Pathology Associated with Hormones of Adrenal Cortex

Adrenal gland is an endocrine organ comprising of an outer cortex and inner medulla. These secrete various hormones that have a vital role in maintaining the normal homeostasis of the body. Lesions of adrenal cortex are quite common to encounter and most of these are related to the hormones secreted by three layers of adrenal cortex: the zona glomerulosa, the zona fasciculata, and the zona reticularis. Also it is very infrequent to encounter metastatic lesions in the adrenal glands too. So it is very important as a part of a clinician as well as a pathologist to know the pattern in which these hormones are secreted along with their physiological roles. Thus this chapter includes the disease that are related to excess as well as deficien-cies of the hormones secreted by adrenal cortex. The chapter also includes various genetic syndromes that are associated with the disorders associated with hormones of adrenal cortex. The last part of the chapter includes a brief description of various benign as well as malignant lesions, the pathological as well as the etiologi-cal aspects and the hormonal abnormalities associated. This chapter thus mainly focuses on the pathology associated with the adrenal cortex and hormones secreted by the various layers of adrenal cortex. hyperplasia). Decreased levels of this hormone also lead to an increase in lymphocytes and eosinophils, as a result of decreased immune-modulatory action of hydrocortisone. Measurement of baseline cortisol levels between 8:00 and 9:00 AM is the test used to diagnose AI. A serum cortisol level of value less than 5 μ g/mL favors diagnosis of AI. Stimulation test with cosyntropin which stimulates the cortex helps in differentiating primary and secondary AI. In this test 250 μ g of cosyntropin is administered intramuscularly or intravenously, and serum cortisol is measured 30 min after infusion. Serum cortisol value of ≥ 18 μ g/dL indicates a normal response. A cortisol peak <18 μ g/dL confirms the diagnosis of AI. Serum cortisol level ≥ 100 pg/mL confirms the diagnosis of Addison’s syndrome. Serum cortisol value of <10 pg/mL confirms diagnosis of secondary AI [35–39].


Introduction
Adrenal gland consists of an outer cortex and inner medulla; the cortex is further subdivided into three distinct zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis. Mineralocorticoids (aldosterone) secreted from the zona glomerulosa are essential for fluid and electrolyte balance and the reninangiotensin-aldosterone system. The fasciculata secretes glucocorticoids (mainly cortisol). The zona reticularis produces steroid sex hormones called androgens. These hormones play an important role in maintaining the normal homeostasis of the body [1][2][3]. However, it is quite common to encounter disorders related to the hormones of these three layers. These disorders could be possibly due to adrenal cortical masses secondary to cortical hyperplasia. It is very infrequent to encounter metastatic lesions in the adrenal glands.
This chapter mainly focuses on the pathology related to adrenal cortex which includes various forms of adrenocortical hyperplasia and benign and malignant neoplasms of the adrenal gland which lead to various hormonal imbalances encountered in clinical practice. Hormonal deficiency is due to inherited glandular or enzymatic

Adrenal hyperplasia
Adrenal hyperplasia is characterized as a smooth, diffuse, bilateral enlargement of the adrenal glands, wherein the glands retain their adreniform shape. Hyperplasia can be either macronodular or micronodular. They are commonly unilateral; however bilateral cases are also observed [7,8]. Broadly adrenal cortical hyperplasia can be grouped into three main categories: ACTH-dependent (adrenocorticotropic hormone), ACTH-independent, and congenital adrenal hyperplasia (CAH). Cushing's syndrome is one of the common functional manifestations of adrenal gland hyperplasia and therefore is discussed first [8,10,11].

Definition
It is a syndrome which encompasses various clinical features due to chronic excess of glucocorticoids. The incidence is nearly 1-2 per 100,000 population per year. Harvey Cushing was the first to observe pituitary adenomas associated with hypercortisolism in 1932 [10][11][12][13]. Cushing's syndrome, caused by prolonged exposure of tissues to high levels of cortisol, presents as constellation of symptoms including central obesity, muscle fatigue/atrophy, hirsutism, infertility, osteoporosis, moon facies, dorsocervical and supraclavicular fat pads, and wide purple striae [8,10,12]. The syndrome may be ACTH-dependent or ACTH-independent. A fair number of cases attributed to iatrogenic causes are also identified. Most of the cases of Cushing's syndrome are due to ACTH hypersecretion from the anterior pituitary and are associated with pituitary cortical adenoma. Majority of the cases, about 80-90%, show diffuse hyperplasia of the adrenal cortex [9,10]. Nearly 15% of cases do present with ectopic ACTH secretion associated with small cell lung carcinoma or bronchial carcinoid. Thymic carcinoids, pancreatic islet cell tumor, pheochromocytomas, and medullary carcinoma of thyroid form minor group of tumors associated with ectopic ACTH secretion [12]. In a study by Ejaz et al., lung tumors constituted 44.4% of all cases of neoplasm-related ectopic ACTH secretion causing Cushing's syndrome [14]. Clinically patients with Cushing's syndrome present with diastolic hypertension, hypokalemia, and edema. Hypogonadism and amenorrhea can also be seen in these patients which are attributed to suppression of gonadotropin secretion secondary to excess glucocorticoid secretion [10][11][12][13][14].
1. The first group of tests are to screen for the evidence of hypercortisolism. These comprise urine cortisol excretion and low-dose dexamethasone suppression test. b. High-dose dexamethasone suppression test: In this test the patient is administered with 2 mg of dexamethasone, 6 hourly for 48 h, following which plasma cortisol levels are measured. In the case of ectopic ACTH secretion or adrenal limited hypercortisolism, there is a failure of suppression of cortisol secretion. Also it is important to remember that cortisol is not suppressed with either low-or high-dose dexamethasone suppression in adrenal hyperplasia associated with ectopic ACTH production [18].

ACTH-independent Cushing's syndrome
Nearly 15-20% of Cushing's syndrome are associated with ACTH-independent hypercortisolism and are secondary to a functioning adenoma or carcinoma. Diagnosis of ACTH-independent Cushing's syndrome includes clinical features of hypercortisolism, absence of serum cortisol diurnal rhythm, elevated late-night cortisol levels, and incomplete suppression of cortisol production with low-dose dexamethasone suppression test [10,[17][18][19][20].

Pathological findings
Adrenal glands from patients with Cushing's syndrome/hyperplasia appear variably enlarged in size and weigh approximately 6-12 g. The cortical width is widened as compared to the reticulosa. The zona fasciculata usually shows nodular hyperplasia. Nearly 10-20% of the patients reveal bilateral nodular hyperplasia, and up to 30% of patients may have normal adrenal morphology [2,20,21].

Primary pigmented nodular adrenocortical disease (PPNAD)
Primary pigmented nodular adrenocortical disease is a rare cause of childhood Cushing's disease having female preponderance, whereas Cushing's disease is common in prepubertal males [20][21][22]. It is the main endocrine manifestation of Carney complex (a multiple neoplasia syndrome caused by mutation in PRKAR1A gene) [23]. This is an autosomal dominant syndrome and is characterized by cutaneous lentigines, myxoma, schwannomas, and endocrinopathy [11,23]. It was first described by Aidan Carney and co-workers in 1985. Almost 25-30% of patients with Carney complex have ACTH-independent Cushing's syndrome. Cutaneous pigmentation is the commonest manifestation of the disease [24]. Lentigines are seen in most patients, and this characteristic manifestation can be used to make the definitive diagnosis. The name is derived from the macroscopic appearance of the adrenals that show characteristic small pigmented micronodules in the adrenal cortex. The disease typically involves bilateral adrenal glands. Grossly the adrenal glands may have variable size. The most characteristic finding is the presence of multiple brown-black pigmented cortical nodules that measure 1 mm to 3 cm in diameter. The adjacent cortical tissue invariable shows atrophy. These pigmented nodules may extend into corticomedullary junction or peri-adrenal fat [9,11,24].
On microscopy these tumors appear as sharply circumscribed, unencapsulated tumors composed of large eosinophilic lipid-poor cells similar to the zona reticularis arranged predominantly in trabecular growth pattern. However the nucleus appears enlarged, with a variable degree of pleomorphism and prominent nucleoli. There is prominent lipofuscin deposit. Lipid-rich fasciculata-like cells are also seen invariably. The tumor may have focal areas of necrosis, mitotic activity, myelolipomatous change, and lymphocytic infiltrates [9,11,24].
AIMAH is a disorder characterized by bilateral adrenocortical nodules, associated with ACTH-independent hypercortisolism, without any clinical features of pigmented nodular adrenocortical disease and histological features consistent with atrophic internodular cortex [25]. It is a rare cause of ACTH-independent Cushing's syndrome with slightly male preponderance. The patients present usually at later age (average: 48 years) [24][25][26]. In few patients with AIMAH, ectopic expression and/or increased sensitivity to gastric inhibitory peptide, vasopressin receptors, and beta-adrenergic receptors is also seen [25].
Grossly these lesions are characterized by nodules in the adrenal cortex, ranging from 1 to 4.2 cm. The adrenal gland weighs approximately 16.7-218 g. The adrenal gland may have a large mass of cortical tissue and multiple bilateral nodules measuring up to 5 cm. Combined adrenal gland weight of more than 300 g has also been noted (normal range: 8-12 g). Histology demonstrates large, yellow macronodules comprising of small cells with eosinophilic cytoplasm. Bilateral adrenalectomy and well-controlled glucocorticoid replacement is the most accepted treatment modality [2,3,9,25,26].

Congenital adrenal hyperplasia
CAH is an autosomal recessive disorder characterized by impaired steroidogenesis finally leading to mineralocorticoid and cortisol deficiency secondary to reduced activity of enzymes required for cortisol biosynthesis in the adrenal cortex. These patients usually present during the perinatal period with ambiguous genitalia in females and salt wasting in males. The milder forms of disease may present later with virilization at puberty or even as irregular menses. Most of the cases (nearly 95%) are attributed to deficiency of the 21-hydroxylase enzyme [27,28].
Abnormal growth and development, adverse effects on bone and the cardiovascular system, and infertility are few long-term effects seen in these patients. These patients are usually managed by reducing glucocorticoid exposure and improving excess hormone control [29,30].

Congenital adrenal hyperplasia: Classical 21-hydroxylase deficiency
This form is the most common form of CAH, occurring due to 21-hydroxylase (21-OH) deficiency, accounting for almost 90% of the cases. It occurs with the frequency of 1:12000 to 1:15000 births, and nearly 75% of patients with classic 21-OH Multiple endocrine neoplasia (MEN) type 1 Adrenocortical lesions are seen in nearly 36-41% of individuals with MEN type I syndrome, the commonest being bilateral nonfunctioning adrenal cortical hyperplasia or adenoma; adrenocortical carcinoma is exceedingly rare. The pathogenesis of these lesions is proposed to be due to influence of locally secreted insulin and insulin-like growth factors and not due to menin gene mutations

Carney complex
This syndrome encompasses multiple endocrine hyperplasia, with tumors of two or more endocrine glands, including primary pigmented adrenocortical disease (PPNAD), GH-and prolactin-producing pituitary adenomas, testicular neoplasms, thyroid adenoma or carcinoma, and ovarian cysts. This autosomal dominant syndrome is mapped to two genetic loci, one present on chromosome 2p16 and another locus at chromosome 17q22- 24  deficiency also have defect in synthesizing aldosterone. These patients die in the neonatal period due to shock from salt wasting. CAH is associated with multiple tumors like testicular tumors arising from ectopic adrenal cortical rests, testicular and ovarian Leydig cell tumor, and ovarian tumor of the adrenogenital syndrome as ovarian and paraovarian brown masses. Grossly the adrenal gland is marked enlarged having a cerebriform appearance. On cut surface the gland appears tan-brown in color. Under the microscope the adrenal gland reveals diffuse cortical hyperplasia. The cells are compactly arranged like how they are in the zona reticularis [2,[27][28][29][30]. Table 1 illustrates various syndromes associated with adrenocortical lesions [31].

Primary hyperaldosteronism (Conn's syndrome)
This disease was defined first by Conn in 1955, with a prevalence of 5-13%. This syndrome is characterized by an inappropriate increase in production of aldosterone which is relatively independent from the renin-angiotensin mechanism and is non-suppressible by sodium loading. This is one of the leading causes of secondary hypertension in hypertensive adults [32]. Patients with primary aldosteronism may exhibit adrenal cortical hyperplasia or adenoma in 30% of sporadic cases, and nearly 1% of sporadic cases may have adrenocortical carcinoma [33]. Clinically these patients present most commonly as normokalemic hypertension, and severe cases do show hypokalemia ( The aldosterone-to-renin ratio (ARR), a gold standard method to differentiate primary from secondary causes of hyperaldosteronism, is defined as the ratio of plasma aldosterone (expressed in ng/dL) to plasma renin activity (PRA, expressed in ng/mL/h). The cutoff value of ARR is 30 ng/dL per/mL per hour (or 750 pmol/L per ng/mL per hour). The principle behind this test is that as aldosterone secretion rises, PRA in ex vivo testing falls due to sodium retention. This negative feedback response should occur when the aldosterone levels are supraphysiologic for that individual patient, and PRA may fall well before plasma aldosterone is clearly increased. Primary aldosteronism is suspected if the ARR is >30 ng/dL per mL per hour. This method is also helpful in differentiating aldosterone-producing adenoma from bilateral adrenal hyperplasia [34].

Familial primary aldosteronism
Familial primary aldosteronism is mainly of three types, all of which are inherited in an autosomal dominant manner [8, 10, 32, 33]: 1. Familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism): accounts for less than 1% of cases. This disorder is caused by a recombination between the CYP11B2 and CYP11B1 genes.
2. Familial hyperaldosteronism type II: nearly 3-5% cases of primary aldosteronism belong to this category and are attributed to 7p22. This disorder still lacks a specific gene.

Gross features
Grossly, the adrenal gland in cases of idiopathic hyperaldosteronism is rather unremarkable or may exhibit slight enlargement. The enlargement could be due to the presence of micronodules or macronodules. Usually, adenomas are unilateral and solitary. However few cases of bilateral disease have also been reported. These adenomas  are mostly intra-adrenal and do not show a capsule. Few cases may reveal the presence of a true capsule or a pseudocapsule [2,3,35]. The cut surface of this tumor appears homogenous and golden yellow and is classically described as "canary yellow" [2]. Focal areas of hemorrhage or cystic changes can be present in few cases [35].

Microscopic features
Microscopically these adenomas appear encapsulated by compressed fibrous rim or fibrous "pseudocapsule." The tumor cells are most commonly arranged in the form of nests or in alveolar pattern. Occasionally these cells may be arranged in short cords and trabeculae. Few cases may show mixed histological patterns. The tumor is composed of four different varieties of cells which may be present in varying proportions. More commonly seen are clear cells, having optically clear cytoplasm and centrally placed nuclei similar to those of the zona fasciculata cells; then there may be cells resembling to the zona glomerulosa or zona reticularis which appear small with compact eosinophilic cytoplasm. Then we have cells that are designated as "hybrid" cells. These hybrid cells have cytological features resembling both the zona fasciculata and glomerulosa (Figure 1). The uninvolved portion of adrenal cortex reveals atrophy. This atrophy is secondary to the negative feedback suppression effect of the hypothalamic-pituitary axis. Spironolactone bodies which appear as small, intracytoplasmic eosinophilic inclusions, round to oval, measuring 2-12 mm, are often encountered in adrenal cortical adenoma in patients on spironolactone treatment. These inclusions are delineated from the surrounding cytoplasm by a small, clear halo [2,7,9,35].

Introduction and definition
Adrenal insufficiency was first described by Thomas Addison in 1855 and was popularly known as Addison's disease. This disorder can occur either due to failure of the adrenal gland or impairment of the hypothalamic-pituitary axis [36]. Clinically this syndrome is characterized by weakness, fatigue, anorexia, abdominal pain, weight loss, orthostatic hypotension, and salt craving. Characteristic hyperpigmentation is seen in patients with primary adrenal failure [37]. This disease has been reported in three forms [7,9,37]:  1. Primary disease also known as Addison's disease, a result of destruction of 90% or more of the adrenocortical gland or conditions that involve decreased production of adrenal steroids, resulting in subnormal synthesis of aldosterone, cortisol, and androgens.
2. Secondary and tertiary insufficiency occurs due to deficiency of secretion of corticotropin (ACTH) and corticotropin-releasing hormone (CRH), respectively.
Most of the cases (80-90%) of primary adrenal insufficiency are caused by autoimmune adrenalitis. Most of the cases fall under the autoimmune polyendocrinopathy syndrome (60%) [1,2,19,[32][33][34]. Cell-mediated immune mechanisms are implicated in pathogenesis. Various antibodies have been identified, antibodies against steroid 21-hydroxylase (85% cases) and autoantigens like steroid 17α-hydroxylase and cholesterol side-chain cleavage enzyme. Other associations include cytotoxic T-lymphocyte antigen 4, protein tyrosine-phosphatase nonreceptor type 22, and the MHC class II transactivator. Secondary adrenal insufficiency results from any process that involves the pituitary gland and interferes with corticotropin secretion. Tertiary adrenal insufficiency results from processes that involve the hypothalamus and interfere with secretion of corticotropin-releasing hormone, arginine vasopressin, or both. Suppression of the hypothalamic-pituitary-adrenal (HPA) axis by long-term administration of high doses of glucocorticoids is the most common cause [9,36,38].

Laboratory investigations
The patients of AI usually present with hyponatremia and hyperkalemia due to decreased aldosterone. Hypoglycemia also occurs due to cortisol. Decreased levels of this hormone also lead to an increase in lymphocytes and eosinophils, as a result of decreased immune-modulatory action of hydrocortisone. Measurement of baseline cortisol levels between 8:00 and 9:00 AM is the test used to diagnose AI. A serum cortisol level of value less than 5 μg/mL favors diagnosis of AI. Stimulation test with cosyntropin which stimulates the cortex helps in differentiating primary and secondary AI. In this test 250 μg of cosyntropin is administered intramuscularly or intravenously, and serum cortisol is measured 30 min after infusion. Serum cortisol value of ≥18 μg/dL indicates a normal response. A cortisol peak <18 μg/dL confirms the diagnosis of AI. Serum cortisol level ≥ 100 pg/mL confirms the diagnosis of Addison's syndrome. Serum cortisol value of <10 pg/mL confirms diagnosis of secondary AI [35][36][37][38][39].

Definition and introduction
ACC is a highly aggressive and a very rare malignancy. The incidence of this malignancy is approximately 0.72 per million cases per year according to the study by Surveillance, Epidemiology, and End Results (SEER) database [39]. The median age of diagnosis is usually fifth to sixth decade; however the German ACC Registry reports a median age at diagnosis of 46 years with a predilection for the female gender (female to male ratio: 1.5-2.5:1) [35,38,39].
Adrenocortical carcinomas (ACC) are rare tumors with an estimated annual inci¬dence of 0.7-2 cases by year and a global prevalence of 4-12 cases per million with a 5-year survival rate inferior to 35% in most of the studies published.

Pathogenesis of adrenocortical carcinoma
Various mutations have been implicated in association with ACC. Most common are germ-line TP53 mutations, associated with childhood ACCs. The adult population shows a prevalence of 3-7% of similar mutation. Childhood ACC can be found in association with Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, Lynch syndrome, and multiple endocrine neoplasia type 1. Of late an association with familial adenomatous polyposis (FAP), neurofibromatosis type 1, Werner syndrome, and Carney complex has also been postulated [39,40].

The TP53 alterations
Protein p53, "guardian of genome," is located at the 17p13 locus, and alterations in this gene have been noticed in various cancers including adrenocortical carcinoma, more so at the somatic level. p53 gene mediates cellular response to stress, and adult sporadic ACCs usually reveal loss of heterozygosity at this locus (nearly 85%) [48]. Stress leads to inhibition of degradation of p53 by E3 ubiquitin ligase MDM2, leading to inhibition of cell cycle arrest in response to DNA damage as well as apoptosis. These tumors tend to be larger and present at more advanced stage of tumor progression with shorter disease-free survival. Various genetic alterations have been reported in patients with adrenal cortex carcinoma like loss of PTTG1 has been reported in nearly 84%, mutation in retinoblastoma protein (pRb) in nearly 27% cases and mutation in RB1 gene in 7% of the cases. Inactivating mutations or homozygous deletions of CDKN2A have also been reported in 11-16% cases. High-level amplifications of CDK4 and MDM2 were reported in 2-7% ACCs [49][50][51]. It is surprising to see that majority of the TP53 mutations occur at the DNA-binding domain. Some tumors also have shown abnormalities in genes that encode for negative regulators of TP53, like PTTG1 which encodes for securin, noted in 84% of ACC. It is considered as a marker of poor survival [44,46,49].

Wnt/beta-catenin signaling pathway
Wnt family consists of highly conserved growth factors having similar amino acid sequences and is responsible for various developmental and homeostatic processes [4,44,[46][47][48]51]. A prevalence of 39 and 84% has been reported by various authors on immunohistochemistry for β-catenin. The Wnt receptor is composed of members of the frizzled family and low-density lipoprotein receptor-related Pathology Associated with Hormones of Adrenal Cortex DOI: http://dx.doi.org /10.5772/intechopen.84815 protein. β-Catenin accumulates in the cytoplasm and gets translocated into the nucleus and then binds with Wnt receptor leading to inhibition of the axin-adenomatous polyposis coli-glycogen synthase kinase 3β (GSK-3) complex. This blocks the phosphorylation of β-catenin, leading to increased accumulation of β-catenin in the cytoplasm which further translocates into the nucleus. Interaction between β-catenin with the T cell-specific transcription factor/lymphoid enhancer-binding factor-1 family of transcription factors occurs in the nucleus, thus regulating transcription of Wnt target genes. If Wnt stimulation of GSK-3 phosphorylating β-catenin does not occur, degradation by proteosomes occurs following ubiquitylation of this receptor. Wnt pathway has been implicated in patients with familial adenomatous polyposis and in the development of colorectal carcinomas as well as ACCs. Wnt/beta-catenin pathway can be activated in both benign and malignant tumors by CTNNB1 mutations and by ZNRF3 inactivation in adrenal cancer. ZNRF3 is a recent gene that encodes a cell-surface transmembrane E3 ubiquitin ligase which acts as a negative feedback regulator of Wnt signaling. Recently, ZNRF3 was found to be the most frequently altered gene in study cohorts of ACC investigated by integrated genomics, with a prevalence of 21 and 19% in studies by Assié et al. and Zheng et al.,respectively [50,51].

Insulin growth factor II (IGF-II)
Nearly 85-90% of the adult adrenocortical carcinomas are attributed to IGF-II overexpression. This molecular abnormality is associated with DNA demethylation at IGF-II locus in most of cases. Various transcriptome studies have confirmed that IGF-II is the most upregulated gene in ACC [52,53].

Biochemistry
ACC are the tumors characterized by adrenocortical hormone production in nearly 45-70% of patients. Hypercortisolism is the most common presentation of patients presenting with hormone excess leading to a plethora of symptoms like diabetes mellitus, hypertension, hypokalemia, muscle weakness/atrophy, and osteoporosis [40][41][42][43]. Excess of androgens which comprise nearly 40-60% of hormone-secreting ACCs can cause rapid-onset male pattern baldness, hirsutism, virilization, and menstrual irregularities in women. Estrogen production occurs in 1-3% of male ACC patients, causing gynecomastia and testicular atrophy (through suppression of the gonadal axis). In the evaluation of adrenal tumors, regardless of size, androgen or estrogen production should always raise the suspicion of a malignant tumor [44].

Microscopy findings
Microscopically these tumors have variable architectural patterns. The tumor cells are arranged in a trabecular, alveolar, or diffuse pattern. Occasionally mixed patterns are also noted. Some areas may also exhibit free-floating tumor cells forming balls [2,3,6,9,35] (Figure 2A, B).

Interpretation
Adrenal cortical adenoma: total score < 3. Adrenal cortical carcinoma: total score ≥ 3. Thus if the modified Weiss score is ≥ 3, then a diagnosis of adrenocortical carcinoma is given.

Conclusion
Adrenal glands have an essential role in maintaining the normal hemostasis. However the three layers of adrenal cortex, the zona glomerulosa, zona fasciculata, and zona reticularis, secrete essential hormones that are involved in fluid and electrolyte balance, regulating renin-angiotensin-aldosterone system, production of glucocorticoids, and synthesis of sex hormones. These hormones play an important   role in maintaining the normal homeostasis of the body. Various lesions in adrenal, benign as well as malignant, are known to cause disturbances in the internal milieu of our body. It is therefore essential to know the physiology as well as various types of disorders that can be encountered so as to define proper management of the patient. Also lesions of adrenal gland are attributed to various genetic abnormalities, knowledge of which can be implicated to study the pathogenesis and in applying this knowledge in prognosis as well as developing targeted therapy for these lesions.
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