The Spectrum of Endocrine Pathology

Abstract

Endocrine pathology comprises a spectrum of disorders originating in various sites throughout the body. Some disorders affect endocrine glands, and others arise from endocrine cells that are dispersed in non-endocrine tissues. Endocrine cells can broadly be classified as neuroendocrine, steroidogenic, or thyroid follicular cells; these three families have distinct embryologic origins, morphologic structure, and biochemical hormone synthetic pathways. Lesions affecting the endocrine system include developmental abnormalities, inflammatory processes that can be infectious or autoimmune, hypofunction with atrophy or hyperfunction caused by hyperplasia secondary to pathology in other sites, and neoplasia of many types. Understanding endocrine pathology requires knowledge of both structure and function, including the biochemical signaling pathways that regulate hormone synthesis and secretion. Molecular genetics has clarified sporadic and hereditary disease that is common in this field.

Introduction

Endocrine pathology is a relatively new subspecialty in the field of pathology [1] and it has not yet been defined with any formal accreditation standards. Most institutions do not recognize a dedicated scope of practice, and in many that do acknowledge its existence, it is assigned haphazardly to specialists who have other areas of expertise (such as “Head and Neck” or “Gastrointestinal” pathology) as an additional responsibility. In a few institutions, there is a dedicated team of experts who work with oncologists, endocrinologists, surgeons, and radiologists to form a multidisciplinary group with a depth of understanding of the scope of endocrine diseases.

The complexity of this field is emphasized by the fact that endocrine pathology has not only structural and functional implications for the affected organ, but also causes dysregulation of other organs. Endocrine disorders therefore have systemic implications, affecting target organs, controlling organs, overall physical homeostasis, and psychosocial wellbeing. The endocrine pathologist must understand not only the structure of the various endocrine cells and organs, but also must be familiar with the biochemistry of hormones, including the various assays and their limitations. In addition, the molecular genetics of endocrine pathology has been pivotal to making progress in our understanding of sporadic and hereditary disease. Endocrine pathology incorporates some of the most commonly inherited tumor syndromes, and has led the way in developing genotype–phenotype correlations in oncology. The complexity results in a need for extensive immunohistochemistry, second only to hematopathology, and for critical analysis of predictive and prognostic biomarkers.

Endocrine tissues can be generally divided into three types (Table 1). The thyroid is the site of the most common endocrine pathologies that come to the attention of the pathologist. Neuroendocrine cells are the most numerous and widely dispersed throughout the entire body. Steroidogenic tissues are critical for survival and reproduction; they include the adrenal cortex as well as the gonads that are often managed by experts in gynecologic and genitourinary pathology but there is a great deal of overlap of specific steroidogenic pathologies with the adrenal.

Table 1.

The spectrum of endocrine tissues

Tissue	Presumed embryologic origin	Hormone product(s)	Diagnostic biomarkers
			Transcription factors	Cytoplasmic enzymes and others	Hormone products	Others
Thyroid	Endoderm	Thyroid hormones: T3, T4	PAX8, TTF1	NIS	Thyroglobulin
Neuroendocrine — epithelial	Endoderm (?neuroectoderm)	Peptide hormones	INSM1 Others based on location	Synaptophysin, chromogranins	Many	Keratins
Neuroendocrine — paraganglia	Neuroectoderm	Catecholamines	INSM1, GATA3, PHOX2B	Synaptophysin, chromogranins, tyrosine hydroxylase		Keratin negative
Steroidogenic	Mesoderm	Steroid hormones	SF1	CYP11B1, CYP11B2

In this review, we will summarize the current understanding of the scope of endocrine pathology.

Thyroid

The thyroid develops from the endodermal median anlage (which arises from the floor of the foregut) that gives rise to follicular epithelial cells and two lateral anlagen (which arise from the endoderm of the fourth and fifth branchial pouches as the ultimobranchial bodies) that are the source of C cells, the neuroendocrine cells of this gland.

Follicular thyroid cells are epithelial cells characterized by the ability to produce thyroglobulin and thyroid hormones T3 and T4. These cells form follicles lined by a single epithelial cell layer surrounding colloid which is thyroglobulin (Fig. 1a). To ensure the retention of thyroglobulin, they form tight junctions along their lateral borders; their luminal surface has numerous microvilli that allow resorption of colloid. They express thyroid peroxidases, the sodium iodide symporter (NIS) to enhance iodine uptake, and pendrin at the apex to regulate chloride/iodide exchange, all involved in the iodination of thyroid hormones. Follicular cells are characterized immunohistochemically by expression of TTF1 (Fig. 1b), thyroglobulin (Fig. 1c), PAX8 (Fig. 1d), and keratins [2, 3]. Thyroid C cells comprise 0.1% of the glandular mass of the thyroid and produce calcitonin; they are located predominantly at the junction between the upper one-third and middle third of the lateral lobes of the thyroid but may be difficult to identify on histologic sections. C cells express TTF1, calcitonin, chromogranin A, synaptophysin (inset in Fig. 1c), CEA, and keratins, while staining for PAX8 is dependent on the antibody utilized (monoclonal PAX8 antibodies are generally negative) [2, 4].

Fig. 1.

Normal thyroid. a Thyroid tissue is characterized by follicles comprised of a single layer of thyroid epithelial cells surrounding colloid. b TTF1 immunostain show a strong diffuse nuclear reactivity throughout the follicular thyroid cells. c Thyroglobulin shows immunopositivity in the thyroid follicular cells as well as the colloid. The inset shows rare C-cells (neuroendocrine cells) which are positive for the neuroendocrine marker synaptophysin; they also stain for a chromogranin A and calcitonin (not shown). d PAX8 antibody, particularly the monoclonal antibody (not the polyclonal antibody), stains thyroid follicular cells and distinguishes them from C-cells and C-cell neoplasms (medullary thyroid carcinoma) and parathyroid tissue and tumors which are generally negative for monoclonal PAX8

Developmental Disorders

Developmental disorders include hypothyroidism due to genetic defects that prevent normal thyroid development, transcription, iodination/deiodination, and organification of thyroid hormones and aberrant/ectopic thyroid tissue, as well as thyroglossal duct cysts.

Primary congenital hypothyroidism is caused by thyroid dysgenesis (aplasia is absent thyroid, or hypoplasia which is underdeveloped thyroid), by dyshormonogenesis (defects in thyroid hormone synthesis), and by disorders of thyroid hormone transport and action [5]. Thyroid dysgenesis is the most common cause of primary congenital hypothyroidism and is associated with alterations in genes that are required for thyroid follicular cell differentiation: TSHR, FOXE1, PAX8, NKX201, and NKX2-5. Dyshormonogenesis is associated with alterations in genes involved in hormone synthesis: SLCA5, DEHAL1, DUOX2, DUOXA2, SCL6A4, TPO, Tg [5]. Mutations in a thyroid hormone transporter monocarboxylate transporter 8 (MCT8) reduce intracellular bioavailability of TH, and thyroid hormone resistance can be due to mutations in thyroid hormone receptors [6]. The lack of feedback suppression in patients with dyshormonogenesis or reduced thyroid hormone transport and action causes elevated TSH that may result in goiter.

Ectopic thyroid tissue is functioning thyroid tissue outside the usual location of the thyroid gland. In addition to being located along the normal developmental path of the thyroid gland, including lingual thyroid and thyroid remnants along the anterior neck, ectopic thyroid tissue has been reported in unusual locations such as the heart, esophagus, and gallbladder [7–9].

Thyroglossal duct cysts arise in remnants of the developing gland and usually contain small groups of follicles in the cyst wall.

Inflammatory Lesions

Inflammatory processes affecting the thyroid include acute processes such as infection, granulomatous disorders, and chronic inflammatory autoimmune-type thyroiditis.

Acute inflammation in the thyroid gland is rare and usually associated with infection. Acute inflammation can also be seen with trauma or radiation. Acute suppurative thyroiditis is rare, accounting for 0.1 to 0.7% of all thyroid disease [10].

Granulomatous inflammation can be seen in the thyroid due to trauma, infection, sarcoidosis, and what is clinically regarded as subacute thyroiditis. Small poorly formed “granulomas” referred to as “palpation thyroiditis” — multifocal granulomatous folliculitis [11] — are common incidental findings in surgically resected thyroids (Fig. 2a); they are due to rupture of follicles by compression, resulting in release of thyroglobulin that is a sequestered antigen and incites a foreign body type of reaction. Infections associated with granulomatous inflammation in the thyroid include bacteria, such as tuberculosis, and fungal organisms. The thyroid can, although very infrequently, be involved directly by sarcoidosis in individuals with systemic sarcoidosis [12].. Materials such as Teflon from implants for vocal cord paralysis may rarely migrate to the thyroid, cause granulomas, and clinically may be mistaken for a thyroid tumor [13]. Subacute thyroiditis (deQuervain thyroiditis) (Fig. 2b) is a rare disease usually occurring in adults, possibly under-recognized, that disproportionately affects women, often associated with HLA subtype Bw35, that presents with fever neck pain and malaise. Subacute (granulomatous) thyroiditis may be a response to a systemic viral infection or postviral inflammatory process. It has also been reported in patients with breast implants [14], suggesting that the immune reaction may be precipitated by foreign material. Most recently, SARS-CoV-2 infection has been associated with subacute thyroiditis [15]; previous thyroid disease may predispose an individual to develop subacute thyroiditis after SARS-CoV-2 mRNA vaccine [16]. SARS-CoV-2 can be associated with other thyroid conditions including Graves’ disease, Hashimoto thyroiditis, and thyrotoxicosis [17]. The thyroid in subacute thyroiditis may be enlarged symmetrically or asymmetrically and is firm, and unlike Riedel thyroiditis, the inflammation is restricted to the gland and does not extend into surrounding tissues [18]. The changes have functional implications in subacute thyroiditis with three clinical phases — a hyperthyroid, a hypothyroid, and a recovery phase — which are accompanied by specific histologic features [18]. Early in the disease, there is destruction of the follicular epithelium leading to hyperthyroidism. An inflammatory infiltrate of neutrophils and microabscesses progresses to an infiltrate of lymphocytes and histiocytes with granulomas and multinucleated giant cells. Colloid may be encircled by histiocytes. When a substantial amount of the thyroid tissue has been destroyed, the hypothyroid phase ensues with a mixture of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells. In the recovery phase, the follicles regenerate and there is fibrosis.

Fig. 2.

Thyroiditis. a A common finding in surgically resected thyroids is focal granulomatous inflammation known as “palpation thyroiditis,” a histiocytic reaction to thyroglobulin that escapes from ruptured follicles. b De Quervain’s thyroiditis is a more diffuse form of granulomatous thyroiditis that is thought to be due to viral or cross-reacting antigens. c Chronic lymphocytic thyroiditis is a diffuse lymphoplasmacytic infiltrate that forms germinal centers and destroys the thyroid; the residual parenchymal cells show oncocytic change. d Graves’ disease is characterized by hyperplasia with papillary proliferations within well-developed follicles; the cells can become columnar and there is scalloping of colloid where there is enzymatic digestion for resorption of thyroglobulin to produce thyroid hormones (insert). Although this is an autoimmune disorder, inflammatory cells are sparse or absent

The most common etiology for chronic inflammation of the thyroid is autoimmune. Hashimoto thyroiditis, like most autoimmune disorders, most frequently affects females, particularly middle-aged females, can affect children, and is the most common cause of primary hypothyroidism. The thyroid gland in Hashimoto thyroiditis is enlarged with a lobulated cut surface; histologically, the lymphocytic infiltrate forms germinal centers and there is oncocytic metaplastic change of the follicular epithelium (Fig. 2c). The fibrous variant (fibrosing thyroiditis) of Hashimoto thyroiditis has the same female predominance as Hashimoto thyroiditis but is also common in men; it often presents with a markedly enlarged thyroid and marked hypothyroidism [19]. Although some authors have suggested that IgG4 disease is a cause of fibrosing variant of Hashimoto thyroiditis, fibrosing thyroiditis is confined to the thyroid unlike Riedel thyroiditis [19]. The fibrous atrophic variant of Hashimoto thyroiditis is associated with a small and fibrotic thyroid gland with extensive destruction of the thyroid parenchyma which is replaced by fibrous stroma. Postpartum thyroiditis is included as a rare autoimmune form of clinical transient hyperthyroidism which is followed by persistent hypothyroidism in the first postpartum year [20].

Riedel thyroiditis is a diffusely destructive disorder in which the thyroid gland is replaced by fibrous tissue which extends into the extrathyroidal tissues, unlike the fibrous variant of Hashimoto thyroiditis or subacute thyroiditis. Unlike the paucicellular variant of anaplastic thyroid carcinoma, Riedel thyroiditis lacks nuclear atypia and mitotic activity. Histologically, sclerotic acellular fibrous tissue replaces the thyroid parenchyma. A mixed infiltrate of predominantly lymphocytes and plasma cells may be seen. The extensive destruction of the thyroid is associated with hypothyroidism. Riedel thyroiditis is considered a possible manifestation of idiopathic fibrosing IgG4-related disorders [21].

Inflammation may be seen in the thyroid in a variety of other settings as well. It is the most common endocrine immune-related adverse event caused by immune checkpoint inhibitors used in cancer therapy, occurring in approximately 40% of patients [22, 23]. Foci of lymphocytes may be seen in the thyroid parenchyma (focal lymphocytic thyroiditis), most often of older females — with focal lymphocytic infiltrates identified in 17% of thyroid glands at autopsy in individuals without known autoimmune disease [24]. Peritumoral lymphocytes or lymphoplasmacytic foci can be seen around tumors in the thyroid.

Secondary Hypofunction/Atrophy

While chronic autoimmune thyroiditis is the most common cause of primary hypothyroidism, hypothyroidism may be due to genetic disease as well as the thyroid follicular parenchyma being destroyed due to radiation, trauma, infection, infiltrative diseases, lymphoma, and medications [25]. Hypothyroidism may be divided clinically into primary, central, and peripheral hypothyroidism [25]. Central hypothyroidism may be due to destruction of the pituitary gland by neoplasia, inflammation, or radiotherapy [23, 25]. Congenital defects such as pituitary hormone deficiencies and midline defects may also cause central hypothyroidism. A variety of additional causes of hypothyroidism with thyroid atrophy include radioactive iodine, external radiation to the head and neck, and medications such as lithium. Administration of exogenous thyroid hormone causes atrophy.

Hyperplasia

The commonest cause of hyperplasia with hyperthyroidism is Graves’ disease, an autoimmune disorder due to thyroid stimulating antibodies, that usually affects young female patients who present with tachycardia, weight loss, tremors, and heat intolerance [26]. Histologically, the thyroid gland is diffusely enlarged and shows characteristic “diffuse hyperplasia” (Fig. 2d); the follicles are lined by tall cells with scalloping of the colloid due to vacuoles in the colloid where the enzymes resorb the colloid at follicular cell apex. There are often small intrafollicular papillae throughout the thyroid gland.

Secondary and tertiary hyperthyroidism is extremely rare, comprising less than 1% of hyperthyroidism [26]. Pituitary TSH-producing tumors can cause hyperthyroidism. Tumors, granulomatous diseases, and other lesions of the hypothalamus resulting in excess TSH-releasing hormone may also be associated with hyperthyroidism.

Hyperthyroidism may also be caused by thyroid tissue at ectopic sites such as struma ovarii; this usually results in atrophy of the normal thyroid. In contrast, ectopic production of thyroid stimulating hormone and thyrotropin releasing hormone by non-endocrine tumors is associated with hyperthyroidism and thyroid hyperplasia.

Hyperthyroidism can also be caused by medications (such as amiodarone, IL2, tyrosine kinase inhibitors, and immune checkpoint inhibitors) although hypothyroidism is more commonly associated with medications in general [22]. Although immune checkpoint inhibitors may be associated with thyrotoxicosis, a hypothyroid state usually occurs and 40% of these individuals may have permanent hypothyroidism [22]. Rapid destruction of the thyroid parenchyma (such as from anaplastic carcinoma or lymphoma) may result in rapid release of thyroid hormone leading to non-hyperthyroid thyrotoxicosis [26].

Neoplasia

In some instances, neoplasia in the thyroid gland can be difficult to define. In the setting of multiple follicular cell nodules in the thyroid, it may be difficult to discern which are clonal based on the histologic features alone. Thyroid follicular nodular disease is the term suggested for multiple nodules within the thyroid, and when severe, this is the pathologic correlate of what clinically is referred to as “multinodular goiter” [27].

The spectrum of neoplasia of thyroid follicular cells is highly variable ranging from well-differentiated follicular adenomas and follicular carcinomas to anaplastic carcinomas (Fig. 3). Some thyroid tumors, such as classic papillary thyroid carcinoma, may be associated with a very good prognosis (even when metastatic to regional lymph nodes). However, even within a particular type of thyroid cancer, such as papillary thyroid carcinoma, there are many histologic subtypes with varying prognosis. For example, hobnail papillary thyroid carcinoma may be more aggressive than conventional/classic papillary thyroid carcinoma [28–32]. The 2022 WHO classification includes high-grade differentiated thyroid carcinomas (papillary, follicular, oncocytic) based on well-differentiated cytology but increased mitotic activity and/or necrosis (Fig. 4a) [27], as well as poorly differentiated thyroid carcinoma (Fig. 4b, c). Anaplastic thyroid cancer (Fig. 4d) is one of the most aggressive malignancies in humans with survival usually measured in weeks to months.

Fig. 3.

Differentiated thyroid carcinomas. a Follicular neoplasms are characterized by follicular architecture and relatively subtle nuclear atypia; malignancy is defined by invasive behavior as shown in this example of capsular invasion. b Papillary carcinomas have complex disorganized papillary architecture and striking nuclear atypia as well as psammoma bodies. c The most common mutation in papillary carcinoma is BRAF.p.V600E that can be readily identified with immunohistochemistry using the VE1 antibody

Fig. 4.

Aggressive thyroid carcinomas. a High-grade differentiated thyroid carcinomas are characterized by mitoses (arrows) and necrosis. b Poorly differentiated thyroid carcinoma has loss of differentiated architecture with solid growth as well as necrosis. c Anaplastic thyroid carcinoma has no differentiated features apart from the focal expression of PAX8 d

Benign and malignant thyroid tumors can arise in association with syndromes. The pathogenesis of familial syndromic and nonsyndromic follicular cell-derived thyroid carcinomas is becoming increasingly understood [33, 34]. Thyroid tumors may occur in syndromes characterized by a predominance of non-thyroid tumors, such as familial adenomatous polyposis, Cowden syndrome, Werner syndrome, DICER syndrome, and Carney complex. Familial syndromes may also be characterized by a predominance of thyroid tumors, such as familial papillary thyroid carcinoma with papillary renal cell carcinoma, pure familial papillary thyroid carcinoma with or without oxyphilia, and familial papillary carcinoma with multinodular goiter.

Neuroendocrine Tissues

Neuroendocrine (NE) cells are found in most organs. Their main function is the synthesis and secretion of peptide hormones and amines; accordingly, they are characterized by the presence of two regulated pathways of secretion associated with large dense core vesicles (LDCV) and small synaptic-like vesicles (SSV) to produce, store, and secrete peptide hormones, amines, and small mediators. Antigens associated with LDCV comprise the chromogranin family including chromogranin A and those associated with SSV comprise synaptophysin [35, 36]. Tissues and cells expressing chromogranins and synaptophysin as well as INSM1 are bona fide defined as neuroendocrine.

There are two families of neuroendocrine tissues; the epithelial family is generally thought to derive from the endoderm and usually expresses keratins of some type whereas the non-epithelial family, which arises from the neuroectoderm, generally does not express keratins. Non-epithelial neuroendocrine cells are almost exclusively paraganglia that can be found anywhere in soft tissue or organs at all body sites except the extremities. One might potentially add hypothalamic neurons to the non-epithelial family, as these neurons secrete hormones into the bloodstream.

Neuroendocrine cells exert their function either as an independent neuroendocrine organ (e.g., the pituitary (Fig. 5a), the parathyroid (Fig. 5b), the pancreas islet (Fig. 5c–e), the adrenal medulla) or as isolated cells interspersed in non-neuroendocrine organs (e.g., the thyroid, the respiratory system, the digestive system) (Fig. 5f, g). Neuroendocrine tissues control all major endocrine and metabolic body functions through tightly regulated pathways. They participate in the regulation of growth, maturation, and almost every metabolic function, including calcium homeostasis (regulated by parathyroid and thyroid C cells), glucose metabolism (regulated by insulin, glucagon, somatostatin, glucose insulinotropic peptide (GIP)–producing cells of the small intestine, etc.), and in fine-tuning the organ major function (e.g., gastric pH control by gastrin-/histamine-/somatostatin-producing gastric cells, gallbladder function by cholecystokinin and gut motility by multiple peptide hormones of the gastroenteropancreatic system). Each cell type expresses a pattern of transcription factors, hormones, enzymes, and, in the case of epithelial NE cells, keratins that define the cell type and its function (Table 1).

Fig. 5.

Normal neuroendocrine cells. The neuroendocrine system is composed of organs including the pituitary (a) and parathyroid (b), small neuroendocrine organs within an exocrine organ as in the islets of Langerhans (c, d, e), and single cells scattered within other tissues, as in the small bowel (f, g). a The pituitary is composed of multiple cell types; basophils represent corticotrophs, and acidophils are either somatotrophs, lactotrophs, or mammosomatotrophs while chromophobes may be any of those cell types in a degranulated state, thyrotrophs, and gonadotrophs. b The parathyroid is composed of chief cells that focally show oncocytic change; the parenchyma is distributed within stromal fat. c A pancreatic islet is seen within the parenchyma of the exocrine pancreas. There is a well-organized pattern of staining for glucagon at the periphery of the endocrine cell cords (d), with insulin-containing cells comprising the center of the cords (e) and scattered cells that contain somatostatin and pancreatic polypeptide (not shown). The small bowel mucosa (f) contains numerous neuroendocrine cells that are readily identified with stains for chromogranin A (CGA)

A detailed description of pathology associated with NE tissues is beyond the scope of this section, but we provide a brief synopsis of the most relevant pathologic conditions.

Developmental Disorders

A number of developmental disorders are known to affect independent NE organs like pituitary and parathyroids and may include abnormal location (ectopia, heterotopia), agenesia/aplasia, or incomplete development/hypoplasia [37, 38]. Congenital predisposition to hyperplasia is a feature of specific genetic syndromes, including Beckwith-Wiedenmann syndrome for adrenal medulla [39] and nesidioblastosis with persistent hyperinsulinemic hyoglycemia of the newborn [40].

Inflammatory Lesions

Inflammatory lesions of NE tissue are observed at most sites in both independent neuroendocrine organs and interspersed NE cells. Inflammatory changes may associate with infections of any type (including tuberculosis and fungi) and inflammation-promoting conditions due to known agents or unknown causes (e.g., in the digestive system exposure to chemicals vs idiopathic inflammatory disease). Autoimmune conditions can target one or multiple neuroendocrine components in the autoimmune polyglandular syndromes [41]. Also, they may be part of systemic conditions including for instance IgG₄-related disease [21]. As immune checkpoint inhibitors are increasingly utilized in cancer treatments, the patterns of endocrinopathies of the inhibitors such as cytotoxic T lymphocytes antigen 4 and program cell death protein 1 or program cell death protein 1 ligand pathways are being increasingly identified to affect most endocrine tissues including the neuroendocrine system [23].

Secondary Hypofunction

Secondary hypofunction can be the result of hormonal dysregulation; the classical example of this in neuroendocrine cells is in the pituitary where feedback suppression can cause involution of corticotrophs, causing a characteristic alteration known as Crookes’ Hyaline change [42]. It also results from NE tissue annihilation due to vascular, inflammatory, and neoplastic disorders, or iatrogenic, such as organ ablation following, surgery, radiation, or chemotherapy. Every independent NE organ may be affected (e.g., hypoparathyroidism following complete thyroidectomy or panhypopituitarism following pituitary apoplexy). No known hypofunctional clinical-pathological picture of interspersed NE cells is so far known. This likely has to do with the little current knowledge of NE cell function at most anatomical sites.

Secondary Hyperplasia

Hyperplasia is the adaptive response of independent NE organs and interspersed NE cells to tissue-specific growth stimuli. In NE organs, hyperplasia may develop due to either physiological (e.g., pituitary lactotroph cell hyperplasia during pregnancy) or pathological stimuli (e.g., again in the pituitary somatotroph cell hyperplasia due to ectopic neoplastic hyperproduction of growth hormone releasing factor, GHRF, or parathyroids in patients with renal failure and calcium depletion). For interspersed NE cells, physiological and pathological causes may be recognized also. As example in the stomach, the pH-gastrin axis undergoes adaptation following proton-pump inhibitor therapy resulting in gastrin cell hyperplasia or, on the same line, chronic atrophic gastritis results in elevated pH and hypergastrinemia due to gastrin cell hyperplasia/hyperfunction. The causes of neuroendocrine cell hyperplasia are however poorly understood for conditions like the diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) [43] and for hyperplastic changes described at other sites of the digestive tract [44].

Neoplasia

Neuroendocrine neoplasms (NEN) are described in most organs as epithelial-lineage- or neural-lineage-derived. The neural-derived NENs are well differentiated and classified as paraganglioma [45]. Epithelial-lineage NENs are either well differentiated and defined as neuroendocrine tumor (NET) (Fig. 6) or poorly differentiated and defined as neuroendocrine carcinoma (NEC) of small or large cell type (SCNEC, LCNEC) (Fig. 7) [46]. The incidence of NET and NEC may vary; in many organs, NETs predominate but, in the lungs and due to smoking, there is a striking NEC prevalence (small cell lung carcinoma, SCLC) [47, 48]. NETs display an extraordinary organ-related degree of complexity, directly referring to the different cell population present in different organs [36, 45, 46, 49, 50]. The uniform nomenclature framework defined by WHO [45] is now widely implemented and makes relatively consistent the NEN definition at various sites [45, 46]. Still, in some organs, NETs are named differently, the reason being understandable clinical and historical reasons (e.g., medullary thyroid carcinoma is the thyroid NET; parathyroid adenoma is the commonest parathyroid NET). Depending on whether sporadic or heritable, NENs may be multiple or solitary. While most NENs are indeed sporadic, paragangliomas are among the most frequently hereditary tumors [51] and NETs are increasingly being recognized to have a genetic predisposition [46, 49].

Fig. 6.

Well-differentiated epithelial neuroendocrine neoplasm (NEN), neuroendocrine tumor (NET) of the pancreas. a The tumor has classical well-differentiated neuroendocrine morphology with trabecular structures and no necrosis. b There is diffuse and intense expression of the neuroendocrine marker chromogranin A, as well as c somatostatin receptor type 2. d The tumor has a low proliferation fraction as shown by Ki67 localization (MIB1 clone). Same case all pictures; × 200 original magnification

Fig. 7.

Poorly differentiated epithelial neuroendocrine neoplasm (NEN), neuroendocrine carcinoma (NEC) of the lung. a This tumor with classical poorly differentiated neuroendocrine morphology features solid architecture, ample necrosis, prominent nuclear atypia, and brisk mitotic activity. b There is diffuse though granular and sparse expression of the neuroendocrine marker chromogranin A, c diffuse but faint synaptophysin expression, d a high proliferation fraction as shown by Ki67 localization (MIB1 clone), and diffuse expression of the transcription factors INSM1 (e) and TTF1 (f). Same case all pictures; × 200 original magnification

Steroidogenic Tissues

Steroidogenic tissues are derived from mesenchymal precursors and are characterized by the ability to take up cholesterol for the purpose of converting it into steroid hormones. They include the adrenal cortex (Fig. 8a), the ovarian theca and granulosa cells (Fig. 8b), and the Leydig cells of the testes (Fig. 8c). While the gonadal tissues are truly endocrine, they are usually the subject of analysis by experts in gynecologic and genitourinary pathologists and will not be discussed in detail here, but it is important to recognize the overlap with adrenal and the need for collaborative studies that often include gonadal locations of adrenal rest tissue. The placenta is also a site of steroidogenic hormone production and the brain is an important site of steroidogenesis but these special sites will not be discussed here.

Fig. 8.

Normal steroidogenic cells. a The adrenal cortex is composed of three layers. The outermost one under the adrenal capsule (left) is known as the zona glomerulosa; this discontinuous layer of clusters of small cells produce the mineralocorticoid aldosterone. The zona fasciculata (middle) is a zone composed of large clear cells that store abundant glucocorticoid hormone. The zona reticularis (right) is a zone of active hormone synthesis and secretion, primarily of glucocorticoid but also sex steroids; the cells have acidophilic cytoplasm filled with smooth endoplasmic reticulum. b An ovarian follicle surrounding a developing egg is lined by glomerulosa cells that are surrounded by thecal cells, all lying within the ovarian stroma (figure kindly provided by Dr. Christina Bagby, University Hospitals, Case Western Reserve University, Cleveland, OH, USA). c The testis is composed of seminiferous tubules that are lined with steroidogenic Sertoli cells (examples shown with curved arrows) in which spermatogenic elements proliferate and mature; between the tubules are nests of plump steroidogenic Leydig cells (straight arrows) that produce testosterone (case provided by Dr. Holly Harper, University Hospitals, Case Western Reserve University, Cleveland, OH, USA)

Steroidogenic cells feature abundant smooth endoplasmic reticulum, numerous mitochondria, and only short profiles of rough endoplasmic reticulum [1, 52]. With the exception of the small number of cells showing zona glomerulosa differentiation that have typical flat plate-like mitochondrial cristae, all other steroidogenic cells have tubulovesicular cristae that are a unique identifying feature [52]. They are characterized immunohistochemically by the expression of steroidogenic factor 1 (SF1), a transcription factor that plays a critical role in their development, differentiation, and function [53]. They also express inhibin and several enzymes that are used for steroid hormone production.

Steroid hormones are divided into glucocorticoids (mainly cortisol/cortisone), mineralocorticoids (mainly aldosterone), and sex steroids (that include progesterone, estrogens such as estrone/estradiol, and the various androgens such as testosterone, androsterone, and others). In the normal adrenal cortex (Fig. 8a), there are three layers: the zona reticularis which is composed of small nests of cells with acidophilic cytoplasm that is full of steroidogenic subcellular organelles, the zona fasciculata that is composed of elongated trabeculae of clear cells with abundant fat storage and scant steroidogenic organelles, and the zona glomerulosa that is an incomplete layer of small nests of small clear cells that are dedicated to mineralocorticoid production.

Developmental Disorders

Several developmental disorders result from deficiency of specific steroidogenic enzymes and cofactors. They all fall into the class of diseases known as congenital adrenal hyperplasia (CAH) [54, 55].

The first step in hormone synthesis involves P450scc that cleaves cholesterol into pregnenolone (the C₂₁ precursor of all active steroid hormones) and isocaproaldehyde; mutations that inactivate this enzyme result in atypical lipoid CAH. Inactivation of the steroidogenic acute regulatory (StAR) protein that mobilizes cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane prevents delivery of cholesterol to P450scc and causes lipoid CAH. Both lipoid and atypical lipoid CAH are autosomal recessive disorders that are potentially lethal early in life due to severe hyponatremia, hyperkalemia, and metabolic acidosis; the adrenals are enlarged with massive lipid droplet deposition.

Classic CAH can be due to defects in a number of other enzymes in the steroidogenic pathway that result in cortisol deficiency; these are among the most common autosomal recessive disorders and the presentation varies depending on which enzyme is affected. Salt-wasting forms are due to insufficient aldosterone production; simple or virilising forms cause shunting of the pathway due to compensatory hyperplasia resulting mainly in virilization as the name implies. Both are usually identified in infancy or childhood. The most common is 21-hydroxylase deficiency; others include 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase 2, and 17α-hydroxylase deficiency.

Non-classic or late onset CAH is due to less severe androgen excess that manifests in late childhood or at puberty or even in adulthood. Cortisol levels are usually normal but there is compensatory adrenal hyperplasia.

Aberrant adrenal tissue is not uncommon and usually is of no clinical significance; however, it may be important in patients with congenital adrenal hyperplasia or in those with secondary hyperplasia when therapy involves adrenalectomy and the residual ectopic tissue produces steroid hormones [52].

Inflammatory Lesions

Inflammatory lesions of the adrenal can be infectious or autoimmune. Infectious etiology can be viral, bacterial, fungal, or parasitic. Isolated inflammation of one adrenal can cause a mass lesion; bilateral disease can cause adrenal insufficiency known as Addison’s disease. Indeed, the first description of adrenal insufficiency by Thomas Addison was bilateral tuberculous adrenalitis [56]. The autoimmune form of this disease is often part of one of three hereditary polyendocrine autoimmune syndromes [57] that include more obvious but less critical manifestations such as vitiligo, alopecia, and mucocutaneous candidiasis; the adrenal form can be lethal if not diagnosed and managed with prophylactic steroid administration during times of illness and stress.

Secondary Hypofunction

Adrenal atrophy is a common finding due to the common administration of glucocorticoids for the treatment of diseases including allergies, rashes, autoimmunity, and cancers. Exogenous steroids suppress pituitary ACTH, causing Crooke’s hyaline change, and the adrenal cortex involutes as a result. The cortex becomes thin; in the normal gland, the cortex on each side of the central medulla comprises one-third of the size of the gland, but in atrophic glands, the thickness is less than that of the medulla. The cortex is composed almost exclusively of clear cells that store fat but lack smooth endoplasmic reticulum and have scant mitochondria.

Secondary Hyperplasia

The adrenal cortex is mainly regulated by ACTH and excess circulating ACTH results in adrenal cortical hyperplasia. The cortex become thick, much thicker than the size of the medulla, and it is almost entirely composed of compact cells with abundant pink granular cytoplasm. This disorder can be due to pituitary ACTH excess in patients with pituitary corticotroph proliferations, or may be due to ectopic ACTH excess from any neuroendocrine neoplasm; the latter is usually far more severe, resulting in massive hyperplasia and lipid depletion.

Cysts

The adrenal is often the site of cyst formation. These cysts can be infectious, vascular, or benign epithelial cysts; a frequent lesion is a hemorrhagic pseudocyst.

Neoplasia

Adrenal cortical neoplasms can be solitary or multiple, benign or malignant, and functioning or clinically silent. Cortical nodularity that is frequently composed of multiple small clonal proliferations is common in older adults and is known as adrenal cortical nodular disease [58]. Small and multifocal lesions can be the cause of Conn’s syndrome [59] or Cushing’s syndrome in patients with Carney complex who develop primary pigmented nodular adrenocortical disease (PPNAD) [60]; massive multifocal proliferations causing Cushing’s syndrome are known as primary bilateral macronodular adrenocortical disease [61]. Clinically diagnosed neoplasms range from benign adenomas that are incidental findings to large aggressive carcinomas. In between are adenomas (Fig. 9) that cause Cushing’s or Conn’s syndrome, and carcinomas that are well-differentiated cortical neoplasms that cause the same disorders or can be clinically non-functioning. The large lesions are often difficult to characterize as adrenal cortical in origin and require immunohistochemical assessment for expression of SF1 and other biomarkers [62] (Fig. 10); similarly, immunohistochemistry and molecular analysis can be helpful in assessing borderline lesions to determine malignancy [62]. Both benign and malignant neoplasms can arise in patients with well-characterized genetic disorders including sporadic McCune-Albright disease and hereditary Carney complex, multiple endocrine neoplasia syndromes, and Lynch syndrome [34]. Recent progress has yielded a great deal of information that is beyond the scope of this article and is well reviewed in recent publications.

Fig. 9.

Adrenal cortical adenoma. a The adrenal cortex is compressed under the capsule of the gland by a tumor composed of well-differentiated clear cells with abundant cytoplasm, and bland nuclei (seen better in the higher magnification insert). b An adrenal cortical adenoma producing aldosterone and causing Conn’s syndrome stains diffusely for CYP11B2. c Steroidogenic cells have abundant smooth endoplasmic reticulum and their mitochondria have unique tubulovesicular cristae with the exception of cells that produce aldosterone (mineralocorticoid) (d) that have mitochondria with more usual flat plate-like cristae

Fig. 10.

Adrenal cortical carcinoma. a This tumor in the adrenal gland is not obviously a cortical steroidogenic neoplasm; its epithelioid morphology could represent a number of primary or metastatic lesions. b Its steroidogenic differentiation is confirmed by nuclear reactivity for SF1. c Steroidogenic cells also typically express cytoplasmic inhibin. d The Ki67 labeling index is higher than would be expected for a benign tumor

Conclusion

The scope of endocrine pathology is broad and encompasses developmental, inflammatory, functional, and neoplastic disorders in three families of cells that are distributed throughout the body (Table 2). It is important to be familiar with these tissues and their many lesions, as well as the relationships between the different tissues and organs, their hormones, and regulatory signaling pathways. The common occurrence of genetic predisposition is well characterized in many syndromes that should always be considered when managing patients with endocrine pathology.

Table 2.

The spectrum of endocrine pathologies

Disease type	Developmental disorders		Inflammatory disorders		Atrophy	Hyperplasia	Neoplasia
	Ectopias	Metabolic	Infectious	Autoimmune
Thyroid	Aberrant thyroid Thyroglossal duct cyst	Thyroid dysgenesis Dyshormonogenesis	Acute Granulomatous	Acute Granulomatous Chronic lymphocytic Riedel (IgG4) disease	Post-inflammatory Pituitary/hypothalamic failure Exogenous thyroid hormone	Graves’ disease Pituitary/hypothalamic disease Ectopic TSH/TRH Medication-induced	Benign Low risk Malignant
Neuroendocrine	Ectopias	Aplasia Hypoplasia	Acute Granulomatous	Acute Granulomatous Chronic lymphocytic Xanthomatous IgG4 disease	Post-inflammatory Secondary	Physiological Secondary to disease elsewhere Medication-induced Idiopathic	Epithelial well-differentiated NET Epithelial poorly differentiated NEC Non-epithelial paraganglioma
Steroidogenic	Aberrant adrenal rests	Congenital adrenal hyperplasia syndromes	Acute Granulomatous	Chronic lymphocytic	Post-inflammatory Pituitary/hypothalamic failure Exogenous steroids	Pituitary or ectopic ACTH excess	Benign Malignant

Author Contribution

Conception and design: SLA, LE, GR; data collection and analysis: SLA, LE, GR; manuscript preparation and editing: SLA, LE, GR; approval of final manuscript: SLA, LE, GR.

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All authors consent to publication.

Competing Interests

The authors declare no competing interests.