leading to the primary site of istic morphology, although he underwent ana- the neoplasia. plastic change after treatment. Including these four cases a total of 14 were reported in the litera- Complementary Examinations ture, with cutaneous metastasis of thyroid follicu- Complementary examinations are crucial to the lar carcinoma in most patients: that is, 10 out of proper identification of the cutaneous metastases 14 patients had primary site histopathology [60]. because they allow the identification of the lesion’s primary site. Clinical Presentation Anatomopathologic examination of cutaneous The morphology of cutaneous metastases is metastases of papilliferous carcinoma and thy- variable. The lesions may manifest as macules, roid follicular carcinoma also show characteris- plaques, papules or nodules. They can imitate tics similar to those of the primary site. other conditions, such as alopecia, infections Immunohistochemistry may be also useful for (erysipelas and paronychia), benign cysts (epi- diagnostic confirmation and exclusion of tumors dermoid or pilar), pyogenic granuloma, and originating in other organs. 36 Diseases of Thyroid 749

Thyroid papillary and follicular carcinomas Hyaluronic acid A biopolymer made of the express the thyroid transcription factor 1 (TTF-1) glucuronic acid and N-acetylglucosamine. and thyroglobulin (a glycoprotein synthesized in With a viscous texture, it exists in the syno- the cytoplasm of the thyroid follicular cells, and vial fluid, the vitreous humor, and the connec- detected in 95% of papillary carcinomas) [69]. tive tissue of numerous organisms, being an important glycosaminoglycan in articulation Therapeutic Approach composition. The therapeutic approach is determined accord- Lymphedema The accumulation of interstitial ing to clinical staging of the neoplasia. fluid rich in proteins of high molecular weight. Macroglossia The abnormal growth of the Management includes a partial or total thyroidec- tongue so that it reaches a size larger than the tomy followed by adjuvant radiotherapy to treat one allowed by the buccal cavity, resulting in invasion of the cervical region. It can be associ- impaired phonation and respiratory, suction, ated with chemotherapy with isolated doxorubi- and/or swallow function. cin, or associated with other chemotherapeutic Plasmapheresis An extracorporeal process agents, as well as the use of radioactive iodine. by which the blood collected from a patient Molecular targeted therapy aimed at specific is separated into its plasma and cell element receptors has shown promising outcomes. compounds. The prognosis for patients with thyroid met- Proptosis Proptosis is characterized by a dis- astatic papilliferous carcinoma of the skin is placement of the eyeball to the front of one usually unfavorable [64, 66]. There are, never- eye, or both eyes. theless, individuals with thyroid cutaneous Proto-oncogene (RET) RET proto-oncogene metastases who survived many years after the activating mutations may result in the devel- diagnosis [68, 66, 70]. Furthermore, with the opment of the thyroid medullary carcinoma. advent of molecular targeted therapies, such as Its research study is useful for the genetic tyrosine kinase inhibitors, the prognosis for tracking of thyroid medullary carcinoma. patients with metastatic disease, and mainly for Radioactive iodine Radioactive iodine treats those with a rearrangement during aberrant hyperthyroidism by gradually shrinking the transcription of the oncogenesis (RET), is bet- thyroid, ultimately destroying the gland. ter than the observed prognosis in individuals Rituximab A monoclonal chimeric antibody with thyroid papilliferous carcinoma who (murine/human) against an antigen that is the underwent treatment before the discovery of protein of the cell surface, CD20 these agents [71]. Thyroxine (T4) A hormone that plays a role in several body functions, including growth and metabolism. Tri-iodothyronine (T3) T3 and T4 (thyroxine) Glossary are hormones produced by the thyroid gland. They help to control the rate at which the body Cutis marmorata Manifests as skin changes uses energy, and are regulated by a feedback displaying violet spots on the trunk and limbs, system. which can be highlighted by cold temperature. Thyroid-stimulating hormone (TSH) Diplopia The condition when an individual TSH stimulates the production and release sees two images of the same object. of T4 (primarily) and T3. As necessary, T4 is Glycosaminoglycans Components of the converted to T3 by the liver and other tissues. connective tissue. They represent 30% of the Thyroid transcription factor 1 (TTF-1) body’s organic material and can exist as dif- TTF-1 regulates the transcription of the spe- ferent types, such as chondroitin sulfate for cific genes of the thyroid, the lung, and the cartilage, bone, or cornea; dermatan sulfate diencephalon. It is used in anatomic pathology for the dermis and the tendons; and heparan as a marker to determine whether a tumor has sulfate for the liver, lungs, and aorta. its origin in the lung or the thyroid. 750 S.I.T. Dornelles et al.

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