Abstract
Adrenocortical carcinoma (ACC) and pheochromocytoma (PHEO) are the two most prevalent primary malignancies in the adrenal gland. ACC diagnosis relies on multiparametric scoring systems or diagnostic algorithms that are endorsed by the WHO classification. These systems incorporate multiple histopathological features, with or without ancillary investigations, but none of them is unequivocally superior to the others. PHEO is a non-epithelial neuroendocrine neoplasm and, in line with a general concept for neuroendocrine neoplasms in other organs, it is biologically malignant by definition. However, histopathology is a key element in predicting clinical malignancy, although the scoring systems proposed to date are not as well established as for adrenocortical tumors, and therefore have low impact and insufficient reliability to be accepted by the WHO as mandatory in the diagnostic workup. Immunohistochemistry is an essential complement of the pathology workup for both entities, as it helps to define the adrenocortical or medullary origin of the lesions and adds information of prognostic relevance. Moreover, both in ACC and PHEO, immunohistochemistry is a very useful approach to screen for the presence of familial predisposition, considering the high prevalence of hereditary forms in these tumor entities.
You have full access to this open access chapter, Download chapter PDF
Keywords
14.1 Introduction
Adrenocortical carcinoma (ACC) and pheochromocytoma (PHEO) are the two most frequent types of malignant primary tumors of the adrenal gland. ACC is classified within the spectrum of adrenocortical tumors that also include adrenocortical adenoma and adrenocortical nodular disease, the latter being a group of lesions that are now considered neoplasms, but were previously termed primary forms of adrenocortical hyperplasia. By contrast, PHEO originates from chromaffin cells in the adrenal medulla, belongs to the family of sympathetic paragangliomas, and—in line with the general concept of classification for neuroendocrine neoplasms—is malignant by definition, although most cases have an indolent clinical course.
Pathologically, the diagnosis of both ACC and PHEO is not straightforward, and the evaluation of several pathological parameters—mostly coded into scoring systems—is needed to define the risk of clinical malignancy. In the present chapter, we will summarize the most relevant pathological findings of ACC and PHEO, focusing on diagnostic algorithms and clinically useful tissue biomarkers; the pathology flow-chart is reproduced in Fig. 14.1.
Pathology flow-chart for adrenocortical carcinoma and pheochromocytoma. IHC immunohistochemical
14.2 Adrenocortical Carcinoma
14.2.1 Gross Pathology
The macroscopic appearance of ACC is extremely heterogeneous and may present either an encapsulated lesion or a mass infiltrating surrounding structures. ACC is usually large, with a mean size of about 11 cm and an average weight of about 400 g [1]. It usually loses the yellowish homogeneous cut surface typical of adrenocortical adenoma, and most often combines a more whitish-to-grayish appearance, with a more or less prominent stromal component and hemorrhagic and/or necrotic areas. The overall appearance is usually suggestive of malignancy and, more than with adrenocortical adenoma, it requires a differential diagnosis with other malignant tumors in the adrenal gland, such as other malignant primaries (aggressive forms of PHEO or sarcomas) or metastatic tumors. However, some cases are smaller, and their size and weight are not indicative of malignancy. Small lesions show a more homogeneous and less suspicious appearance, with clear demarcation and no apparent invasion of capsular and extracapsular structures; if adequate sampling is not performed, these cases may risk being underdiagnosed as benign.
More than being informative per se in supporting ACC diagnosis, an accurate macroscopic description and evaluation is key to guiding a precise and exhaustive sampling procedure and correctly defining the status of the resection margins.
14.2.2 Cytological and Histological Findings
Cytologically, ACC usually contains a predominance of lipid-depleted cells with a dense eosinophilic cytoplasm. The cytoplasmic features of ACC cells do not correlate with any specific endocrine syndrome nor are they associated with specific functional properties. Nuclear pleomorphism and the presence of nucleoli are almost always a prominent feature in ACC, some cases having a very high degree of atypia. However, nuclear atypia may also occur in benign adrenocortical lesions and is therefore a fairly non-specific feature.
The tumor architecture in ACC is frequently heterogeneous, with different growth patterns frequently coexisting within the same lesion. Irrespective of the tumor architecture, a consistent finding in ACC is the loss of the well-organized alveolar pattern seen in non-tumorous adrenocortical tissue and in adrenocortical adenoma, and this observation is the key item of one of the algorithms for ACC diagnosis, the reticulin algorithm [2] (see below). Characteristic architectural patterns in ACC include a broad trabecular growth, with anastomosing columns and cords of cells, a nesting or alveolar arrangement or a more diffuse or solid growth with a pattern-less histological architecture. Such heterogeneity is a relevant issue in the histological differential diagnosis of ACC. Uncommon architectural patterns include pseudopapillary and storiform, the latter typical of the sarcomatoid variant.
Necrosis, either punctate or extensive, is frequent and should be kept separate from ischemic-type necrosis, which may occur as a consequence of fine-needle aspiration biopsy procedures in benign lesions.
The mitotic c index is usually elevated in ACC, accepting the fact that—as for other endocrine tumors—mean mitotic activity in malignant lesions is generally lower than in other malignancies (i.e., lung, breast, or colon cancer). An elevated mitotic index is probably the most specific feature of malignancy and is incorporated in all scoring systems or diagnostic algorithms, using the same cut-off of >5 mitoses per 10 mm2 (50 high power fields). However, the distribution of mitotic figures is heterogeneous and they usually cluster in hot-spots; therefore, the evaluation of different fields within the same slides and/or of different slides is advisable. Atypical mitotic figures are suggestive of abnormal chromosome content (aneuploidy) and, when present, represent a hallmark of malignancy, even when a single but unequivocal mitotic figure is identified.
Invasive properties in ACC include capsular, vascular and sinusoidal invasion. Capsular invasion is defined as complete penetration of the tumor capsule, although it can be difficult to evaluate in cases where the tumor capsule is irregular and distorted by fibrous septa. Vascular invasion is another parameter highly specific of malignancy, but it may be missed in a relevant proportion of cases. If recorded using stringent criteria, it was also shown to be an adverse predictor of metastatic disease and clinical outcome [3]. Sinusoidal invasion is equivocally considered either as the presence of tumor cells in thin-walled vascular spaces within the tumor or—more consistent with current guidelines for pathology reporting [4]—as the invasion of lymphatic vessels at the periphery of the tumor.
14.2.3 Scoring Systems
The diagnosis of ACC is based on the combination of architectural and cytological features, of necrosis and mitotic activity and of the above-mentioned invasion-related parameters. At variance with other endocrine neoplasms (i.e., thyroid tumors), no parameter is reliable enough to code malignancy, but all of them have to be considered and assessed individually, and the final diagnosis results from the application of specific scoring systems or algorithms endorsed by the WHO classification.
Strengths of such an approach are the definition of diagnostic rules, a comprehensive pathology report describing all the relevant pathological parameters, and the assessment in some cases of a quantitative evaluation that is also relevant for prediction of clinical outcome. The systems/scorings proposed by the WHO classification of endocrine and neuroendocrine tumors [5] are detailed in Table 14.1. No single system has been shown to be completely sensitive or specific in all settings, nor has any of them proven to have complete observational concordance in individual lesions. Therefore, the WHO continues to suggest the use of multiple approaches to describe the lesion and predict its clinical behavior along with the recording of data for future validation studies. In general terms, it is advisable that pathologists use their judgment to select the appropriate system or multiple systems according to the morphological features of the single lesion they are observing.
The Weiss score is the first scoring system for assessing malignancy described in ACC and is by far the most widely adopted and validated [6]. It consists of nine parameters, and malignancy is defined by the presence of ≥3 positive parameters (range 0 to 9). The Helsinki score is more recent and in principle it has been designed to simplify the Weiss score by limiting the number of variables (thus improving reproducibility), and to integrate Ki67 as an additional tool [7]. Two pathological parameters (mitotic index and necrosis) are considered with different statistical power, together with the exact value of the Ki67 proliferation index (as %). A Helsinki score >8.5 points is associated with metastatic potential with 100% sensitivity and 99.4% specificity. The Helsinki score has been largely evaluated and validated in independent series [8] for both conventional ACC and ACC variants and it has been shown to outperform the Weiss system [9].
The reticulin algorithm proposal stems from evidence that the vascular network is almost invariably regular in adrenocortical adenoma, closely mimicking the normal adrenal cortex, whereas it is disrupted at a variable degree of distribution and quality in ACC. This difference is easily highlighted by silver-based staining procedures, both in terms of qualitative and quantitative changes [1, 2]. To increase specificity for malignancy, in the algorithm the presence of a disrupted reticulin framework should be associated with one or more among the following: increased mitotic index (same cut-off as for the Weiss and Helsinki scores), necrosis, and vascular invasion. The diagnostic performance of the reticulin algorithm has been validated in several studies and endorsed by the WHO classification [5].
For predominant oncocytic tumors (see below), the Helsinki score and reticulin algorithm approaches are both indicated, but the Weiss score has a high risk of overestimating malignancy due to the presence of three parameters linked to the finding of oncocytic cells irrespective of their biological nature (i.e., eosinophilic cytoplasm, nucleoli and diffuse growth). Therefore, about 20 years ago, a group of pathologists designed an alternative system based on major (to define malignant cases) and minor (to define cases with uncertain malignant potential) criteria [10].
14.2.4 Histological Subtypes
The heterogeneity of histological features corresponds to the presence of histological variants. Apart from conventional ACC, three main variants are encountered in the WHO classification, namely—in order of decreasing frequency—oncocytic, myxoid and sarcomatoid [11].
Oncocytic ACC represent about 25% of cases, with clinical characteristics, in terms of epidemiology and functional properties, similar to conventional ACC apart from a higher prevalence of functioning tumors secreting sex steroid hormones [12]. Oncocytic ACC histologically is characterized by the presence of a predominant population of oncocytes, whereas cases with a lesser component of oncocytic cells are included in the conventional type. As for oncocytes in other pathological conditions, tumor cells in oncocytic ACC are characterized by abundant eosinophilic and granular cytoplasm, enlarged nuclei with nucleoli and a diffuse growth pattern. The ultrastructural hallmark is the presence of an abnormal accumulation of functionally defective and morphologically altered mitochondria. Myxoid ACC has been only recently recognized as a specific ACC variant. It is rarer than the oncocytic type, but prevalence data in large series are still missing. Histologically, they are characterized by small uniform cells, with mild atypia, embedded in an abundant extracellular matrix made of myxoid material [13]. Sarcomatoid ACC is very rare, with few cases reported in the literature [14]. Most cases have biphasic morphology, with an epithelioid component of conventional type admixed to a variable extent with a sarcomatoid pattern, characterized by spindle cell architecture and highly pleomorphic cells. When monophasic, sarcomatoid ACC can be indistinguishable from true sarcomas of the adrenal gland.
14.2.5 Pediatric Adrenocortical Tumors
Pediatric adrenocortical tumors deserve separate mention due to their peculiar clinical characteristics and pathological features. They more frequently occur before the age of 5 years, with a second peak in adolescence, and females are more frequently affected [15]. Functional tumors are more frequent than in adults, accounting for up to 85% of cases, and virilization is the most frequent functional manifestation. The pathological classification is challenging since the inconsistency of the correlation between tumor behavior and histopathological findings is more pronounced than in adult cases [16]. The Weiss score has been shown to have good specificity for detecting cases with an aggressive clinical course [17], but it generally overestimates malignant potential in pediatric tumors. In 2003, a new proposal was made by the Armed Forces Institute of Pathology (AFIP) which includes the following parameters: tumor weight >400 g, tumor size >10.5 cm, extra-adrenal extension, invasion into the vena cava, venous invasion, capsular invasion, tumor necrosis, mitotic index >15/20 high power fields (HPF) and atypical mitotic figures [18]. The presence of 0 to 2 criteria defines a lesion as benign, a score of >3 is indicative of malignancy, whereas a score of 3 classifies a lesion as indeterminate for malignancy. As for the other scoring systems/algorithms used in adults, the Helsinki score has been demonstrated to possess a high specificity for malignancy [19]. Moreover, the reticulin algorithm has been recently shown to be easy to apply and the most sensitive histopathological approach to identify aggressive behavior in pediatric adrenocortical tumors [20].
14.2.6 Grading
Grading of ACC was called for several years ago [21] but finally adopted by the AJCC TNM staging system eighth edition and more recently by the WHO classification [5]. Despite the wide range of morphological parameters assessed for diagnostic scoring systems, the mitotic index is the only parameter considered for grading. Differently from the diagnostic cut-off, ACC is segregated into low- or high-grade based on a cut-off of 20 mitoses/10 mm2).
14.2.7 Staging
Current TNM staging of ACC (Table 14.2) is based on integration of the AJCC eighth edition of TNM system and the staging proposal by the European Network for the Study of Adrenal Tumors (ENSAT) [22]. Pathological stage T1 and T2 ACC are tumors limited to the adrenal gland (≤5 cm or >5 cm, respectively), whereas T3 tumors show invasion of the surrounding tissues and T4 invasion of adjacent organs or vena cava or renal vein. N1 and M1 are defined by any type of lymph node or distant involvement, respectively, irrespective of the number of lesions and site.
In pediatric ACC the staging system was developed by the International Pediatric Adrenocortical Tumor Registry (IPACTR) and the Children’s Oncology Group (COG) and include resection margins, presence of metastases, and weight [23].
14.2.8 Immunohistochemical Profile
Immunohistochemical profiling is an essential complement for ACC characterization. It is needed to prove the adrenocortical nature of the lesion, to assist the definition of malignancy, to assess the expression of prognostic markers and to screen for the presence of hereditary predisposition.
For the definition of primary adrenocortical origin, the use of a panel of markers is advisable to balance the sensitivity and specificity of each single marker. ACC is usually negative or only focally positive for cytokeratins, a clue that may help to distinguish ACC from metastatic carcinomas. The best marker for the definition of adrenocortical primary origin is SF1, which is considered the most reliable and specific. It is expressed in steroidogenic cells of the gonads, in the gonadotrophs of the pituitary gland and in normal adrenal cortex and all types of adrenocortical neoplasms [24]. SF1 specificity for adrenocortical origin is up to 100% and its sensitivity is about 95%, especially if monoclonal antibodies are used [25]. Other markers to be considered in the panel are melan-A, synaptophysin, alpha-inhibin and calretinin [26]. However, these markers are also positive in other tumors that may involve the adrenal, and a positive result should be interpreted in relation to the overall pathological picture.
For the definition of malignancy, the use of phospho-histone-H3 immunohistochemistry may help to highlight mitoses, especially in carcinomas with low mitotic counts [27]. Other markers have also been proposed to assist in the distinction between adrenocortical adenoma and ACC (i.e., IGF2 and beta-catenin), but their real clinical usefulness is still a matter of debate. Among them, p53 expression is often altered (overexpressed or lost) in the presence of TP53 mutations. Altered p53 expression has been widely used to support the diagnosis of ACC but not all ACC have TP53 mutations, thus undermining its sensitivity. More interestingly, p53 altered expression has been also demonstrated to be associated with a poorer prognosis [28].
Ki67 per se is a diagnostic marker now integrated in the Helsinki score. However, its major role is linked to its strong and independent prognostic impact [29]. Consensus on prognostic cut-offs has not been reached and both three-tier and two-tier categorization approaches are described. Moreover, reproducibility and standardization of Ki67 index evaluation is rather poor [30].
Molecular characterization of ACC has improved in recent years, and transcriptome and pan-genomic studies clearly underpinned the role of molecular risk stratification in ACC. However, this evidence lacks translation and validation into well-established biomarkers to be assessed in routine clinical work, with special reference to immunohistochemical biomarkers assessable in every pathology laboratory. Among them, the loss of ATRX and ZNRF3 expression [31] reflects the presence ACC-specific molecular alterations, and has been proposed to be associated with a more aggressive biological behavior, but the use of such markers in clinical practice still needs validation.
Finally, mismatch-repair (MMR) proteins and PD-L1 immunohistochemistry may also help to determine the eligibility for immunotherapy in select patients, although these markers have no clear indication to date, nor have they been shown to be definitely associated with patient response in large studies [32]. However, the WHO strongly recommend testing for MMR proteins in all ACC patients to screen for the presence of hereditary cases linked to the Lynch syndrome, as indicated for other cancer types (i.e., endometrial or colon cancer). Indeed, ACC is part of the Lynch syndrome phenotype and up to 10% of ACC cases are inherited in this context [33].
14.3 Malignant Pheochromocytoma
14.3.1 Gross Pathology
The most common appearance of a sporadic PHEO is a solitary, round or oval mass that distorts the adrenal gland. Tumor size and weight can vary widely, with tumors measuring more than 10 cm and weighting up to several 100 g. On section, the tumor is usually well circumscribed and may even appear encapsulated. PHEOs more commonly have a variegated tan brown and red soft cut surface with areas of frank hemorrhage and central degeneration with necrosis, fibrosis or cystic change. All such features are not indicative alone of a malignant clinical behavior. Multiple nodules on a background of diffusely expanded medulla are suggestive of a hereditary predisposition.
14.3.2 Cytological and Histological Findings
The neoplastic cells are usually large and polygonal with abundant granular basophilic or eosinophilic cytoplasm and indistinct cell borders. The nuclei are round to oval, with prominent nucleoli and nuclear inclusions. Some tumors exhibit significant nuclear pleomorphism with occasional multinucleation.
PHEOs have a characteristic architecture of well-defined nests of tumor cells known as “zellballen”, surrounded by a thin fibrovascular stroma and non-neoplastic sustentacular cells. The periphery of the lesion is usually delineated from the surrounding gland, but most tumors do not have a well-defined capsule or pseudo-capsule, and it is not uncommon to see intermingling tumor cells and cortical cells. There may be areas of degeneration associated with hemorrhage, fibrosis, and hemosiderin deposition, but coagulative necrosis is unusual. As for other neuroendocrine neoplasms, melanin pigment can be found and, when abundant, may be a worrisome feature in the differential diagnosis with other pigmented lesions such as melanoma. Some pathological features are suggestive of a specific pathogenetic mechanism and, although not completely specific, may suggest a hereditary context. The presence of a myxoid, hyalinized stroma with edema together with enlarged cytoplasm with lipid vacuoles should prompt consideration of von Hippel-Lindau (VHL), whereas tumors with succinate dehydrogenase (SDH) mutations may be composed of large cells with particularly abundant eosinophilic granular cytoplasm. The presence of multifocal disease is also strongly suggestive of genetic predisposition and the identification of adrenal medullary hyperplasia raises the possibility of MEN 2.
14.3.3 Pathological Prediction of a Clinically Aggressive Course
As stated, PHEO is a tumor with potentially malignant biological behavior by definition. Clinical malignancy is certain in the presence of metastases. However, the diagnosis of metastatic disease must be made with great caution, especially in patients with known germline predisposition who are likely to develop multifocal disease in various locations, including visceral organs (such as the liver and lungs). Exceptions are the brain, bone, and lymph nodes, and these are the only sites that can be accepted a priori as metastatic locations, if confirmed histologically.
A number of histologic scoring schemes have been developed to predict clinical malignancy in PHEO (Table 14.3), but, unlike those used in ACC, they are not definitely validated or sufficiently accurate to be endorsed by the WHO classification [34]. The oldest score, which applies to PHEO but not to paraganglioma, is the PASS (Pheochromocytoma of the Adrenal gland Scaled Score). This includes 12, differently weighted, histologic parameters [35]. The advantage of the scheme is that it is only based on morphological parameters and does not incorporate clinical data, which are frequently not available to pathologists. The PASS scheme is an excellent rule-out model, with a low PASS score indicating a non-metastatic clinical course, whereas it is poorly specific [36] and affected by high interobserver variability [37]. The GAPP (Grading system for Adrenal Pheochromocytoma and Paraganglioma) score was developed as an alternative and includes a series of histologic criteria, the Ki67 labeling index, and the patient’s biochemical catecholamine status [38]. According to this system, lesions are stratified into a three-tier scheme of “well-differentiated”, “moderately differentiated”, and “poorly differentiated”, a terminology that is not endorsed by the WHO classification. More recently, the COPPS score (Composite Pheochromocytoma/paraganglioma Prognostic Score) has been proposed that incorporates tumor size, necrosis, vascular invasion and immunohistochemical biomarkers [39] but has not been widely validated.
14.3.4 Staging
Despite the current viewpoint that all pheochromocytomas/paragangliomas (PPGLs) may exhibit metastatic potential, the first PPGL staging system was introduced in the eighth edition of the AJCC Cancer Staging Manual. It is based on tumor localization, tumor size, and presence or absence of regional or distant metastases. This staging system is only applied to sympathetic paragangliomas and PHEOs and has been validated in large retrospective series [40] but requires further validation studies to be used in clinical practice.
14.3.5 Immunohistochemical Profile
PHEO has a characteristic immunohistochemical profile [41]. The tumor cells are diffusely positive for common neuroendocrine markers, such as INSM1, synaptophysin and chromogranin A. Due to their nonepithelial origin, they are negative for cytokeratins, a characteristic that may assist in the differential diagnosis with other neuroendocrine neoplasms. In this context, another relevant marker is GATA3, whereas functional markers such as tyrosine hydroxylase are also specific but usually not accessible in routine diagnostic laboratories. S100/SOX10 sustentacular cells may be present also in other neuroendocrine neoplasms and are not specific for a chromaffin cell origin. However, a positive S100 and SOX10 immunohistochemistry may be used to rule out a metastatic lesion, since sustentacular cells are absent in distant metastases. Neuroendocrine hormones secreted by PHEO cells are a variety, but they are usually not used for diagnostic purposes, if not to characterize specific cases with unexpected functional properties (i.e., ACTH-secreting cases associated with Cushing’s syndrome) [42]. As for other neuroendocrine neoplasms, Ki67 labeling is used to define the proliferative rate, but unlike in the gastroenteropancreatic system it is not indicative of a specific grade, although a high proliferation rate has been shown to be associated with a worse clinical outcome [43]. A major role of immunohistochemistry is to guide assessment of genetic predisposition [44]. The most widely used tool is immunostaining for SDHB. This test is useful because it has been found that mutation in any SDH-related gene (SDHA, SDHB, SDHC, SDHD or SDH-AF2) results in a loss of SDHB expression in tumor cells. Other immunohistochemical reactions may be surrogate markers of hereditary predisposition. For example, CAIX expression has been associated with VHL-associated disease, and a loss of FH immunoreactivity may help to identify rare cases of FH-mutated PHEOs, together with intact staining for 2-succinocysteine (2SC).
References
Duregon E, Fassina A, Volante M, et al. The reticulin algorithm for adrenocortical tumor diagnosis: a multicentric validation study on 245 unpublished cases. Am J Surg Pathol. 2013;37(9):1433–40.
Volante M, Bollito E, Sperone P, et al. Clinicopathological study of a series of 92 adrenocortical carcinomas: from a proposal of simplified diagnostic algorithm to prognostic stratification. Histopathology. 2009;55(5):535–43.
Mete O, Gucer H, Kefeli M, Asa SL. Diagnostic and prognostic biomarkers of adrenal cortical carcinoma. Am J Surg Pathol. 2018;42(2):201–13.
Giordano TJ, Berney D, de Krijger RR, et al. Data set for reporting of carcinoma of the adrenal cortex: explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting. Hum Pathol. 2021;110:50–61.
Mete O, Erickson LA, Juhlin CC, et al. Overview of the 2022 WHO classification of adrenal cortical tumors. Endocr Pathol. 2022;33(1):155–96.
Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol. 1989;13(3):202–6.
Pennanen M, Heiskanen I, Sane T, et al. Helsinki score—a novel model for prediction of metastases in adrenocortical carcinomas. Hum Pathol. 2015;46(3):404–10.
Duregon E, Cappellesso R, Maffeis V, et al. Validation of the prognostic role of the “Helsinki Score” in 225 cases of adrenocortical carcinoma. Hum Pathol. 2017;62:1–7.
Minner S, Schreiner J, Saeger W. Adrenal cancer: relevance of different grading systems and subtypes. Clin Transl Oncol. 2021;23(7):1350–7.
Bisceglia M, Ludovico O, Di Mattia A, et al. Adrenocortical oncocytic tumors: report of 10 cases and review of the literature. Int J Surg Pathol. 2004;12(3):231–43.
de Krijger RR, Papathomas TG. Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants. Virchows Arch. 2012;460(1):9–18.
Kanitra JJ, Hardaway JC, Soleimani T, et al. Adrenocortical oncocytic neoplasm: a systematic review. Surgery. 2018;164(6):1351–9.
Papotti M, Volante M, Duregon E, et al. Adrenocortical tumors with myxoid features: a distinct morphologic and phenotypical variant exhibiting malignant behavior. Am J Surg Pathol. 2010;34(7):973–83.
Papathomas TG, Duregon E, Korpershoek E, et al. Sarcomatoid adrenocortical carcinoma: a comprehensive pathological, immunohistochemical, and targeted next-generation sequencing analysis. Hum Pathol. 2016;58:113–22.
Zambaiti E, Duci M, De Corti F, et al. Clinical prognostic factors in pediatric adrenocortical tumors: a meta-analysis. Pediatr Blood Cancer. 2021;68(3):e28836.
Dehner LP, Hill DA. Adrenal cortical neoplasms in children: why so many carcinomas and yet so many survivors? Pediatr Dev Pathol. 2009;12(4):284–91.
Riedmeier M, Thompson LDR, Molina CAF, et al. Prognostic value of the Weiss and Wieneke (AFIP) scoring systems in pediatric ACC—a mini review. Endocr Relat Cancer. 2023;30(4):e220259.
Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol. 2003;27(7):867–81.
Jangir H, Ahuja I, Agarwal S, et al. Pediatric adrenocortical neoplasms: a study comparing three histopathological scoring systems. Endocr Pathol. 2023;34(2):213–23.
Lopez-Nunez O, Virgone C, Kletskaya IS, et al. Diagnostic utility of a modified reticulin algorithm in pediatric adrenocortical neoplasms. Am J Surg Pathol. 2024;48(3):309–16.
Giordano TJ. The argument for mitotic rate-based grading for the prognostication of adrenocortical carcinoma. Am J Surg Pathol. 2011;35(4):471–3.
Fisher SB, Habra MA, Chiang YJ, et al. Comparative performance of the 7th and 8th editions of the American Joint Committee on Cancer staging manual for adrenocortical carcinoma. World J Surg. 2020;44(2):544–51.
Lam AK. Adrenocortical carcinoma: updates of clinical and pathological features after renewed World Health Organisation classification and pathology staging. Biomedicines. 2021;9(2):175.
Sbiera S, Schmull S, Assie G, et al. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J Clin Endocrinol Metab. 2010;95(10):E161–71.
Duregon E, Volante M, Giorcelli J, et al. Diagnostic and prognostic role of steroidogenic factor 1 in adrenocortical carcinoma: a validation study focusing on clinical and pathologic correlates. Hum Pathol. 2013;44(5):822–8.
Mete O, Asa SL, Giordano TJ, et al. Immunohistochemical biomarkers of adrenal cortical neoplasms. Endocr Pathol. 2018;29(2):137–49.
Duregon E, Molinaro L, Volante M, et al. Comparative diagnostic and prognostic performances of the hematoxylin-eosin and phospho-histone H3 mitotic count and Ki-67 index in adrenocortical carcinoma. Mod Pathol. 2014;27(9):1246–54.
Hescot S, Faron M, Kordahi M, et al. Screening for prognostic biomarkers in metastatic adrenocortical carcinoma by tissue micro arrays analysis identifies P53 as an independent prognostic marker of overall survival. Cancers (Basel). 2022;14(9):2225.
Beuschlein F, Weigel J, Saeger W, et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab. 2015;100(3):841–9.
Papathomas TG, Pucci E, Giordano TJ, et al. An international Ki67 reproducibility study in adrenal cortical carcinoma. Am J Surg Pathol. 2016;40(4):569–76.
Brondani VB, Lacombe AMF, Mariani BMP, et al. Low protein expression of both ATRX and ZNRF3 as novel negative prognostic markers of adult adrenocortical carcinoma. Int J Mol Sci. 2021;22(3):1238.
Remde H, Schmidt-Pennington L, Reuter M, et al. Outcome of immunotherapy in adrenocortical carcinoma: a retrospective cohort study. Eur J Endocrinol. 2023;188(6):485–93.
Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol. 2013;31(24):3012–8. Erratum in: J Clin Oncol. 2013;31(28):3612.
Mete O, Asa SL, Gill AJ, et al. Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas. Endocr Pathol. 2022;33(1):90–114.
Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol. 2002;26(5):551–66.
Stenman A, Zedenius J, Juhlin CC. The value of histological algorithms to predict the malignancy potential of pheochromocytomas and abdominal paragangliomas—A meta-analysis and systematic review of the literature. Cancers (Basel). 2019;11(2):225.
Wu D, Tischler AS, Lloyd RV, et al. Observer variation in the application of the Pheochromocytoma of the Adrenal Gland Scaled Score. Am J Surg Pathol. 2009;33(4):599–608.
Kimura N, Takayanagi R, Takizawa N, et al. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer. 2014;21(3):405–14.
Pierre C, Agopiantz M, Brunaud L, et al. COPPS, a composite score integrating pathological features, PS100 and SDHB losses, predicts the risk of metastasis and progression-free survival in pheochromocytomas/paragangliomas. Virchows Arch. 2019;474(6):721–34.
Stenman A, Zedenius J, Juhlin CC. Retrospective application of the pathologic tumor-node-metastasis classification system for pheochromocytoma and abdominal paraganglioma in a well characterized cohort with long-term follow-up. Surgery. 2019;166(5):901–6.
Juhlin CC. Challenges in paragangliomas and pheochromocytomas: from histology to molecular immunohistochemistry. Endocr Pathol. 2021;32(2):228–44.
Birtolo MF, Grossrubatscher EM, Antonini S, et al. Preoperative management of patients with ectopic Cushing’s syndrome caused by ACTH-secreting pheochromocytoma: a case series and review of the literature. J Endocrinol Investig. 2023;46(10):1983–94.
Wang LL, Wei XJ, Zhang QC, Li F. Morphological and immunohistochemical characteristics associated with metastatic and recurrent progression in pheochromocytoma/paraganglioma: a cohort study. Ann Diagn Pathol. 2022;60:151981.
Juhlin CC, Mete O. Advances in adrenal and extra-adrenal paraganglioma: practical synopsis for pathologists. Adv Anat Pathol. 2023;30(1):47–57.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Open Access This chapter is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits any noncommercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if you modified the licensed material. You do not have permission under this license to share adapted material derived from this chapter or parts of it.
The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Copyright information
© 2025 The Author(s)
About this chapter
Cite this chapter
Vocino Trucco, G., Volante, M. (2025). Pathology of Adrenocortical Carcinoma and Malignant Pheochromocytoma. In: Tiberio, G.A.M. (eds) Primary Adrenal Malignancies. Updates in Surgery. Springer, Cham. https://doi.org/10.1007/978-3-031-62301-1_14
Download citation
DOI: https://doi.org/10.1007/978-3-031-62301-1_14
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-62300-4
Online ISBN: 978-3-031-62301-1
eBook Packages: MedicineMedicine (R0)