Residency · Residency · Pathology
Adrenal and Neuroendocrine Tumor Pathology
Introduction
Adrenal and neuroendocrine tumors encompass a diverse group of neoplasms arising from endocrine and neuroendocrine cells throughout the body. The pathologist must distinguish benign from malignant adrenal cortical tumors, accurately grade neuroendocrine neoplasms, and apply site-specific classification systems that directly impact prognosis and treatment.
Adrenal Cortical Tumors
Adrenal Cortical Adenoma vs. Carcinoma
Adrenal cortical adenoma is a common incidental finding (adrenal incidentaloma in approximately 5% of CT scans), usually measuring less than 5 cm and well circumscribed. Adrenal cortical carcinoma (ACC) is rare (approximately 1-2 per million), typically larger than 6 cm at diagnosis, with a bimodal age distribution affecting children and adults in their 40s to 50s. The distinction between adenoma and carcinoma is based on histologic scoring systems.
Weiss Criteria for Malignancy
The Weiss system uses nine histologic criteria, each scored as 0 or 1: (1) high nuclear grade (Fuhrman grade III or IV), (2) mitotic rate greater than 5 per 50 HPF, (3) atypical mitotic figures, (4) clear cells comprising 25% or less of the tumor, (5) diffuse architecture (more than 33% of tumor), (6) necrosis, (7) venous invasion, (8) sinusoidal invasion, and (9) capsular invasion. A score of 3 or more is suspicious for or diagnostic of ACC, while a score below 3 favors adenoma. The modified Weiss (Helsinki) score and the reticulin algorithm are also used.
Molecular Features of ACC
TP53 mutations are found in approximately 25% of sporadic ACC and are associated with Li-Fraumeni syndrome. IGF2 overexpression is present in approximately 90% of ACC due to 11p15 imprinting alterations. CTNNB1 (beta-catenin) mutations are present in approximately 15-40% of cases. ZNRF3 inactivation and telomerase activation are additional molecular features. The Ki-67 index above 10% is associated with aggressive behavior and is prognostic, guiding adjuvant therapy decisions.
Pediatric Adrenal Cortical Tumors
Pediatric adrenal cortical tumors have a higher incidence in southern Brazil due to the TP53 R337H founder mutation. The Weiss criteria are less reliable in children, and the Wieneke criteria are used for pediatric tumors. Many pediatric tumors classified as malignant by adult criteria behave in a benign fashion after complete resection.
Pheochromocytoma and Paraganglioma
Classification
Pheochromocytoma arises from adrenal medullary chromaffin cells. Paraganglioma arises from extra-adrenal paraganglia, with sympathetic tumors occurring in the retroperitoneum and pelvis and parasympathetic tumors in the head and neck (carotid body, jugulotympanic). Both produce catecholamines, with norepinephrine predominating over epinephrine in extra-adrenal tumors. Under the WHO 2022 classification, all pheochromocytomas and paragangliomas have metastatic potential and are classified as malignant.
Histopathology
The characteristic Zellballen pattern consists of nests (cell balls) of tumor cells surrounded by sustentacular cells (S100-positive by IHC). Immunohistochemistry shows chromogranin A+, synaptophysin+, and GATA3+, with sustentacular cells being S100+. The PASS (Pheochromocytoma of the Adrenal gland Scaled Score) evaluates 12 histologic features, with a PASS of 4 or more associated with potentially aggressive behavior. The GAPP (Grading system for Adrenal Pheochromocytoma and Paraganglioma) integrates histology, biochemical profile, and Ki-67.
Hereditary Syndromes
Approximately 40% of pheochromocytomas and paragangliomas are hereditary. SDHx mutations (SDHA, SDHB, SDHC, SDHD) affect succinate dehydrogenase subunits, with SDHB associated with the highest metastatic risk. On IHC, loss of SDHB staining suggests an SDHx mutation in any subunit, while loss of SDHA is specific for SDHA mutation. VHL (von Hippel-Lindau) is associated with pheochromocytoma, renal cell carcinoma, and CNS hemangioblastoma. RET (MEN2A/2B) is associated with medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. NF1 (neurofibromatosis type 1) is associated with pheochromocytoma, neurofibromas, and optic glioma.
| Hereditary Syndrome | Gene | Associated Tumors | Metastatic Risk | |
|---|---|---|---|---|
| SDHx (esp. SDHB) | SDHA/B/C/D | Paraganglioma, pheo, RCC | High (SDHB) | |
| VHL | VHL | Pheo, clear cell RCC, hemangioblastoma | Low–moderate | |
| MEN2A/2B | RET | MTC, pheo, parathyroid hyperplasia | Low | |
| NF1 | NF1 | Pheo, neurofibromas, optic glioma | Low | Genetic testing is recommended for all patients with pheochromocytoma or paraganglioma. |
Neuroendocrine Tumors (NETs): General Principles
WHO Classification Framework
Neuroendocrine neoplasms (NENs) are classified into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). NETs and NECs are fundamentally different biologic entities, not a continuum. NETs are low to intermediate grade, retain differentiation markers, and have slower growth. NECs are high grade, often harbor TP53/RB1 mutations, are aggressive, and are treated with platinum-based chemotherapy.
Grading (WHO)
Grade 1 (G1) tumors have a mitotic rate below 2 per 10 HPF and a Ki-67 index below 3%. Grade 2 (G2) tumors have a mitotic rate of 2-20 per 10 HPF and/or a Ki-67 index of 3-20%. Grade 3 (G3) tumors have a mitotic rate above 20 per 10 HPF and/or a Ki-67 index above 20%. G3 NETs (well-differentiated but high-grade) must be distinguished from NECs (poorly differentiated), as they follow different treatment paradigms. When the mitotic rate and Ki-67 are discordant, the higher grade is assigned.
| WHO Grade | Mitotic Rate (per 10 HPF) | Ki-67 Index | Differentiation |
|---|---|---|---|
| G1 (NET) | <2 | <3% | Well-differentiated |
| G2 (NET) | 2–20 | 3–20% | Well-differentiated |
| G3 (NET) | >20 | >20% | Well-differentiated |
| NEC (small cell) | >20 | >20% | Poorly differentiated (TP53/RB1 loss) |
| NEC (large cell) | >20 | >20% | Poorly differentiated (TP53/RB1 loss) |
Immunohistochemistry
Synaptophysin is the most sensitive general neuroendocrine marker. Chromogranin A is more specific but less sensitive and correlates with secretory granule density. INSM1 is a nuclear transcription factor that is sensitive and specific for neuroendocrine differentiation. Ki-67 (MIB-1) is counted in the hotspot area and is crucial for grading. To distinguish NET from NEC, p53 shows wild-type staining in NET but aberrant overexpression or complete loss in NEC, and Rb is retained in NET but lost in NEC.
Site-Specific Neuroendocrine Tumors
Gastroenteropancreatic NETs (GEP-NETs)
Pancreatic NETs may be functioning (insulinoma, gastrinoma, VIPoma, glucagonoma) or non-functioning, and are MEN1-associated in approximately 10% of cases. Small intestinal NETs are the most common NET site, produce serotonin, and cause carcinoid syndrome when hepatic metastases are present. Gastric NETs include Type 1 (autoimmune gastritis with ECL cell hyperplasia, benign), Type 2 (MEN1/ZES), and Type 3 (sporadic, aggressive). Appendiceal NETs are the most common appendiceal tumor, usually incidental, and those smaller than 2 cm with clear margins can be managed with appendectomy alone. Rectal NETs are usually small and incidentally found at colonoscopy, generally indolent if less than 1 cm without adverse features.
Pulmonary Neuroendocrine Neoplasms
Typical carcinoid has fewer than 2 mitoses per 10 HPF and no necrosis, is low-grade, and has excellent prognosis (approximately 95% 5-year survival). Atypical carcinoid shows 2-10 mitoses per 10 HPF and/or necrosis, is intermediate-grade, with approximately 60-70% 5-year survival. Large cell neuroendocrine carcinoma (LCNEC) is a high-grade NEC with more than 10 mitoses per 10 HPF, large cell morphology with neuroendocrine markers, and is treated like NSCLC. Small cell lung carcinoma (SCLC) is a high-grade NEC with small cells, scant cytoplasm, nuclear molding, and crush artifact, harbors TP53/RB1 mutations, and is extremely aggressive.
Merkel Cell Carcinoma
Merkel cell carcinoma is an aggressive cutaneous neuroendocrine carcinoma occurring in older adults on sun-exposed areas. Merkel cell polyomavirus (MCPyV) is associated with approximately 80% of cases. On IHC, the tumor is CK20+ (paranuclear dot pattern), synaptophysin+, chromogranin+, and TTF-1 negative, which distinguishes it from metastatic SCLC. Staging and sentinel lymph node biopsy are important, and immunotherapy (pembrolizumab, avelumab) is effective.
Clinical Pearls
The Weiss criteria remain the standard for distinguishing adrenal cortical adenoma from carcinoma; a score of 3 or more criteria favors malignancy, with mitotic rate and atypical mitoses being particularly important features. All pheochromocytomas and paragangliomas carry metastatic potential, and approximately 40% are hereditary; SDHB immunohistochemistry is a cost-effective screen for SDHx mutations. Well-differentiated G3 neuroendocrine tumors must be distinguished from poorly differentiated neuroendocrine carcinomas using p53 and Rb immunohistochemistry, as the treatment approaches are fundamentally different. Ki-67 index must be counted in the proliferative hotspot using standardized methodology, as accurate grading directly determines prognosis and treatment for neuroendocrine tumors.
References
- Lam AK. Update on adrenal tumours in 2017 World Health Organization (WHO) of endocrine tumours. Endocr Pathol. 2017;28(3):213-227.
- Lenders JWM, et al. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942.
- WHO Classification of Tumours Editorial Board. WHO Classification of Tumours: Endocrine and Neuroendocrine Tumours. 5th ed. IARC; 2022.
- Rindi G, et al. A common classification framework for neuroendocrine neoplasms: an IARC-WHO expert consensus proposal. Mod Pathol. 2018;31(12):1770-1786.