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Adrenocortical Carcinoma Review of the Pathologic Features, Production of Adrenal Steroids, and Molecular Pathogenesis
Yasuhiro Nakamura, MD, PhDª, Yuto Yamazaki, MDª,
Saulo J. Felizola, MD, PhDa, Kazue Iseª, Ryo Morimoto, MD, PhDb, Fumitoshi Satoh, MD, PhDb, Yoichi Arai, MD, PhDC, Hironobu Sasano, MD, PhDa, *
KEYWORDS
. Adrenocortical carcinoma . Weiss criteria . Molecular pathology . Steroidogenesis
· Immunohistochemistry
KEY POINTS
· Adrenocortical carcinoma (ACC) is a rare malignant neoplasm with an aggressive biolog- ical behavior.
· The Weiss criteria of adrenocortical malignancy are known as the most reliable tool for his- topathological scoring system.
· Genomic features of adrenocortical carcinoma have been recently reported and may be used for the diagnosis of ACC.
· ACC cases may be hormonally functional, and immunohistochemical analysis of steroido- genic enzymes is utilized for the analysis of intratumoral production of corticosteroids.
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare malignant neoplasm arising from adrenocor- tical parenchymal cells. ACC is also known to have unique features compared with other tumors. In particular, ACC often secretes several types of steroid hormones with a pattern of disorganized steroidogenesis. This article summarizes the clinical,
The authors have nothing to disclose.
a Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; b Division of Nephrology, Endocrinology, and Vascular Med- icine, Department of Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-ma- chi, Aoba-ku, Sendai 980-8575, Japan; ” Department of Urology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
* Corresponding author. Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980- 8575 Japan.
E-mail address: hsasano@patholo2.med.tohoku.ac.jp
Endocrinol Metab Clin N Am 44 (2015) 399-410
http://dx.doi.org/10.1016/j.ecl.2015.02.007
histopathological, and biological features of ACC that are relevant to its pathogenesis, diagnosis and prognosis.
CLINICAL AND HISTOPATHOLOGICAL FEATURES OF ADRENOCORTICAL CARCINOMA
The incidence of ACC is estimated to be approximately 0.7 to 2 cases per 1 million population, accounting for 0.05% to 2% of all malignant tumors.1 The age distribution of ACC is bimodal; the first peak is in early infancy under the age of 5 years, mainly derived from hereditary syndromes such as the Li-Fraumeni and Beckwith- Wiedemann syndromes.2 The second peak is the fourth to fifth decades of life. The frequency in both genders is similar, but some reports indicate a slightly higher inci- dence in women.2 The average overall survival in ACC cases was reported to be 14.5 months, with a 5-year mortality rate of approximately 75% to 90%.3,4 Presently, only 30% of all ACCs are potentially curable at early stages after diagnosis. Metasta- ses of ACC have been detected in the liver (48%-85%), lung (30%-60%), lymph nodes (7%-20%), and bones (7%-13%).5,6 Clinical staging of ACC is usually based on the presence or absence of invasion or distant metastases.7 Tumor size and weight are also reliable clinical parameters of staging ACC. Appropriate cut-off value of tumor weight (50 g) and tumor size (6.5 cm) indicates the high sensitivity (91%) and speci- ficity (100%) in distinguishing ACC from adrenocortical adenoma (ACA).8
The histological diagnosis of ACC is pivotal in order to establish the final diagnosis. The Weiss criteria of adrenocortical malignancy comprise the most reliable histopathological scoring system differentiating ACC from ACA (Table 1).9-11 ACC can be diagnosed by the presence of at least 3 of the 9 Weiss criteria. Three relate to cytological features (nu- clear grade, mitoses and atypical mitoses); three refer to tumor structure (clear cells, diffuse architecture, and confluent necrosis), and three relate to invasion (venous inva- sion, sinusoidal invasion, and capsular infiltration). Most ACC cases are associated with relatively high scores in the Weiss criteria and do not pose major diagnostic chal- lenges or problems for surgical pathologists involved in the diagnosis of resected adrenal neoplasms. However, occasionally some cases such as pediatric tumors or adrenocortical oncocytomas do pose diagnostic challenges if the final diagnosis is based solely on the Weiss criteria. In addition, as in any of the histopathological scoring
| Table 1 | |
|---|---|
| Summary of Weiss criteria | |
| Scoring Points | |
| Criteria | 0 1 |
| Nuclear grade (Fuhrmann nuclear grade system) | I/II III/IV |
| Mitoses | <6/10 HPF ≥6/10 HPF |
| Atypical mitoses | - 1 |
| Clear cell component | <25% ≥25% |
| Diffuse architecture | <1/3 ≥1/3 |
| Confluent necrosis | - 1 |
| Venous invasion | - 1 |
| Sinusoidal invasion | - 1 |
| Capsular infiltration | - 1 |
Three or more of the following 3 criteria indicate malignancy. Nuclear grade assessed by Fuhrmann nuclear grade, and grade III and/or IV indicates malignancy in adrenal tumors.
Abbreviation: HPF, high power fields.
Data from Refs. 9-11
systems, interobserver differences among surgical pathologists are also by no means negligible factors, particularly when the tumors are possibly low grade carcinomas. Therefore, diagnostic markers other than histopathological factors augmenting this scoring system as an auxiliary diagnostic modality have been explored.
IMMUNOHISTOCHEMICAL MARKERS IN ADRENOCORTICAL CARCINOMA
Several immunohistochemical markers have been reported to be of diagnostic value in the differential diagnosis of resected adrenocortical neoplasms. These include the Ki67 proliferative index, p53, insulin-like growth factor (IGF)-II, cyclin E, ß-catenin, and steroidogenic factor-1 (SF1).11
The Ki67 proliferative index is one of the most widely employed diagnostic immuno- histochemical markers in differentiating ACC from ACA. A Ki67 labeling index of more than 5% confirms the diagnosis of ACC.12 However, a cut-off value in the range of 2.5% to 5% between carcinoma and adenoma has been proposed.13 In addition, the Ki67 labeling index has also been reported to serve as a reliable prognostic factor in patients with ACC. For instance, Morimoto and colleagues14 reported that a Ki67 labeling index over 7% was associated with significantly worse clinical outcomes in patients with ACC. However, because of the enormous intratumoral heterogeneity of ACC, determining the sites in which Ki67 labeling index is obtained markedly influ- enced the results. In particular, the question of whether the Ki67 labeling index should be calculated as the average of the entire tumor specimen or rather the summation of hot spots in the specimens has not been resolved. This flaw or limitation should be kept in mind when applying the Ki67 labeling index.
Overexpression of IGF-II has been reported in approximately 60% to 90% of ACC cases, and only rarely in ACA.15,16 Epidermal growth factor receptor (EGFR) and p21 were also reported to be overexpressed in ACC.17,18 Stojadinovic and col- leagues19 compared immunohistochemical markers between ACA and ACC: p21 (36.4% vs 69.4%), p53 (0% vs 5.4%), mdm-2 (36.4% vs 20.4%), and p27 (68.8% vs 94.4%). SF1 immunohistochemistry has been generally considered the most reli- able method of identifying the primary lesion as being of adrenocortical origin.20
GENETIC OR MOLECULAR ASPECTS IN ADRENOCORTICAL CARCINOMA
It has been recently elucidated that several genes are related to the pathogenesis of ACC. Most ACC cases are sporadic, but several hereditary syndromes have been re- ported to be associated with the development of ACC, such as the Li-Fraumeni syndrome (TP53 gene mutation), the Beckwith-Wiedemann syndrome (11p15.5 chro- mosomal lesion alteration), multiple endocrine neoplasia type 1 (11q13 chromosomal lesion loss), 21-23 and Gardner syndrome (inactivating mutation of APC genes located in 5q21 chromosomal lesion).24 The Li-Fraumeni syndrome occurs as a result of a germ line mutation of the TP53 gene, and the loss of heterozygosity at 17p13.1 results in the development of several malignant neoplasms such as breast cancer, hemato- logical neoplasia, brain tumor, and ACC.25,26 In particular, R175H and R337H are com- mon mutations detected in southern Brazil, which are associated with a 10- to 15-fold increase in the occurrence of ACC.27,28 Somatic mutations of TP53 genes have also been identified in sporadic ACC demonstrating overexpression of p53 protein in car- cinoma cells.29-31 The Beckwith-Wiedemann syndrome occurs as a result of an 11p15.5 chromosomal alteration, and presents with various developmental abnormal- ities, and some pediatric malignancies. This chromosomal lesion is linked to overex- pression of factors of ACC tumorigenesis, IGF-II, CDKN1C, and H19.32 Among
those previously mentioned, the best recognized is IGF-II, which is overexpressed 100-fold in 60% to 90% of ACCs. 15,16
MICRORNA PROFILES IN ADRENOCORTICAL CARCINOMA
Aberrant expression of microRNAs (miRs) may also play a role in the pathogenesis of ACC. MiRs are short (18 to 25 nucleotides) noncoding RNAs that regulate specific gene expression in the level of transcription in adhesion to mRNA by complementary sequence. In ACC, several miRs have been reported to be correlated with clinical and pathologic features of the tumors. In 2014, Duregon and colleagues33 reported that miR-483-3p, miR-483-5p, and miR-210 expression levels were elevated, while miR- 195 expression levels were lower in ACC, compared with ACA. In addition, these miRs were also reported to be associated with clinicopathological features of ACC.33 These three miRs are all known to target IGF-II. High expression levels of miR-210 were positively associated with hypoxic conditions, and were also reported to be associated with aggressive clinical characteristics and a poor prognosis, Furthermore, high miR-210 expression levels significantly correlated with a high Ki67 labeling index and the presence of necrosis. 33 Interestingly, they reported that miR-483-3p, miR-483-5p, and miR-210, which are upregulated in ACC in general, were all significantly downregulated in oncocytic variant tumors, compared with other histological variants (classical and myxoid variants) of ACC.33 Oncocytic variants of ACC are noted to express rich mitochondria in their cytoplasm, and are associated with an even poorer prognosis, compared with other ACC histological variants. Onco- cytic ACC is difficult to diagnose by Weiss criteria, unless it clearly identifies the ma- lignant potential findings, including coagulation necrosis, distant metastasis, invasion to adjacent organs and venous invasion. This reason is that several component of Weiss criteria, including nuclear atypism, diffuse architecture, and eosinophilic (oxyphilic) cytoplasm are commonly observed in both benign and malignant oncocytic adrenal neoplasms. 34,35 These miRs might be valuable in diagnosis of oncocytic ACC, distinguishing it from other histological variants of ACC. However, the distinction be- tween adrenal oncocytic adenoma and carcinoma is still controversial.
MiRs can be detected not only in the tumor tissues, but also circulation of the pa- tients, and if these miRs can be of clinical value, the analysis of miRs in the sera from patients with ACC can provide important information as to the clinical postoper- ative follow-up in terms of early detection of recurrence or metastasis.
ENDOCRINE FEATURES OF ADRENOCORTICAL CARCINOMA
Functional tumors account for approximately 60% of all ACC cases.8,36 However, symptoms caused by hormone oversecretion are only present in about 40% of all cases of ACC. The most common hormone that is secreted by ACC is cortisol, and patients may present with signs/symptoms of Cushing syndrome such as hyperten- sion, glucose intolerance or frank diabetes, osteoporosis, central obesity, acne, and/or hirsuitism. Functional tumors produce cortisol in 30% to 40% of cases, andro- gens in 20% to 30% of cases, estrogen in 6% to 10% of cases, and aldosterone in 2% to 2.5% of cases (Fig. 1).2 Among such symptoms, virilization was reported in 24% of all ACCs, reported as a characteristic feature of presentation, because adrenal androgen precursors could not necessarily be efficiently converted into glucocorti- coids.2 In general, ACCs rarely produce and secrete a single steroid hormone in excess and usually are associated with overproduction and hypersecretion of multiple hormones and precursors. Most cases (24%-35%) produce different types of steroid hormones.2,37,38 Therefore, excessive production or secretion of a single
2-2.5%
Aldosterone
40%
Cortisol
30-40%
Androgen
Estrogen
Non-function
6-10%
20-30%
adrenocortical steroid usually indicates benign nature of adrenocortical neoplasm, but there are several exceptions. Aldosterone- or estrogen-producing ACCs, although rare, have been reported. The remaining cases, which are nonfunctional, are inciden- tally detected by computed tomography (CT) or MRI or nonspecific symptoms because of the relatively large nature of the retroperitoneal mass, such as back pain, abdominal mass, weakness, fever, and myalgias.1 The clinical features of func- tional ACC are summarized in Table 2.1,2
ALDOSTERONE-PRODUCING ADRENOCORTICAL CARCINOMA
The incidence of pure aldosterone-producing ACC (APAC) is extremely low, account- ing for only 2% of all cases.2 The clinical presentation of this type of tumor is identical to that seen in primary aldosteronism from benign tumors and hyperplasia, namely hypertension and hypokalemia. The most common cause of primary aldosteronism
| Table 2 Characteristics of functional adrenocortical carcinoma | |||
|---|---|---|---|
| Hormones | Frequency | Dominancy | Clinical Presentation |
| Aldosterone | 2%-2.5% | Women | Hypokalemia and hypertension |
| Cortisol | 30%-40% | — | Cushing syndrome |
| Androgen | 20%-30% | Women, children | Virilization, hirsuitism, and acne |
| Estrogen | 6%-10% | Middle-aged men | Female: precocious puberty and post-menopausal bleeding Male: gynecomastia |
| Nonfunctional | 40% | — | Tumor growth, abdominal mass, and weakness |
Data from Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2009;91(6):2027-37; and Ng L, Libertino J. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 2003;169:5-11.
is aldosterone-producing adenoma (35%), bilateral idiopathic hyperaldosteronism (60%), although APAC cases are extremely rare, with less than 1% with Conn syn- drome.39,40 Four published cases were reported as APAC without hypertension. 41-45 These cases all presented with either hypokalemia or an abdominal mass, associated with a systolic blood pressure of 120 to 130 mm Hg. However, the mechanisms under- lying the lack of hypertension in these rare cases have not been elucidated. Approx- imately 60 APAC cases have been previously reported. Seccia and colleagues44 summarized these cases that report a peak incidence was in the fourth decade of life, with a female predominance (57%). Metastases were detected in 10% of the cases examined; median overall survival was 546 days, and median recurrence-free survival was 212 days. Plasma aldosterone concentration was increased on average by 14-fold, and plasma renin activity was suppressed in 55% in all cases.
CORTISOL-PRODUCING ADRENOCORTICAL CARCINOMA
Cortisol-producing ACC is the most common type, occurring in 30% to 40% of all ACCs. Combined hypersecretion of both cortisol and androgens is the most common hormonal pattern seen and suggests the presence of malignancy. Clinical presenta- tions include features of Cushing syndrome such as hypertension, obesity, acne, and glucose intolerance or frank diabetes.2,46 Abvien and colleagues reported that 63% of 202 ACC cases had evidence of cortisol hypersecretion. Sasano and col- leagues reported 9 ACC cases (6 cases with Cushing syndrome, 1 case with primary aldosteronism, 2 cases without clinically symptoms associated with steroidogenic ab- normalities). Six of these 9 cases expressed all the steroidogenic enzymes required for synthesis of cortisol or aldosterone only in small compact or clear cells; however, many carcinoma cells did not express steroidogenic enzymes required for synthesis of biologically active steroids. In these cases, 21-hydroxylase activity was markedly low, and 11-beta hydroxylase activity was moderately low, whereas, 17-alpha hydrox- ylase was positive in tumor cells. This disorganized steroidogenic enzyme expression indicates overproduction of precursor products of aldosterone or cortisol.47
ANDROGEN-PRODUCING ADRENOCORTICAL CARCINOMA
The frequency of androgen-producing ACC is approximately 20% to 30% of all ACCs. However, pure androgen-producing ACC is rare. Androgen and cortisol cosecreting ACCs are hormonally predominant. These cosecreting tumors occur more frequently in female and pediatric patients. Androgen-producing ACC is female dominant, males accounting for 10%-35%, because the presentation is clinically more apparent in fe- males. 48-50 In pediatric cases, almost all adrenal tumors are functional, and virilization is the most frequent presentation. Pure androgen-secreting adrenal tumors (PASATs) comprise 40% to 60% of all pediatric adrenal tumors.5º Most pediatric adrenocortical tumors are associated with a relatively good clinical course following the resection, with 90% overall long-term survival.51
Two recent studies concerning adult cases of PASAT were published.52,53 Cordera and colleagues52 and Moreno and colleagues53 reported that approximately 50% of all female PASATs are malignant utilizing the Weiss criteria. Hirsuitism, acne, and clitoral enlargement are the common presening signs. Moreno and colleagues53 found that malignant PASATs demonstrated 2.6-fold higher testosterone levels than benign PASATs. Tumor sizes and weights are also significantly higher in malignant PASATs.52,53
ESTROGEN-PRODUCING ADRENOCORTICAL CARCINOMA
Estrogen-producing ACC is a very rare type of functional ACC, accounting for approx- imately 6% to 10% of all ACCs. Common findings in female cases are precocious puberty or postmenopausal bleeding, while gynecomastia, testicular atrophy, and diminished libido may occur in men. Most cases occur between 24 and 45 years in men.54,55 The criteria for confirmation of pure estrogen-producing ACC remains controversial elevation of serum estrogen levels indicates extraglandular aromatiza- tion of adrenal steroid precursors. Secretion of estrogen in ACC requires the local expression of aromatase and 17 ß-hydroxysteroid dehydrogenase. It is also postu- lated that part of estrone is derived directly from ACC, and the rest is derived from the peripheral conversion of androstenedione into estrone.56,57
IMMUNOHISTOCHEMICAL EVALUATION OF FUNCTIONAL ADRENOCORTICAL CARCINOMA
ACC secretes various types of steroid hormones. In addition to the clinical presenta- tion caused by overproduction of these steroid hormones, immunohistochemical analysis is pivotal in identifying the potential capacity of steroid production. Immuno- histochemistry of steroidogenic enzymes expression including 3ß-hydroxysteroid dehydrogenase (3BHSD), 17a-hydroxylase (P450c17), 21-hydroxylase (P450c21), 11ß-hydroxylase (P450c11), DHEA-sulfotransferase (DHEA-ST), 17ß-hydroxysteroid dehydrogenase type 5 (17ß-HSD5), and aromatase should be performed on tumor specimens (Fig. 2).47,58 However, immunohistochemical analysis of these enzymes is quite difficult, and their expression pattern is different from that of ACA. Sasano58 previously named these patterns of intratumoral steroidogenesis of ACC as “disorga- nized steroidogenesis”, resulting in intratumoral heterogeneity of steroidogenesis and
Cholesterol
P450scc
P450c17
P450c17
DHEA-ST
Pregnenolone
17OH-pregnenolone
DHEA
DHEA-S
3฿HSD
Progesterone
17OH-progesterone
Androstendione
P450c21
17₿HSD5
Deoxycorticosterone (DOC)
11- Deoxycortisol
Testosterone
P450c11
P450 aromatase
Corticosterone
Cortisol
Estradiol (E2)
P450c11
Aldosterone
subsequently overproduction and oversecretion of precursor steroids. In addition, the discrepancy between the expression levels of mRNA and protein has been reported in several steroidogenic enzymes, such as P450c17, which has not been reported in any of the cases of ACA. 58 Here is shown representative illustrations of this pivotal immu- nohistochemical analysis of steroidogenic enzymes in ACC associated with Cushing syndrome and amenorrhea before surgery (Fig. 3). Clinically, serum levels of cortisol (32.88 µg/dL), testosterone (189 ng/dL), and DHEA-S (4000 ng/ml) are remarkably elevated. It is indeed appreciated that 3B-HSD and 17B-HSD5 staining are diffusely positive, but P450c17 and DHEA-ST are only partially immunopositive in carcinoma cells (see Fig. 3), indicative of disorganized steroidogenesis or intratumoral heteroge- neity of adrenocortical steroidogenesis. Aromatase is negative, indicating the absence of estrogen production in this case (see Fig. 3).
A
B
C
D
E
F
1
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SUMMARY AND FUTURE PROSPECTIVE
In this article, the current status of clinical, histopathological, and biological character- istics of ACC was briefly summarized. The Weiss criteria of adrenocortical malignancy is generally considered of diagnostic value, but it is also clear that histopathological or morphologic diagnosis alone may not be sufficient to provide the definitive final diag- nosis of ACC. Molecular/cell biological aspects and functional status could provide significant information to augment the Weiss criteria. Hormonally, most ACCs are functional, and the production of several adrenal cortical steroid hormones and precursors is considered characteristic of adrenocortical malignancy.
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