Non-Neoplastic Diseases of the Thyroid Gland

Clinical

• Heterotopic thyroid tissue may be seen in any location from the tongue (foramen cecum at the base of the tongue) to the suprasternal notch (site of the normal gland):

  • May represent failure of descent from foramen cecum (median anlage) or, less likely, differentiation of thyroid tissue in abnormal locations

• Excluding thyroglossal duct cysts, presence of heterotopic thyroid tissue is rare and almost exclusively seen in suprahyoid locations usually located in or close to midline:

  • Most common heterotopic focus for thyroid tissue is base of tongue, referred to as lingual thyroid (see below)

  • Other sites include (cranial to caudal direction):

    • –

      Sella turcica

    • –

      Submandibular region

    • –

      Larynx

    • –

      Trachea

    • –

      Mediastinum (superior > posterior)

    • –

      Aortic arch, pericardium, and heart

    • –

      Esophagus

  • More distant sites of heterotopic thyroid tissue include:

    • –

      Duodenal wall

    • –

      Hepatobiliary (liver, porta hepatis, gallbladder, common bile duct)

    • –

      Pancreas

    • –

      Adrenal gland

    • –

      Retroperitoneum

    • –

      Vagina and inguinal region

    • –

      Ovarian thyroid tissue is referred to as struma ovarii (see below).

• Rarely, multiple ectopic thyroid tissue may be present in separate sites in same patient.

• Diseases that affect thyroid gland proper may also affect ectopic thyroid tissues, including:

  • Inflammatory diseases (e.g., Hashimoto thyroiditis, Graves disease, others)

  • Goiter

  • Neoplasms

• Imaging with ¹²³ I may establish the diagnosis noninvasively.

• Etiology:

  • None known

  • Rarely, familial thyroid heterotopia may occur.

Pathology

• Histologically, heterotopic thyroid tissue includes presence of normal-appearing, colloid-filled thyroid follicles:

  • Cytomorphologic findings include round to oval nuclei with coarse nuclear chromatin lacking constellation of nuclear features diagnostic for thyroid papillary carcinoma.

  • C-cells are absent.

• Immunohistochemistry:

  • Unnecessary for identification but cells will be:

    • –

      Reactive for thyroglobulin, thyroid transcription factor 1, PAX8, CD56

    • –

      Nonreactive for calcitonin, neuroendocrine markers (e.g., synaptophysin, chromogranin)

• Cytogenetics and molecular genetics:

  • Few reports evaluating molecular alterations in thyroid ectopia were without molecular alterations associated with malignant tumors of follicular cell derivation (BRAFV600E, N-RAS, H-RAS, K-RAS).

Differential Diagnosis

• Any thyroid tissue found lateral to large neck vessels (i.e., carotid artery, jugular vein) should be considered metastatic tumor rather than ectopia:

  • Especially true for foci of thyroid follicles in lymph nodes:

    • –

      Represent metastatic papillary thyroid carcinoma even in absence of diagnostic nuclear features

• Different types of malignant neoplasms may be seen uncommonly associated with heterotopic tissues, including papillary carcinoma and follicular carcinoma:

  • In such circumstances, evaluation indicated to exclude origin from thyroid gland proper

    • –

      In presence of malignant follicular-derived neoplasm within thyroid gland proper, presence of thyroid carcinoma in “ectopic” site represents metastatic disease.

    • –

      Only in absence of malignant follicular-derived neoplasm within thyroid gland proper can presence of thyroid carcinoma in “ectopic” site be considered as originating from the ectopic site.

• Presence of thyroid follicles in midline or paramidline lymph nodes may represent thyroid inclusions or metastatic papillary carcinoma (see Thyroid Tissue in Lymph Nodes later in this chapter).

Treatment and Prognosis

• In general, heterotopic thyroid tissue is benign.

• Complete or partial agenesis of thyroid gland is extremely rare.

Clinical

• Thyroid tissue restricted to lingual region is rare, occurring in 1 in 100,000 persons.

• Affects women more than men (3 : 1 to 7 : 1); most often diagnosed in adolescence but may occur over a wide age range from birth to the seventh decade of life

• Most frequently seen along the midline of base of the tongue between the foramen cecum and the epiglottis; rarely, body of the tongue (sublingual) may be affected.

• Majority of patients who are symptomatic are women; contributing factors are thought to be related to puberty, pregnancy, and menopause.

• Most common symptom is dysphagia.

  • Lingual thyroid may grow large, resulting in dys­pnea, orthopnea, and severe respiratory distress.

  • Other symptoms may include bleeding, voice changes, a foreign body sensation, snoring, and sleep apnea.

• Clinical presentation:

  • 70% of patients with symptomatic lingual thyroid are hypothyroid.

  • 10% suffer from cretinism.

  • Hyperthyroidism exceptionally rare finding

• In greater than 75% of patients, cervical thyroid tissue is absent (total migration failure) and lingual thyroid represents only thyroid tissue present:

  • In such situations surgical removal of lingual thyroid results in hypothyroidism.

• Appropriate preoperative clinical work-up for lingual thyroid includes:

  • Routine blood work, including thyroid function tests thyrotropin, thyroxine, and thyroid hormone binding ratio

  • Scintigraphy with technetium or radioiodine studies, computerized tomography, or magnetic resonance imaging to:

    • –

      Determine whether normally placed thyroid tissue is present or absent

    • –

      Determine whether there are other ectopic foci of thyroid tissue (thyroid follicles may be found in hyoid region)

    • –

      Determine functional activity of lingual thyroid tissue

• Incisional biopsies must be performed with caution because this may cause sloughing of gland, infection, necrosis, or hemorrhage.

• Radiology:

  • Tc-99m pertechnetate scanning is an efficient diagnostic tool that yields high-quality images in this clinical setting.

  • Computed tomography shows a mass at the base of the tongue with a greater density than the tongue.

  • On MR imaging, a well-defined mass of low-intermediate T2 signal in the midline base of the tongue, neither with invasive tendency nor with a cervical thyroid gland in the normal site, strongly indicates a lingual thyroid.

Pathology

Differential Diagnosis

• Lymphoepithelial cyst of oral cavity

• Cribriform adenocarcinoma of minor salivary glands of oral cavity (See Section 7):

  • May show histologic similarities to papillary thyroid carcinoma

  • Absence of immunoreactivity for thyroglobulin and TTF-1

• Low-grade nasopharyngeal papillary adenocarcinoma (See Section 3):

  • May show histologic similarities to papillary thyroid carcinoma

  • Lesional cells are:

    • –

      TTF-1 positive (nuclear staining)

    • –

      Thyroglobulin negative

Treatment and Prognosis

• Therapy varies:

  • Asymptomatic euthyroid patients with ectopic thyroid do not usually require therapy but are kept under observation.

  • For symptomatic patients, surgical excision (intraorally or pharyngotomy) is preferred treatment:

    • –

      Transoral robotic surgery (TORS) has provided minimally invasive approach to completely and safely excise ectopic lingual thyroid.

    • –

      In patients without normally situated cervical thyroid tissue or other ectopic foci of thyroid tissue, auto-transplantation of thyroid tissue into the neck muscles can be done.

  • Other modes of therapy include:

    • –

      Shrinking the mass by using thyroid hormones or use radioactive iodine ( ¹³¹ I) to ablate the lingual thyroid

    • –

      Use of radioactive iodine results in destruction of other thyroid tissue and may also cause sloughing of the gland and hemorrhage.

  • In case of absence of orthotopic thyroid tissue, long-term thyroid hormone replacement recommended

• Prognosis is good:

  • Surgical resection of lingual thyroid glands achieves significant improvement in patient symptoms with low rates of recurrence.

  • Complications of surgery are uncommon and may include:

    • –

      Postoperative bleeding and epiglottic perforation, airway obstruction secondary to angioedema

• Malignant neoplasms may arise from lingual thyroid:

  • Papillary thyroid carcinoma is the most common type.

  • May be associated with cervical nodal metastasis

  • Treatment best managed with surgical excision of all thyroid tissue followed by radioactive iodine ablation

  • In such circumstances, evaluation indicated to exclude origin from thyroid gland proper

    • –

      In presence of malignant follicular-derived neoplasm within thyroid gland proper, presence of thyroid carcinoma in “ectopic” site represents metastatic disease.

    • –

      Only in absence of malignant follicular-derived neoplasm within thyroid gland proper can presence of thyroid carcinoma in “ectopic” site be considered as originating from the ectopic site.

Clinical

• No gender predilection; occurs over a wide age range but the majority of patients present before the fourth decade of life

• Majority of cases occur in the midline of the neck above the thyroid isthmus but below level of the hyoid bone:

  • Thyroglossal duct cysts are nearly always connected to hyoid bone.

  • Uncommonly, TDCs may occur lateral to midline but do not occur in the lateral portion of the neck (i.e., lateral to jugular vein).

• Clinical presentation of an uninfected TDC usually that of asymptomatic midline neck mass:

  • Mass typically moves upward on swallowing.

  • Inflamed or infected TDCs may be associated with tenderness and pain.

  • Extrinsic airway compression in neonates with apnea, cyanosis, and respiratory compromise may uncommonly occur.

• Radiology:

  • Midline round or elongated cystic lesion

  • Expansion and/or destruction of the cartilaginous structure of the hyoid bone may be seen.

  • Seldom contains enough thyroid follicular tissue to be seen on scintiscan

  • Presence of nodular soft tissue excrescences in a midline cystic neck mass on CT scan may suggest the possibility of a papillary carcinoma arising in a thyroglossal duct cyst.

Pathology

Differential Diagnosis

• Thymic cyst

• Metastatic (cystic) papillary thyroid carcinoma

• Laryngocele

• Branchial cleft cyst

• Squamous cell carcinoma:

  • Presence of extensive squamous metaplasia may raise concern for possible presence of squamous cell carcinoma but metaplastic foci typically bland-appearing lacking cytomorphologic features of carcinoma

Treatment and Prognosis

• Surgery is preferred treatment:

  • Sistrunk procedure includes en bloc surgical resection of cyst, middle third of the hyoid bone, and suprahyoid tract up to base of tongue (foramen cecum).

• Adequate surgery results in cure with low to no recurrences:

  • Reported recurrence rates range from 0% to 11%.

    • –

      Extended surgical procedures prevent recurrence.

• Benign and malignant neoplasms may occur in the setting of a thyroglossal duct cyst:

  • Benign tumors include follicular adenoma.

  • Development of a carcinoma in a thyroglossal duct cyst is rare:

    • –

      Most carcinomas that develop in this setting are papillary carcinomas.

    • –

      Rare examples of follicular carcinoma (oncocytic, nononcocytic types), undifferentiated (anaplastic) thyroid carcinoma, squamous (epidermoid) carcinoma, and adenosquamous carcinoma

      • ▪

        Squamous (epidermoid) carcinoma and adenosquamous carcinoma in all probability arise from cyst lining rather than from thyroid cell component.

  • C-cell–related lesions, including medullary thyroid carcinoma, do not occur in thyroglossal duct cysts due to the different embryologic derivation of the C-cells.

• Papillary thyroid carcinoma arising in the setting of a thyroglossal duct cyst:

  • Occur more commonly in women than men

  • Occur over a wide age range (first through eighth decades of life)

  • Are of usual morphologic type:

    • –

      Variant types may include follicular variant, tall cell variant.

  • Similar (excellent) prognosis to that of papillary thyroid carcinoma arising in thyroid gland proper

  • May recur or metastasize and rarely may be lethal

  • Detailed evaluation of thyroid gland proper indicated

  • No clear consensus exists regarding optimal management, which may include:

    • –

      Sistrunk procedure

    • –

      Sistrunk procedure with total thyroidectomy

    • –

      Sistrunk procedure with total thyroidectomy and neck dissection

  • Following total thyroidectomy:

    • –

      Approximately one third may have concomitant papillary thyroid carcinoma in thyroid gland proper:

      • ▪

        Often represent incidental papillary microcarcinomas

    • –

      Nodal cervical metastasis may be present.

    • –

      Such findings suggest that ultrasonography and, if warranted, fine-needle aspiration biopsy should be performed, and in presence of suspected lesion in thyroid gland proper and/or lymph node, Sistrunk procedure with total thyroidectomy, and neck dissection should be performed.

Clinical

• Presence of thyroid tissue within an ovarian teratoma varies and may be a function of adequate sampling:

  • Benign thyroid tissue occurs in from 5% to 15% of mature ovarian teratomas.

• May occur in a wide range of ages including from second to ninth decades of life

• Clinical presentation (of an ovarian teratoma, in general) is that of an abdominal mass and acute abdominal pain; rarely, may initially be detected as an ovarian mass complicating pregnancy.

• Functional abnormalities may occur and include:

  • Hyperthyroidism

  • Rarely struma ovarii may coexist with Graves disease.

  • Patients may present with ascites that, in the presence of an ovarian mass, may be suspicious for ovarian carcinoma.

  • Ascites and hydrothorax (“pseudo-Meig syndrome”) may occur and may be associated with raised serum CA 125 levels.

• Bilaterality may occur in 5% to 10% of cases.

• Radiology:

  • CT shows cystic components with slightly high density.

  • MRI findings include the presence of multilocular cystic mass with a variable signal intensity within loculi.

  • Loculi or small cysts within septations may show low signal intensity on T1-weighted images and very low signal intensity on T2-weighted images.

  • Gd-DTPA enhanced T1-weighted images may show the presence of thick septations and locally thickened wall with marked enhancement (corresponding microscopically to thyroid tissue).

Pathology

Thyroid Neoplasms in Struma Ovarii

• Thyroid neoplasms arising in setting of struma ovarii are rare:

  • In theory, any neoplasm affecting the thyroid follicular epithelium proper can occur in setting of struma ovarii.

  • Most common type of thyroid neoplasm to occur in this setting is papillary thyroid carcinoma:

    • –

      May be referred to as malignant struma

    • –

      Most are conventional type and follicular variant; less commonly other variants reported, including tall cell variant

    • –

      Diagnosis is based on finding architectural, but more importantly, on the cytomorphologic features of papillary carcinoma.

    • –

      Invasive growth (vascular or stromal) is not required for a diagnosis of papillary carcinoma.

    • –

      Follicular carcinoma may occur in the setting of struma ovarii:

      • ▪

        In contrast to diagnosis of papillary carcinoma in this setting, a diagnosis of follicular carcinoma is based on presence of capsular or vascular invasion and absence of cytomorphologic features of papillary thyroid carcinoma.

Differential Diagnosis

• Metastasis to ovary from a primary thyroid carcinoma:

  • Extraordinarily rare occurrence

  • Synchronous or metachronous papillary thyroid carcinoma within struma ovarii (malignant struma) and thyroid gland reported:

    • –

      Rare case reports

    • –

      Differences in microscopic features, immunohistochemical staining (HBME1, CK19, galectin-3), and molecular genetics (BRAF V600E, RAS, RET/PTC) reported

Treatment and Prognosis

• Treatment for ovarian teratoma including struma ovarii is surgical excision:

  • Unilateral salpingo-oophorectomy or total abdominal hysterectomy and salpingo-oophorectomy (unilateral or bilateral)

• Surgical removal is curative.

• In setting of benign struma ovarii, if there is a normally situated (cervical) thyroid gland without abnormalities, then surgical intervention relative to the normally situated thyroid gland not indicated

• Treatment for malignant struma ovarii is surgical excision:

  • Unilateral salpingo-oophorectomy or total abdominal hysterectomy and salpingo-oophorectomy (unilateral or bilateral)

  • Total thyroidectomy also performed:

    • –

      Required to treat with radioactive iodine

• Metastatic disease from papillary carcinoma in struma ovarii may occur and include such sites as:

  • Contralateral ovary, peritoneum, regional lymph nodes, liver, and brain

• Overall prognosis associated with malignant thyroid tumors in struma ovarii has been good:

  • 89% 10-year survival

  • 84% 25-year survival

  • Recurrence may occur within months or decades following initial resection.

  • Although unusual, fatalities secondary to widespread metastatic disease have occurred:

    • –

      May occur years following initial diagnosis

  • Long-term follow-up indicated

• Clinical features predictive of biologic malignancy in struma ovarii include:

  • Presence of adhesions, peritoneal fluid (> or = 1 L), or a serosal rent

• Pathologic factors predictive of a poorer prognosis in struma ovarii include:

  • Large size (> or = 10 cm), strumal component more than 80%, extensive papillary carcinoma, especially with solid areas, necrosis, and increased mitotic activity (≥5 mitoses per 10 high-power fields)

• So-called benign strumatosis has been used for presence of benign thyroid follicular epithelium within the peritoneum:

  • These foci should be considered as representing metastatic thyroid carcinoma.

• Rare instances of non-Hodgkin malignant lymphomas have been reported in struma ovarii.

Clinical

• Majority of women with strumal carcinoids are postmenopausal, but this tumor may occur over a wide age range from the third through eighth decades of life.

• Clinical presentation is similar to that of any ovarian teratoma presenting as an enlarging abdominal mass or identified as an incidental finding on routine gynecologic (or urologic) evaluation.

  • Other (uncommon) clinical presentations may include:

    • –

      Constipation, pain on defecation, virilization, hirsutism, symptoms related to function of the thyroid component, and association with multiple endocrine neoplasia 2A:

      • ▪

        Peptide YY found in association with symptoms of constipation

    • –

      Extremely rare occurrence of carcinoid syndrome has been reported.

      • ▪

        Similarly rare occurrence of carcinoid heart disease has been reported.

    • –

      Rarely reported in association with struma ovarii and malignant transformation, including follicular variant of papillary thyroid carcinoma, mucinous cystadenomacarcinoma, and strumal carcinoid

• Histogenesis of strumal carcinoid remains contro­versial:

  • Most likely, histologic elements of this tumor arise from a common progenitor cell such as gives rise to the ovarian teratoma (i.e., endodermal germ cell)

  • No evidence to support C-cell origin for carcinoid component

Pathology

Differential Diagnosis

• Atypical carcinoid:

  • Extraordinarily rare examples reported

  • As compared to (typical) strumal carcinoid tumor shows greater degree of nuclear pleomorphism, higher mitotic rate, and focal necrosis

  • May metastasize including to bone

Treatment and Prognosis

• Treatment is surgical removal.

  • May include:

    • –

      Unilateral salpingo-oophorectomy in younger-age patients

    • –

      Bilateral oophorectomy and hysterectomy in older-age patients

• Prognosis:

  • Considered excellent following surgical removal even in presence of metastatic tumor

  • Fatalities have been reported.

Pathology

• Histology of squamous metaplasia includes:

  • Bland appearance in which nests of cells are round to oval (including “morule” formation) without infiltrative growth

  • Keratinization and intracellular bridges can be seen.

  • Basaloid cells may be present.

  • Cytologic atypia absent, including:

    • –

      Lack of significant pleomorphism and atypia

    • –

      Low nuclear-to-cytoplasmic ratio

    • –

      Mitotic figures can be seen but are limited in number and atypical mitoses not present.

  • Absence of associated mucous cells

• Extent of squamous metaplasia may be:

  • Focal (more common)

  • Extensive (less common)

• Immunohistochemistry:

  • Cytokeratin (AE1/AE3) positive

  • Variable reactivity for thyroglobulin, TTF-1 may be negative

  • p63 positivity can be seen with predominant positivity at periphery of cell nests.

  • Calcitonin, chromogranin, carcinoembryonic antigen (CEA), and high molecular weight keratin (e.g., 34βE12) negative

• Mutational analysis:

  • BRAF and RAS negative

Differential Diagnosis

• Primary thyroid squamous cell carcinoma and mucoepidermoid carcinoma (MEC) (see Chapter 28 ):

  • Both thought to arise from squamous metaplasia of thyroid follicular epithelial cells

  • Majority of cases of squamous metaplasia lack the cytologic atypia and/or infiltrative growth of squamous cell carcinoma.

  • Absence of admixture of epidermoid cells, mucous cells, and intermediate cells allows differentiation from MEC.

Treatment and Prognosis

• Predicated on setting in which the squamous metaplasia occurs

Pathology

• Histologically, an oncocytic cell characterized by presence of an abundant eosinophilic granular-appearing cytoplasm

• Oncocytic cytoplasmic changes:

  • Associated with enlargement of the cell nucleus:

    • –

      This alteration in nuclear size may lead to an erroneous diagnosis of papillary thyroid carcinoma.

    • –

      Diagnostic confusion may be minimized by:

      • ▪

        Evaluating the setting in which changes are occurring (e.g., presence of a prominent lymphocytic cell infiltrate as seen in chronic lymphocytic thyroiditis)

      • ▪

        Evaluating for other changes that may support a diagnosis of papillary thyroid carcinoma, in particular constellation of nuclear changes that in addition to nuclear enlargement includes nuclear variation in size and shape, clear to very fine-appearing nuclear chromatin, margination of chromatin along nuclear membrane, nuclear crowding and overlapping, nuclear grooves, and nuclear pseudoinclusions

  • In addition to enlarged nuclei, cytoplasmic oncocytic change is often associated with prominent central-located eosinophilic nucleoli

• Retrogressive changes:

  • Oncocytic cells perhaps due to oxygen-sensitive nature of mitochondria may be easily traumatized, leading to marked degenerative changes following such events as fine-needle aspiration or core biopsy:

    • –

      Degenerative changes may include pseudopapillary or papillary growth, infarction, necrosis, and hemorrhage.

• Clear cell changes in follicular epithelial cells represent a degenerative process and may be associated and perhaps arise from oncocytic metaplasia.

• Special stains for mitochondria include:

  • Phosphotungstic acid hematoxylin (PTAH): red granular appearance

  • Novelli stain: dark purple appearance

• Immunohistochemistry:

  • Cytokeratin and vimentin positive

  • Weakly thyroglobulin reactive; TTF1 positive

  • Synaptophysin, chromogranin, and calcitonin negative

• Electron microscopy:

  • Cytoplasm filled with mitochondria showing abnormalities in size, shape, and content

• No specific treatment:

  • Treatment and prognosis are predicated on the setting in which the oxyphilic cell changes are seen.

Pathology

• Most measure 0.1 mm on average but may attain larger sizes.

• Appear as small, discrete cell nests, cords, or clusters interspersed among thyroid follicles

• Thought to be composed of two cell types, main cells and C-cells:

  • Predominant (main) cells composed of epithelial cells with:

    • –

      Round to oval-shaped cells with elongated to round-appearing nuclei, finely granular nuclear chromatin, and acidophilic cytoplasm

    • –

      Nuclear grooves may be present.

    • –

      Squamoid (epidermoid) differentiation may be present.

      • ▪

        Keratinization (horny pearl formation or individual cell) and intercellular bridges are not found.

    • –

      Cystic change may be present:

      • ▪

        Referred to as cystic SCN

      • ▪

        Lined by flattened multilayered epithelium most often with squamoid features and less commonly by ciliated columnar epithelium

      • ▪

        Dense eosinophilic intraluminal material may be present.

    • –

      Rarely, oncocytic cytoplasmic change reported (oncocytic solid cell nests):

      • ▪

        Acquire mitochondrial alterations similar to those seen in follicular cells and C-cells

  • Second less prominent C-cells composed of cells with clear-appearing cytoplasm and round nuclei

• May merge with thyroid follicle to create so-called mixed follicle

• Mucicarminophilic material can be found:

  • Presence of mucosubstances in SCN thought to be degenerative changes of epidermoid cells, possibly representing true endodermal-derived C-cell conglomerates

• Immunohistochemistry:

  • Main cells are:

    • –

      Cytokeratins (AE1/AE3, CAM5.2, CK903 (34βE12), CK7, CK19) positive

      • ▪

        CK20 negative

    • –

      Strongly express p63, as well as carcinoembryonic antigen

    • –

      Galectin 3 positive

    • –

      Typically negative for thyroglobulin, TTF-1, HBME1, calcitonin, and parathyroid hormone

  • C-cells are:

    • –

      Positive for calcitonin, chromogranin, synaptophysin

    • –

      Positive for cytokeratins (AE1/AE3, CAM5.2, and CK 7)

    • –

      Thyroglobulin negative

    • –

      Focal immunoreactivity for TTF-1 can be found.

    • –

      p63 negative

  • These findings demonstrate a dual cell population in solid cell nests with main cells of the solid cell nests displaying a basal/stem cell phenotype (p63 and basal cytokeratin positivity) and C-cells showing features of parafollicular differentiation.

• Cytogenetics and molecular genetics:

  • Single case of SNC hyperplasia reported to demonstrate BRAF (V600E) mutation and BRAF (G593D) mutation

    • –

      Supporting histogenetic link between main cells of SNC and papillary thyroid carcinoma

    • –

      Suggesting solid cell nest hyperplasia as precursor lesion of papillary thyroid carcinoma

Differential Diagnosis

• Papillary thyroid carcinoma

• Medullary thyroid carcinoma

Iron

• Following hemorrhage with release of iron from red blood cells, resorption takes place and iron is converted to hemosiderin, which is stored in cell cytoplasm of phagocytizing cells (macrophages) as well as in thyroid follicular cells.

• In thyroid gland, hemosiderin can be found in virtually all pathologic conditions and represents an incidental finding.

• Reflects secondary phenomenon due to hemorrhage and can follow trauma (e.g., post–fine-needle aspiration biopsy, core biopsy) identified in adenomatoid nodules or various neoplasms

• Hemosiderin may be found in macrophages, within the stromal tissues, or within the follicular epithelial cells:

  • Hemosiderin is readily apparent in hematoxylin- and eosin-stained slides and appears as intracytoplasmic coarse brown to yellow pigment.

  • If necessary, iron stains (Prussian blue, Mallory) can be used to identify iron and distinguish it from other pigments.

• Rarely, iron can be stored in the thyroid as a component of a disorder of iron metabolism rather than a secondary phenomenon due to hemorrhage.

• Most cases of iron deposition not associated with thyroid dysfunction:

  • Uncommonly, secondary hypothyroidism may develop.

Lipofuscin

• Lipofuscin pigment represents degenerative (aging) phenomenon in which there is intracytoplasmic accumulation of small yellow to light brown granular-appearing pigment.

• In thyroid gland, lipofuscin pigment can be seen within follicular epithelial cells.

• True nature of lipofuscin has yet to be determined, but it has been shown to react with:

  • Lipid (Sudan IV) and lipofuscin stains

  • Shows diastase-sensitive, periodic acid-Schiff positive intracytoplasmic material

  • Shows lysosomes by electron microscopy

  • Contains the presence of histidine and tryp­tophan

  • Iron staining is absent.

• Lipofuscin deposition in thyroid gland is an incidental finding, more often seen in thyroid glands from older individuals.

• There is no evidence to indicate that presence of lipofuscin within any cell, including thyroid follicular cells, causes dysfunction or functional compromise of that cell.

Clinical

• Most common clinical disorder of thyroid function

• Most often caused by disorder of thyroid gland leading to decrease in thyroidal production and secretion of thyroxine (T ₄ ) and triiodothyronine (T ₃ ) invariably accompanied by increased thyrotropin (TSH) secretion

• May result from diseases or treatments that destroy thyroid tissue or interfere with thyroid hormone biosynthesis

• Causes of hypothyroidism are listed in Box 27-4 :

  • Worldwide, iodine deficiency most common cause of hypothyroidism

  • In areas where iodine intake is adequate, most common causes are chronic autoimmune thyroiditis and radiation-induced hypothyroidism secondary to radioactive iodine treatment of hyperthyroidism.

  Box 27-4

  Causes of Hypothyroidism

  Primary Hypothyroidism

  • Chronic autoimmune thyroiditis (atrophic and goitrous forms)

  • Radiation treatment ( ¹³¹ I therapy, external radiotherapy to head and neck for nonthyroid malignant disease)

  • Surgery (total or subtotal thyroidectomy)

  • Iodine deficiency

  • Drug-induced (antithyroidal medications: lithium, iodine, and iodine-containing drugs and radiographic contrast material)

  • Infiltrative diseases of thyroid (amyloidosis, scleroderma)

  • Defective thyroid hormone biosynthesis

  • Congenital defects in thyroid hormone biosynthesis

  • Developmental abnormalities (thyroid dysgenesis)

  Central Hypothyroidism (Secondary and Tertiary Hypothyroidism)

  • Pituitary disease (neoplasms, infarcts, trauma)

  • Hypothalamic disease (neoplasms, infectious disease, trauma)

  Transient Hypothyroidism

  • Silent (painless) thyroiditis (including postpartum thyroiditis)

  • Subacute thyroiditis

  • After withdrawal of thyroid hormone therapy in euthyroid patients

• Equal gender predilection; may occur in all age groups but more commonly affects adults

• May be clinically overt or subclinical; subclinical hypothyroidism is defined as elevated serum TSH and normal thyroxine (T ₄ ) and T ₃ concentrations.

• Clinical manifestations independent of cause:

  • Overt hypothyroidism defined as:

    • –

      High serum TSH concentrations and low serum free T ₄ concentrations

      • ▪

        Many but not all patients have symptoms and signs of hypothyroidism but clinical spectrum of severity may be broad even in overt hypothyroidism such that some patients may have very subtle manifestations of disease (few signs and symptoms), whereas others may have more extreme manifestations (myxedema coma).

  • Subclinical hypothyroidism defined as:

    • –

      High serum TSH concentrations (usually <10 mU/L) and normal serum free T ₄ concentrations

      • ▪

        Patients typically have few or no symptoms and signs of hypothyroidism.

• Clinical symptoms and signs of hypothyroidism include (in no particular order):

  • Fatigue, lethargy, sleepiness, mental impairment, depression, cold intolerance, slow movements, slow speech, hoarseness, bradycardia, dry skin, decreased perspiration, nonpitting edema, anemia, decreased appetite, constipation, weight gain, arthralgia, hyporeflexia, paresthesia, menstrual abnormalities (typically menorrhagia), and infertility

• Three types of clinical evidence suggest hypothy­roidism:

  • Symptoms and signs consistent with thyroid hormone deficiency

  • Evidence of diseases, previous treatment, or exposure known to cause thyroid or pituitary failure

  • Presence of disorders associated with increased risk of chronic autoimmune thyroiditis

• Myxedema:

  • Severe hypothyroidism sometimes referred to as myxedema but myxedema is not synonymous with hypothyroidism

  • Represents accumulation of glycosaminoglycans in soft tissues (subcutaneous and other interstitial sites), resulting in nonpitting edema of hypothyroid patients

  • Most common in severe (long-standing) primary hypothyroidism

• Factors potentially influencing clinical features of hypothyroidism include:

  • Patient age:

    • –

      In children and adults effects are potentially reversible.

    • –

      In infants, hypothyroidism may result in irreversible mental and physical retardation (see below, endemic cretinism) unless treatment is initiated early.

  • Presence of other diseases:

    • –

      If there is not generalized destruction of thyroid gland, compensatory increase in TSH secretion may maintain thyroid secretion at near normal levels so that the clinical manifestations of hypothyroidism may remain subclinical for years.

  • Rate at which hypothyroidism develops:

    • –

      Those patients with rapid onset of hypothyroidism have more symptoms than those patients who develop it gradually.

• Laboratory testing:

  • Low serum free thyroxine (T ₄ ) levels and elevated serum thyroid-stimulating hormone (TSH) levels confirm presence of hypothyroidism.

  • Serum triiodothyronine (T ₃ ) concentrations also decline but not frankly low until thyroidal T ₃ -secretion and hepatic T ₄ –to-T ₃ conversion.

• Generalized myxedema:

  • Develops in patients with long-standing, severe generalized thyroid deficiency

  • Clinical features result from glycosaminoglycan accumulation in soft tissues resulting in a full face, nonpitting periorbital and cutaneous edema (most marked around the hands), which does not resorb during recumbency (unlike cardiogenic edema).

  • The soft tissue fluid accumulation is composed of a mixture of mucopolysaccharides, hyaluronic acid, and chondroitin sulfate.

  • Fluid may accumulate in virtually every part of the body, some of these sites in which fluid accumulation occurs due to thyroid deficiency and result in clinical signs and symptoms