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New and Emerging Biomarkers in Endocrine Pathology

Papathomas, Thomas G., MD, PhD, FRCPath*; Nosé, Vania, MD, PhD†,‡

Advances in Anatomic Pathology: May 2019 - Volume 26 - Issue 3 - p 198–209
doi: 10.1097/PAP.0000000000000227
Review Articles
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Significant advances in genomics and molecular genetics in recent years have reshaped the practice of endocrine pathology. Pan-genomic studies, including the pioneering ones on papillary thyroid carcinoma, phaeochromocytoma/paraganglioma, and adrenal cortical carcinoma from the Cancer Genome Atlas (TCGA) project, provided a comprehensive integrated genomic analysis of endocrine tumors into distinct molecularly defined subtypes. Better understanding of the molecular landscape and more accurate definition of biological behavior has been accordingly achieved. Nevertheless, how any of these advances are translated into routine practice still remains a challenge in the era of precision medicine. The challenge for modern pathology is to keep up the pace with scientific discoveries by integrating novel concepts in tumor classification, molecular genetics, prognostication, and theranostics. As an example, pathology plays a role in the identification of hereditary disease, while it offers the tools for complementing molecular genetics, for example, validation of variants of unknown significance deriving from targeted sequencing or whole exome/genome sequencing approach. Immunohistochemistry has arisen as a cost-effective strategy in the evaluation either of somatic mutations in tumors and/or germline mutations in patients with familial cancer syndromes. Herein, a comprehensive review focusing on novel and emerging biomarkers is presented in order pathologists and other endocrine-related specialists to remain updated and become aware of potential pitfalls and limitations in the field of endocrine pathology.

*Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

Department of Pathology, Massachusetts General Hospital

Department of Pathology, Harvard Medical School, Boston, MA

The authors have no funding or conflicts of interest to disclose.

All figures can be viewed online in color at www.anatomicpathology.com.

Reprints: Vania Nosé, MD, PhD, Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (e-mail: vnose@mgh.harvard.edu).

Endocrine pathology is a fascinating branch of surgical pathology, which has been continuously evolving the past decade in parallel with advances in the fields of molecular genetics and genomics. This is regarded as a key component of multidisciplinary set of endocrine and endocrine-related specialties, while it stands at the interface of medical genetics and endocrinology. Pathologists are responsible for contributing into diagnostics, prognostics, and theranostics. In this review, we provide an overview of new and emerging diagnostic, functional, prognostic, and predictive biomarkers as utilized in endocrine pathology (Fig. 1). In particular, we discuss diagnostic markers in accurate tumor classification per 2017 World Health Organization (WHO) classification of tumors of endocrine organs, functional markers in identifying hereditary predisposition, prognostic markers in highlighting aggressive endocrine neoplasia, and predictive markers of therapeutic response in endocrine oncology.

FIGURE 1

FIGURE 1

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DIAGNOSTIC MARKERS

A detailed morphologic assessment and judicious use of immunohistochemistry is usually required to characterize any tumor arising in endocrine organs. Per WHO 2017 classification of endocrine neoplasia, pituitary adenomas (or pituitary adenohypophysial neuroendocrine tumors) are classified based on cell lineage utilizing immunohistochemical (IHC) detection of transcription factors.1,2 Key transcription factors underlying development of endocrine cells and/or regulation of specific hormones, for example, PIT-1/ ER-α/ GATA-2/ T-PIT/ SF-1 (pituitary), TTF-1 (NKX2-1)/ TTF-2 (FOXE1)/ PAX-8/ HHEX (thyroid), GATA-3/GCM-2 (parathyroid), SF-1 (adrenal cortex), and CRX (pineal), not only have refined classification of tumors of endocrine organs (Fig. 2), but have been gradually integrated into tumor-specific IHC profiles in primary endocrine organs (Table 1). The pattern of transcription factors that are utilized to classify adenohypophysial tumors has recently expanded as GATA-3 immunoexpression is characteristic both of pituitary gonadotroph and TSH-producing tumors.12 To ensure accurate diagnosis, the reporting pathologist should be aware of the multispecificity of some transcription factors (ie, GATA-3 also in paragangliomas and metastatic carcinomas or steroidogenic factor-1 (SF-1) in adrenocortical/gonadal tumors and adenohypophysial tumors of gonadotroph lineage) and rely on a complete panel of IHC markers.

FIGURE 2

FIGURE 2

TABLE 1

TABLE 1

A rare scenario refers to adrenal cortical tumors arising in ectopic adrenal tissue along the pathway of gonadal descent (eg, celiac axis, broad ligament, spermatic cord, adnexa of testis) and/or at intraparenchymal site (eg, liver, kidney, testis, ovary). IHC detection of SF-1 and enzymes involved in biosynthetic pathways of steroidogenesis, that is, 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, and dehydroepiandrosterone sulfotransferase, is to confirm adrenocortical origin.13–17 Likewise, ectopic thyroid tissue outside the embryonic descent pathway of the medial thyroid anlage and particularly within the adrenals poses a diagnostic challenge.18–21 Although it can be incidental in the infradiaphragmatic area, the possibility that this might represent a clinically undetected papillary thyroid carcinoma (PTC) needs to be excluded.20,21 Lack of an immunoprofile consistent with PTC, that is, HBME-1, CK19, Galectin-3, and BRAF V600E (VE1) immunonegativity, along with a low proliferation (Ki67) index and absence of prevalent molecular aberrations frequently detected in well-differentiated thyroid cancer are in support of benign nature.20,22

It is critical both for management and prognosis to confirm the presence of metastatic disease in cancer patients or establish diagnosis in those cases of occult anatomic site of origin. Additional to the pathologic workup (Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/PAP/A26),23–29 clinicoradiologic correlations are complementarily required to specify the primary site, encompassing a thorough clinical examination, basic laboratory tests including most relevant tumor markers and cross-sectional PET/CT imaging.31 No primary site is detected in a given subset of metastatic malignancies despite thorough investigations with an estimate of 2% to 3% of all cancer diagnoses.30–33 This estimate is consistent with metastases to endocrine organs.34 These cases are defined as cancer of unknown primary site and characterized by early dissemination.33 There has been a growing interest in various molecular applications either to classify cancer of unknown primary site utilizing somatic point mutations along with copy number data, gene expression or epigenetic profiling, and/or to identify clinically actionable genomic alterations by tumor molecular profiling irrespective of the primary site of origin.31,35–42 Molecular profiling might outperform optimal immunohistochemistry not only in metastatic tumors, but in already well-worked-up poorly differentiated neoplasms.32

The molecular diagnostic armamentarium in thyroid pathology has been enriched by ALK IHC/FISH analysis highlighting ALK fusion-driven PTCs, whereas BRAF-mutation and RAS-mutation–specific antibodies (Fig. 3) seem promising in accurate classification of BRAF-like from RAS-like thyroid neoplasms, respectively.43,44 In this context, genotyping could be valuable in thyroid tumor classification, for example, excluding noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) based on the presence of BRAF V600E mutation, RET/PTC rearrangements, and/or telomerase reverse transcriptase promoter (TERT-p) mutations.45 An emerging entity awaiting inclusion in the next WHO classification of tumors of endocrine organs is the so-called “mammary analogue secretory carcinoma” (or secretory carcinoma) of the thyroid gland, which is characterized by specific morphologic features, immunoprofile, and presence of ETV6-NTRK3 fusion (Table 1).6,7

FIGURE 3

FIGURE 3

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FUNCTIONAL MARKERS

In the new era of molecular diagnostics and precision medicine, pathology has been continuously evolving by keeping the pace with technological advances in genomics and clinical breakthroughs in oncology. Predictive and therapeutic immunohistochemistry as well as digital pathology and bioinformatics seem to becoming integral parts of modern practice.46 In this context, immunohistochemistry has emerged as a reliable tool to uncover some of the familial cancer syndromes (FCSs) or hereditary tumor predisposition syndromes (HTPSs) (Figs. 4, 5) by inferring the presence of mutations in the germline of patients presenting with FCS-/HTPS-related tumors.47,48

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

Inherited endocrine tumors have been more and more known in clinical setting, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. For example, paraganglionic tumors might arise in an apparently sporadic manner in SDH mutation carriers. Morphologic traits of endocrine and/or endocrine-related cancer can raise the suspicion of hereditary disease, for example, multiple cellular adenomatous thyroid nodules seen in Cowden syndrome, or a specific type of thyroid tumor, as the cribriform-morular variant of papillary thyroid carcinoma (CMv-PT) in Familial Adenomatous Polyposis (FAP), parafibromin-deficient parathyroid tumors in Hyperparathyroidism Jaw Tumor syndrome, succinate dehydrogenase (SDH)-deficient renal cell carcinomas and gastrointestinal stromal tumors in SDH-related Pheochromocytoma/Paraganglioma (PPGL) syndromes, fumarate hydratase (FH)-deficient renal cell carcinomas and uterine smooth muscle tumors in Hereditary Leiomyomatosis and Renal Cell Cancer syndrome, multiple pancreatic micro-differentiated as well as well-differentiated neuroendocrine tumors in glucagon cell adenomatosis.47–50 Immunohistochemistry should be subsequently performed and integrated in a comprehensive molecular genetic approach.

Hereditary thyroid neoplasms arising from calcitonin-producing C cells are known as familial medullary thyroid carcinomas, and include well-documented syndromes such as multiple endocrine neoplasia type 2A or 2B, and pure familial medullary thyroid carcinoma syndrome. Familial thyroid cancers arising from follicular cells are referred to as familial nonmedullary thyroid carcinoma, or familial follicular cell–derived carcinoma. Familial nonmedullary thyroid carcinoma are subdivided into 2 groups. Among the first group are found syndromes characterized by a predominance of nonthyroidal tumors, including FAP, PTEN hamartoma tumor syndrome/Cowden syndrome, Carney complex, Werner syndrome, and Pendred syndrome. The markers are more specific for these tumors in the first group. The second group is composed by a variety of familial syndromes characterized by a predominance of nonmedullary thyroid tumors, such as pure familial PTC with or without oxyphilia, familial PTC with papillary renal cell carcinoma, and familial papillary carcinoma with multinodular goiter. No markers for this group are available.49,51,52

Table 2 summarizes emerging functional markers for FCS/HTPS identification, which have revolutionized the field of endocrine pathology by highlighting deficiency state, dysregulated downstream pathway, monohormonal status or specific mutation. Loss of expression (menin, p27, PRKAR1A, PTEN, parafibromin, SDHB/SDHA, FH, MAX, NF1, BAP1, MMR proteins, hamartin/tubein) or over-expression [β-catenin, SDHD, S-(2-succinyl) cysteine (2SC), glucagon] is accordingly expected at the protein level in FCS-/HTPS-related endocrine and/or neuroendocrine tumors. Albeit, not all IHC markers are widely available nor recommended for universal screening testing. Awareness of limitations in their applicability and/or pitfalls is critical and worth mentioning given the significant impact of an erroneous interpretation or recommendation in the multidisciplinary context:

  • Discordance between the IHC staining pattern and germline mutation status: (i) global loss of p27 has been recently reported in sporadic functioning corticotroph pituitary tumors adding to its value in identifying patients with multiple endocrine neoplasia type 4;4,70 (ii) SDHB immunonegativity is not always predictive of an underlying germline SDH-x (SDHA, SDHB, SDHC, SDHD, and SDHAF2) pathogenic mutation as site-specific aberrant DNA hypermethylation of the SDHC gene (or SDHC epimutation) can result in loss of SDHB expression;57,71–73 and (iii) mismatch repair (MMR)-proficient adrenocortical carcinoma can arise in the context of Lynch syndrome consistent with various examples of rare disparity between retention of protein expression and germline aberrations.65,74–76
  • Discordance between the IHC status and underlying molecular genetic alterations, for example, MMR-deficient pituitary carcinoma and adrenal cortical carcinomas arising in the setting of Lynch syndrome do not display high levels of microsatellite instability,64,65 contrasting common LynchSyndrome–associated extra-colonic tumors.75,77
  • Diminished specificity for a hereditary pathogenesis given the high proportion of sporadic counterparts: (i) loss of expression of parafibromin is valuable in identifying biallelic CDC73 inactivation in parathyroid tumors within or outside the context of hyperparathyroidism jaw tumor syndrome;56,78 (ii) menin immunodeficiency is also a feature of sporadic neuroendocrine tumorigenesis;67–69 (iii) beta-catenin nuclear expression is indicative of APC or CTTNB1 mutations in CMv-PTC-affected patients with approximately half of the cases harboring APC mutation in the germline (FAP);8 (iv) NF1 IHC seems to be an insufficient method to discriminate between NF1-mutated and nonmutated pheochromocytomas reflecting that NF1 loss of function is a frequent event in sporadic paraganglionic tumorigenesis61,62 and contrasting recent evidence suggesting that neurofibromin-specific antibody could serve a valuable surrogate for identifying NF1-inactivated gastrointestinal stromal tumors.79
  • Weakened sensitivity for pathogenic germline mutations, that is, MAX immunohistochemistry highlights deficiency only in those cases with truncating MAX mutations and/or gross deletions.59,60
  • Heterogenous pattern of immunoreactivity, for example, SDHB/SDHA-proficient and/or PTEN-proficient and PTEN-deficient intratumoral areas in familial succinate dehydrogenase–related PPGL syndromes and Cowden syndrome, respectively.53,57
TABLE 2

TABLE 2

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PROGNOSTIC AND PREDICTIVE MARKERS

Functional Markers in Parathyroid and Paraganglionic Tumors

Apart from an established application to complement morphologic or clinical suspicion of FCS/HTPS, that is, early onset of disease, multifocal synchronous or metachronous disease, precursor lesions with or without concurrent tumors, genotype-specific entities or histopathologic features and specific combinations of histogenetically distinct tumors,48 functional markers might serve as a cost-effective screen for identification of aggressive endocrine neoplastic disease. Parafibromin immunohistochemistry can be utilized to identify aggressive CDC73-related parathyroid neoplasia including parathyroid carcinomas and parathyroid tumors lacking overt malignant features.1 Exemplifying the latter, parafibromin-deficient CDC73-mutated tumors, lacking WHO 2017 criteria for malignancy, can rarely metastasize,56 whereas parafibromin-deficient atypical tumors, as defined by WHO 2004 criteria, have a low risk for recurrence.80 Long-term or even life-long close follow-up of patients with parafibromin-deficient tumors has been accordingly recommended.

SDHB/SDHA immunohistochemistry can identify SDH-related paraganglionic tumors.57,74,81,82 Nonetheless, not all SDH-deficient and/or mutated tumors will metastasize and/or behave in an aggressive manner and only half of metastatic PPGLs harbor germline SDHB mutations.57,74,83 In fact, there is a gradient for risk of metastatic disease across different PPGL molecular subgroups, that is, pseudohypoxia, Wnt signalling, and kinase signalling, as defined by The Cancer Genome Atlas (TCGA) comprehensive integrated analysis.84,85 The highest risk is observed in Krebs cycle–related tumors within the pseudohypoxia subgroup,84 which encompasses PPGLs harboring mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, malate dehydrogenase 2 (MDH2), isocitrate dehydrogenase (IDH1/IDH2/IDH3B) genes, and cases characterized by other mitochondrial genetic defects in GOT2 encoding for glutamic-oxaloacetic transaminase 2 or in SLC25A11 encoding for mitochondrial 2-oxoglutarate/malate carrier.73,86,87

As a subset of aggressive SDH-deficient PPGLs is enriched for TERT-p mutations or hypermethylation, and structural TERT rearrangements have been reported in metastatic pheochromocytoma,88–90 various immortalization-related mechanisms have been very recently under investigation to dissect biological behavior in a well-characterized PPGL series.91 This comprehensive analysis of immortalization included genomic aberrations leading to transcriptional TERT activation (ie, TERT-p mutations/methylation, and chromosomal rearrangement/amplification of TERT locus) as well as to alternative lengthening of telomere (ALT) activation (ie, ATRX mutations and telomere length and heterogeneity analyses by slot blot and telomere FISH, respectively). Of note, combined assessment of telomerase activation and ATRX mutations can identify metastatic PPGLs in the high-risk group for metastatic progression (ie, Krebs cycle–related tumors), while these significantly impact on metastasis-free survival and overall survival as independent risk factors of poor prognosis.91

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Molecular Biomarkers in Thyroid and Adrenocortical Tumors

Emerging molecular biomarkers in the field of thyroid oncology, such as mutations in noncoding functional genomic regions (ie, TERT-p mutations), multiple oncogenic mutations (eg, BRAF, RAS, TP53, PIK3CA, AKT1, and TERT-p mutations) and/or total mutation burden, might have clinical applicability as prognosticators in follicular cell–derived thyroid neoplasms independent of histopathology.44,92–96 On the basis of data deriving from a meta-analysis investigating the impact of genomic aberrations on the prognosis of PTC-affected patients, TERT-p mutations have been highlighted as independent and reliable predictive biomarker for patient outcome and risk stratification, whereas BRAF mutation should be cautiously utilized as stand-alone prognostic marker given poor predictive value in long-term prognosis.92 The latter further supports previous inconsistencies with regard to prognostic significance of BRAF mutations potentially reflecting molecular genetic heterogeneity within BRAFV600E-like PTCs.44,92,93 In keeping with a stepwise progression model in thyroid tumorigenesis, TERT-p mutations have been identified in 8% to 27% of PTCs, 20% of follicular thyroid carcinomas, <25% of Hürthle cell carcinomas, 40% of poorly differentiated thyroid carcinomas, and nearly 75% of undifferentiated thyroid carcinomas.44 These noncoding mutations might also occur in rare subset of aggressive follicular thyroid tumors without overt malignant histologic features and hence be predictive of malignant potential.94,97

Integrated genomic studies revealed subsets of adrenal cortical carcinoma with different pattern of molecular aberrations, associated with different clinical outcome: (i) 2-tier classification into C1A subgroup with poor outcome, characterized by numerous mutations and DNA methylation alterations, and C1B subgroup with good prognosis, characterized by specific microRNA deregulation;98 and (ii) 3-tier classification into 3 subtypes, Cluster of Cluster (CoC) I/II/III: CoC I with good outcome, significantly unregulated genes in immune-mediated pathways and lower Ki67-defined proliferative activity; CoC II with a heterogenous outcome; and CoC III with a dismal outcome, significant dysregulation of genes in mitotic pathways and higher Ki67-defined proliferative activity.99 The latter further reinforces the prognostic value of proliferation marker Ki67 in both localized and advanced adrenocortical cancer, with combined assessment of Ki67 labelling index and VAV2 expression leading to improved patient stratification into low-risk and high-risk subgroups and hence refining prognostic prediction.100–102 Tumor DNA methylation, that is, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, and PAX6), has recently emerged as independent prognostic marker for survival in adrenocortical cancer.103 Towards improved personalized prognostication, it has been recently shown that integrating molecular genetic data (>1 somatic mutation, alterations in Wnt/β-catenin and p53 pathways, high methylation pattern) and clinico-pathologic parameters (tumor stage, age, symptoms, resection status, and Ki67 labeling index) into a combined score yielded the best prediction of progression-free survival.104

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BIOMARKERS OF THERAPEUTIC RESPONSE IN ENDOCRINE ONCOLOGY

The immunoexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is the most well recognized biomarker of response to temozolomide, which is recommended as first-line chemotherapy for patients with aggressive pituitary tumors (ie, pituitary adenomas exhibiting rapid growth, resistance to conventional treatments, and/or early/multiple recurrences) and pituitary carcinomas. Tumors with high levels of MGMT IHC expression are unlikely to respond, whereas low levels are associated with a high likelihood of response.105 Whether MGMT tumoral content predicts survival in the aforementioned patients warrants additional research.106

Robust biomarkers of response to current therapies in well-differentiated thyroid and adrenocortical cancer should be developed to accurately determine which patients will benefit from radioiodine therapy and mitotane, respectively. In this context, TERT-p mutations might serve as early predictor of radioiodine-refractory cases of distant metastatic differentiated thyroid cancer, while human cytochrome P450 2W1, ribonucleotide reductase large subunit 1, and sterol-O-acyl-transferase 1 might represent predictive markers for the response of adrenal cortical carcinoma–affected patients to mitotane, an adrenolytic but significantly toxic agent.107–110 Preliminary evidence also suggests that somatostatin receptor subtype 1 might be a predictor of better response to therapy in medullary thyroid carcinoma.111 Nevertheless, these should be validated on large series and in the prospective setting before being utilized in routine practice.

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CONCLUSIONS

In this comprehensive review, we summarize tumor-specific biomarkers in endocrine organs as well as anatomic site-related and site-specific markers for diagnostic evaluation of challenging neoplasms. Functional markers as tools to uncover some of the FCSs and/or HTPSs are discussed along with limitations in their applicability and/or potential pitfalls in endocrine pathology. We also discuss new and emerging prognostic biomarkers in follicular cell–derived thyroid, parathyroid, paraganglionic, and adrenocortical tumors, as well as biomarkers of therapeutic response in endocrine oncology.

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ACKNOWLEDGMENT

The authors are grateful to Professor M. Beatriz S. Lopes, MD, PhD, Professor of Pathology and Neurological Surgery, Director of Neuropathology and Autopsy, University of Virginia Medical Center for providing us with figures of pituitary tumors.

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REFERENCES

1. Lloyd RV, Osamura RY, Kloppel G, et al. WHO Classification of Tumors of Endocrine Organs, 4th ed. Lyon: IARC; 2017.
2. Asa SL, Casar-Borota O, Chanson P, et al. and the attendees of 14th Meeting of the International Pituitary Pathology Club, Annecy, France, November 2016. From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal. Endocr Relat Cancer. 2017;24:C5–8.
3. Lopes MBS. The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol. 2017;134:521–535.
4. Asa SL, Mete O. Immunohistochemical biomarkers in pituitary pathology. Endocr Pathol. 2018;29:130–136.
5. Liu H, Lin F. Application of immunohistochemistry in thyroid pathology. Arch Pathol Lab Med. 2015;139:67–82.
6. Baloch ZW, LiVolsi VA. Special types of thyroid carcinoma. Histopathology. 2018;72:40–52.
7. Dogan S, Wang L, Ptashkin RN, et al. Mammary analog secretory carcinoma of the thyroid gland: a primary thyroid adenocarcinoma harboring ETV6-NTRK3 fusion. Mod Pathol. 2016;29:985–995.
8. Lam AK, Saremi N. Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer. Endocr Relat Cancer. 2017;24:R109–121.
9. Mohindra S, Sakr H, Sturgis C, et al. LEF-1 is a sensitive marker of cribriform morular variant of papillary thyroid carcinoma. Head Neck Pathol. 2018;12:455–462.
    10. Papathomas TG, de Krijger RR, Tischler AS. Paragangliomas: update on differential diagnostic considerations, composite tumors, and recent genetic developments. Semin Diagn Pathol. 2013;30:207–223.
    11. Miettinen M, McCue PA, Sarlomo-Rikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol. 2014;38:13–22.
    12. Mete O, Kefeli M, Çalişkan S, et al. GATA3 immunoreactivity expands the transcription factor profile of pituitary neuroendocrine tumors. Mod Pathol. 2018. Doi: 10.1038/s41379-018-0167-7.
    13. Yokoyama H, Adachi T, Tsubouchi K, et al. Non-functioning adrenocortical carcinoma arising in an adrenal rest: immunohistochemical study of an adult patient. Tohoku J Exp Med. 2013;229:267–270.
    14. Park WY, Seo HI, Choi KU, et al. Three cases of adrenocortical tumors mistaken for hepatocellular carcinomas/diagnostic pitfalls and differential diagnosis. Ann Diagn Pathol. 2017;31:9–13.
    15. Chentli F, Terki N, Azzoug S. Ectopic adrenocortical carcinoma located in the ovary. Eur J Endocrinol. 2016;175:K17–23.
    16. Sugiyama T, Tajiri T, Hiraiwa S, et al. Hepatic adrenal rest tumor: diagnostic pitfall and proposed algorithms to prevent misdiagnosis as lipid-rich hepatocellular carcinoma. Pathol Int. 2015;65:95–999.
    17. Jain SH, Sadow PM, Nosé V, et al. A patient with ectopic cortisol production derived from malignant testicular masses. Nat Clin Pract Endocrinol Metab. 2008;4:695–700.
    18. Lloyd RV, Douglas BR, Young WF. Endocrine Diseases, AFIP Atlas of Non-Tumor Pathology, Series 1(1). Washington, DC: American Registry of Pathology; 2002.
    19. Gourmaud J, Bongiovanni M, Triponez F, et al. Ectopic thyroid tissue in the adrenal gland. Endocr Pathol. 2014;25:353–355.
    20. Romero-Rojas A, Bella-Cueto MR, Meza-Cabrera IA, et al. Ectopic thyroid tissue in the adrenal gland: a report of two cases with pathogenetic implications. Thyroid. 2013;23:1644–1650.
    21. Bohinc BN, Parker JC, Hope WW, et al. Micropapillary thyroid carcinoma and concomitant ectopic thyroid tissue in the adrenal gland: metastasis or metaplasia? Thyroid. 2011;21:1033–1038.
    22. Lin DM, Javidiparsijani S, Vardouniotis A, et al. Ectopic thyroid tissue: immunohistochemistry and molecular analysis. Appl Immunohistochem Mol Morphol. 2018;26:734–739.
    23. Kandalaft PL, Gown AM. Practical applications in immunohistochemistry: carcinomas of unknown primary site. Arch Pathol Lab Med. 2016;140:508–523.
    24. Kandukuri SR, Lin F, Gui L, et al. Application of immunohistochemistry in undifferentiated neoplasms: a practical approach. Arch Pathol Lab Med. 2017;141:1014–1032.
    25. Lin F, Liu H. Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med. 2014;138:1583–1610.
    26. Wang HL, Kim CJ, Koo J, et al. Practical immunohistochemistry in neoplastic pathology of the gastrointestinal tract, liver, biliary tract, and pancreas. Arch Pathol Lab Med. 2017;141:1155–1180.
    27. Churg A, Sheffield BS, Galateau-Salle F. New markers for separating benign from malignant mesothelial proliferations: are we there yet? Arch Pathol Lab Med. 2016;140:318–321.
    28. Lagana SM, Salomao M, Remotti HE, et al. Bile salt export pump: a sensitive and specific immunohistochemical marker of hepatocellular carcinoma. Histopathology. 2015;66:598–602.
    29. Mendez-Pena JE, Sadow PM, Nose V, et al. RNA chromogenic in situ hybridization assay with clinical automated platform is a sensitive method in detecting high-risk human papillomavirus in squamous cell carcinoma. Hum Pathol. 2017;63:184–189.
    30. Stelow EB, Yaziji H. Immunohistochemistry, carcinomas of unknown primary, and incidence rates. Semin Diagn Pathol. 2018;35:143–152.
    31. Bochtler T, Löffler H, Krämer A. Diagnosis and management of metastatic neoplasms with unknown primary. Semin Diagn Pathol. 2018;35:199–206.
    32. Oien KA, Dennis JL. Diagnostic work-up of carcinoma of unknown primary: from immunohistochemistry to molecular profiling. Ann Oncol. 2012;23(suppl 10):x271–217.
    33. Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet. 2012;379:1428–1435.
    34. Papathomas T, Nose VWass JAH, Arlt W, Semple R. Metastatic disease in endocrine organs. Oxford Textbook of Endocrinology and Diabetes, 3rd ed. Oxford: Oxford University Press; 2019. [In Press].
    35. Soh KP, Szczurek E, Sakoparnig T, et al. Predicting cancer type from tumor DNA signatures. Genome Med. 2017;9:104.
    36. Marquard AM, Birkbak NJ, Thomas CE, et al. TumorTracer: a method to identify the tissue of origin from the somatic mutations of a tumor specimen. BMC Med Genomics. 2015;8:58.
    37. Søndergaard D, Nielsen S, Pedersen CNS, et al. Prediction of primary tumors in cancers of unknown primary. J Integr Bioinform. 2017;14:1–7.
    38. Moran S, Martinez-Cardús A, Boussios S, et al. Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary. Nat Rev Clin Oncol. 2017;14:682–694.
    39. Moran S, Martínez-Cardús A, Sayols S, et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol. 2016;17:1386–1395.
    40. Varghese AM, Arora A, Capanu M, et al. Clinical and molecular characterization of patients with cancer of unknown primary in the modern era. Ann Oncol. 2017;28:3015–3021.
    41. Ross JS, Wang K, Gay L, et al. Comprehensive genomic profiling of carcinoma of unknown primary site: new routes to targeted therapies. JAMA Oncol. 2015;1:40–49.
    42. Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–713.
    43. Chou A, Fraser S, Toon CW, et al. A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma. Am J Surg Pathol. 2015;39:652–659.
    44. Giordano TJ. Genomic hallmarks of thyroid neoplasia. Annu Rev Pathol. 2018;13:141–162.
    45. Kakudo K, El-Naggar AK, Hodak SP, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in thyroid tumor classification. Pathol Int. 2018;68:327–333.
    46. Jones JL, Oien KA, Lee JL, et al. Morphomolecular pathology: setting the framework for a new generation of pathologists. Br J Cancer. 2017;117:1581–1582.
    47. Andrici J, Gill AJ, Hornick JL. Next generation immunohistochemistry: emerging substitutes to genetic testing? Semin Diagn Pathol. 2018;35:161–169.
    48. Agaimy A, Hartmann A. Uncovering hereditary tumor syndromes: emerging role of surgical pathology. Semin Diagn Pathol. 2018;35:154–160.
    49. Guilmette J, Nosé V. Hereditary and familial thyroid tumors. Histopathology. 2018;72:70–81.
    50. Laury AR, Bongiovanni M, Tille JC, et al. Thyroid pathology in PTEN-hamartoma tumor syndrome: characteristic findings of a distinct entity. Thyroid. 2011;21:135–144.
    51. Nosé V. Familial thyroid cancer: a review. Mod Pathol. 2011;24(suppl 2):S19–33.
    52. Nosé V. Thyroid cancer of follicular cell origin in inherited tumor syndromes. Adv Anat Pathol. 2010;17:428–436.
    53. Barletta JA, Bellizzi AM, Hornick JL. Immunohistochemical staining of thyroidectomy specimens for PTEN can aid in the identification of patients with Cowden syndrome. Am J Surg Pathol. 2011;35:1505–1511.
    54. Jayakody S, Reagh J, Bullock M, et al. Medullary thyroid carcinoma: survival analysis and evaluation of mutation-specific immunohistochemistry in detection of sporadic disease. World J Surg. 2018;42:1432–1439.
    55. Reagh J, Bullock M, Andrici J, et al. NRASQ61R mutation-specific immunohistochemistry also identifies the HRASQ61R mutation in medullary thyroid cancer and may have a role in triaging genetic testing for MEN2. Am J Surg Pathol. 2017;41:75–81.
    56. Gill AJ, Lim G, Cheung VKY, et al. Parafibromin-deficient (HPT-JT type, CDC73 mutated) parathyroid tumors demonstrate distinctive morphologic features. Am J Surg Pathol. 2019;43:35–46.
    57. Papathomas TG, Oudijk L, Persu A, et al. SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T). Mod Pathol. 2015;28:807–821.
    58. Niemeijer ND, Papathomas TG, Korpershoek E, et al. Succinate dehydrogenase (SDH)-deficient pancreatic neuroendocrine tumor expands the SDH-related tumor spectrum. J Clin Endocrinol Metab. 2015;100:E1386–1393.
    59. Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–667.
    60. Daly AF, Castermans E, Oudijk L, et al. Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions. Endocr Relat Cancer. 2018;25:L37–L42.
    61. Stenman A, Svahn F, Welander J, et al. Immunohistochemical NF1 analysis does not predict NF1 gene mutation status in pheochromocytoma. Endocr Pathol. 2015;26:9–14.
    62. Burnichon N, Buffet A, Parfait B, et al. Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma. Hum Mol Genet. 2012;21:5397–405.
    63. Wadt K, Choi J, Chung JY, et al. A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell Melanoma Res. 2012;25:815–818.
    64. Bengtsson D, Joost P, Aravidis C, et al. Corticotroph pituitary carcinoma in a patient with Lynch syndrome (LS) and pituitary tumors in a nationwide LS cohort. J Clin Endocrinol Metab. 2017;102:3928–3932.
    65. Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol. 2013;31:3012–3018.
    66. Ohara N, Kaneko M, Ikeda M, et al. Lung adenocarcinoma and adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1. Respir Med Case Rep. 2016;20:77–81.
      67. Grolmusz VK, Borka K, Kövesdi A, et al. MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism. Virchows Arch. 2017;471:401–411.
      68. Corbo V, Dalai I, Scardoni M, et al. MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadicneoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer. 2010;17:771–783.
      69. Trouillas J, Labat-Moleur F, Sturm N, et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol. 2008;32:534–543.
      70. Mete O, Cintosun A, Pressman I, et al. Epidemiology and biomarker profile of pituitary adenohypophysial tumors. Mod Pathol. 2018;31:900–909.
      71. Haller F, Moskalev EA, Faucz FR, et al. Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocr Relat Cancer. 2014;21:567–577.
      72. Richter S, Klink B, Nacke B, et al. Epigenetic mutation of the succinate dehydrogenase C promoter in a patient with two paragangliomas. J Clin Endocrinol Metab. 2016;101:359–363.
      73. Remacha L, Comino-Méndez I, Richter S, et al. Targeted exome sequencing of Krebs cycle genes reveals candidate cancer-predisposing mutations in pheochromocytomas and paragangliomas. Clin Cancer Res. 2017;23:6315–6324.
      74. Evenepoel L, Papathomas TG, Krol N, et al. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 2015;17:610–620.
      75. Djordjevic B, Westin S, Broaddus RR. Application of immunohistochemistry and molecular diagnostics to clinically relevant problems in endometrial cancer. Surg Pathol Clin. 2012;5:859–878.
      76. Witkowski L, Carrot-Zhang J, Albrecht S, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet. 2014;46:438–443.
      77. Goodfellow PJ, Billingsley CC, Lankes HA, et al. Combined microsatellite instability, MLH1 methylation analysis, and immunohistochemistry for Lynch syndrome screening in endometrial cancers from GOG210: an NRG Oncology and Gynecologic Oncology Group Study. J Clin Oncol. 2015;33:4301–4308.
      78. Shattuck TM, Välimäki S, Obara T, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med. 2003;349:1722–1729.
      79. Rossi S, Gasparotto D, Cacciatore M, et al. Neurofibromin C terminus-specific antibody (clone NFC) is a valuable tool for the identification ofNF1-inactivated GISTs. Mod Pathol. 2018;31:160–168.
      80. Kruijff S, Sidhu SB, Sywak MS, et al. Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas. Ann Surg Oncol. 2014;21:426–433.
      81. Blank A, Schmitt AM, Korpershoek E, et al. SDHB loss predicts malignancy in pheochromocytomas/sympathethic paragangliomas, but not through hypoxia signalling. Endocr Relat Cancer. 2010;17:919–928.
      82. Kimura N, Takayanagi R, Takizawa N, et al. Phaeochromocytoma Study Group in Japan. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer. 2014;21:405–414.
      83. Fishbein L, Wilkerson MD. Chromaffin cell biology: inferences from The Cancer Genome Atlas. Cell Tissue Res. 2018;372:339–346.
      84. Crona J, Taïeb D, Pacak K. New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification. Endocr Rev. 2017;38:489–515.
      85. Fishbein L, Leshchiner I, Walter V, et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;31:181–193.
      86. Buffet A, Morin A, Castro-Vega LJ, et al. Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier SLC25A11 gene confer a predisposition to metastatic paragangliomas. Cancer Res. 2018;78:1914–1922.
      87. Richter S, Gieldon L, Pang Y, et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2019;21:705–717.
      88. Papathomas TG, Oudijk L, Zwarthoff EC, et al. Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia. Endocr Relat Cancer. 2014;21:653–661.
      89. Dwight T, Flynn A, Amarasinghe K, et al. TERT structural rearrangements in metastatic pheochromocytomas. Endocr Relat Cancer. 2018;25:1–9.
      90. Svahn F, Juhlin CC, Paulsson JO, et al. Telomerase reverse transcriptase promoter hypermethylation is associated with metastatic disease in abdominal paraganglioma. Clin Endocrinol (Oxf). 2018;88:343–345.
      91. Job S, Draskovic I, Burnichon N, et al. Telomerase activation and ATRX mutations are independent risk factors for metastatic pheochromocytoma and paraganglioma. Clin Cancer Res. 2019;25:760–770.
      92. Vuong HG, Duong UN, Altibi AM, et al. A meta-analysis of prognostic roles of molecular markers in papillary thyroid carcinoma. Endocr Connect. 2017;6:R8–17.
      93. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–690.
      94. Wang N, Liu T, Sofiadis A, et al. TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA. Cancer. 2014;120:2965–2979.
      95. Nicolson NG, Murtha TD, Dong W, et al. Comprehensive genetic analysis of follicular thyroid carcinoma predicts prognosis independent of histology. J Clin Endocrinol Metab. 2018;103:2640–2650.
      96. Nikiforov YE. Role of molecular markers in thyroid nodule management: then and now. Endocr Pract. 2017;23:979–988.
      97. Hysek M, Paulsson JO, Wang N, et al. TERT promoter mutational screening as a tool to predict malignant behaviour in follicular thyroid tumors-three examples from the clinical routine. Virchows Arch. 2018;473:639–643.
      98. Assié G, Letouzé E, Fassnacht M, et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014;46:607–612.
      99. Zheng S, Cherniack AD, Dewal N, et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell. 2016;30:363.
      100. 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;100:841–849.
      101. Libé R, Borget I, Ronchi CL, et al. ENSAT network. Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann Oncol. 2015;26:2119–2125.
      102. Sbiera S, Sbiera I, Ruggiero C, et al. Assessment of VAV2 expression refines prognostic prediction in adrenocortical carcinoma. J Clin Endocrinol Metab. 2017;102:3491–3498.
      103. Jouinot A, Assie G, Libe R, et al. DNA methylation is an independent prognostic marker of survival in adrenocortical cancer. J Clin Endocrinol Metab. 2017;102:923–932.
      104. Lippert J, Appenzeller S, Liang R, et al. Targeted molecular analysis in adrenocortical carcinomas: a strategy toward improved personalized prognostication. J Clin Endocrinol Metab. 2018;103:4511–4523.
      105. De Sousa SMC, McCormack AIDe Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A. Aggressive pituitary tumors and pituitary carcinomas. Endotext. South Dartmouth, MA: MDText.com Inc. 2018 Nov 26.
      106. Bengtsson D, Schrøder HD, Berinder K, et al. Tumoral MGMT content predicts survival in patients with aggressive pituitary tumors and pituitary carcinomas given treatment with temozolomide. Endocrine. 2018;62:737–739.
      107. Yang X, Li J, Li X, et al. TERT promoter mutation predicts radioiodine-refractory character in distant metastatic differentiated thyroid cancer. J Nucl Med. 2017;58:258–265.
      108. Ronchi CL, Sbiera S, Volante M, et al. CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma. PLoS One. 2014;9:e105855.
      109. Volante M, Terzolo M, Fassnacht M, et al. Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. Clin Cancer Res. 2012;18:3452–3461.
      110. Sbiera S, Leich E, Liebisch G, et al. Mitotane inhibits sterol-O-acyl transferase 1 triggering lipid-mediated endoplasmic reticulum stress and apoptosis in adrenocortical carcinoma cells. Endocrinology. 2015;156:3895–3908.
      111. Kendler DB, Araújo ML Jr, Alencar R, et al. Somatostatin receptor subtype 1 might be a predictor of better response to therapy in medullary thyroid carcinoma. Endocrine. 2017;58:474–480.
      Keywords:

      endocrine pathology; tumor classification; functional markers; prognostic and predictive biomarkers

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