A 45-year-old woman presents to her internist with attacks of sweating, tachycardia, and headaches for the past few months. She is found to have high blood pressure and increased levels of vanillylmandelic acid (VMA) in her urine. On a computed tomography scan of her abdomen, a mass is seen in the left adrenal gland. Gross examination of the excised specimen reveals a well-circumscribed, lobulated, yellow-red, brown mass measuring 8.0 cm in greatest dimension with hemorrhagic and necrotic cut surface. The mass infiltrates into the surrounding adipose tissue. There is a rim of compressed adrenal gland surrounding the mass.
Master List of Diagnoses
- Adrenocortical carcinoma
- Renal cell carcinoma
Archive Case and Diagnosis
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 33, and is a pheochromocytoma of the adrenal gland.
Criteria for Diagnosis and Comments
Microscopic sections from the adrenal gland mass show nests of cells with abundant basophilic cytoplasm, marked nuclear pleomorphism, presence of macronucleoli, and increased mitoses including atypical mitoses. The overall histologic features are consistent with pheochromocytoma.
Pheochromocytomas are chromaffin-derived tumors that arise in the adrenal medulla. As the name implies, the tumor develops dusky color when the tumor is immersed in chromaffin salts or other weak oxidizing agents. Most tumors are sporadic, benign, and unilateral. The reported incidence is about 0.4–9.5 per million people. The tumors occur most frequently in the fourth and fifth decades. Familial tumors develop at a younger age and are usually bilateral.
Patients usually present with throbbing headaches, sweating, palpitations, and chest and abdominal pains which may last from 10–60 minutes and may be triggered by positional changes. Hypertension is common and paroxysmal in about 50% of cases. The pheochromocytoma is often called “the 10% tumor” because 10% are bilateral, (at least) 10% outside adrenal medulla, 10% metastasize, and 10% occur in children. Signs and symptoms are similar to those noted in patients with benign disease; however, catecholamine production and the degree of hypertension may be more marked with metastatic disease.
Metastatic disease is the most reliable criteria of malignancy. Imaging studies cannot distinguish benign from malignant pheochromocytomas unless there is metastatic disease. Malignant pheochromocytomas tend to be larger in size, have a more nodular configuration, and show areas of necrosis. Histologic features suggesting malignancy include capsular invasion, vascular invasion, extension into periadrenal adipose tissue, diffuse growth, necrosis, spindling of tumor cells, increased cellularity, marked nuclear pleomorphism, macronucleoli, increased mitoses including atypical mitoses, and absence or decreased hyaline globules. Sustentacular cells are reported to be decreased or absent in malignant pheochromocytomas. MIB-1 labeling index may be helpful in separating benign and malignant pheochromocytomas. However, in some larger studies using 2.5% or 3.0% of cutoff proliferative index had a sensitivity of only 50% in identifying proven malignant tumors.
Two pathologic grading systems exist and attempt to stratify risk of malignant behavior. The Pheochromocytomas of the Adrenal Gland Scaled Score (PASS) system was developed by Thompson to distinguish benign from malignant pheochromocytomas. It uses features such as growth pattern, necrosis, cellularity, cellular monotony, tumor cell spindling, mitotic count, atypical mitosis, invasion, nuclear pleomorphism, and hyperchromasia. A PASS of ≥ 4 is associated with a higher probability for malignancy. The use of the PASS was not validated independently by other endocrine pathologists. The grading system for adrenal pheochromocytoma and paraganglioma (GAPP) scheme developed by Kimura et al. for both pheochromocytoma and paraganglioma includes parameters inherent to the normal growth of the medulla and include Ki-67 proliferative index, size of tumor nests, type of catecholamine production, and tumor phenotype. With a score of 7–10, 100% of patients were found to have clinically malignant tumors.
Pheochromocytomas associated with a variety of inherited conditions including multiple endocrine neoplasia type 2, Von Hippel–Lindau (VHL) disease, neufibromatosis type 1, hereditary paraganglioma syndromes and Sturge–Weber disease. The usual prognosis of malignant pheochromocytomas is approximately a 50% five-year survival rate. Some patients may have indolent disease with a life expectancy of more than 20 years. A series of molecular markers have been reported as markers of malignancy in pheochromocytomas including heat shock protein 9, human telomerase reverse transcriptase, vascular endothelial growth factor, vascular endothelial growth factor receptor hypoxia inducible factor 2-α, cyclooxygenase 2, tenascin C, N cadherin- and secretogranin II-derived peptide EM66. The practical application of these markers requires further studies.
Paragangliomas are tumors arising from the paraganglia that are distributed along the parasympathetic nerves in the head, neck, and mediastinum, and along the para-aortic sympathetic chain within cervical, intrathoracic, and intra-abdominal sites (including remnants of the Organ of Zuckerkandl), and within the urinary bladder. The morphologic differences between pheochromocytomas and paragangliomas are subtle, but molecular differences between tumors arising in the adrenal medulla and extra-adrenal sites are more evident. The frequency of succinate dehydrogenase (SDH) mutations in pheochromocytomas is about 3%–5%. These mutations are much more common in paragangliomas. Loss of SDH-B immunoexpression in paragangliomas predicts potential malignant behavior and can initiate further evaluation of a hereditary condition such as Carney-Stratakis syndrome.
Histopathologic features of pheochromocytomas and paragangliomas are similar and include chief cells with basophilic to amphophilic cells with abundant cytoplasm and large vesicular nuclei. Solid, rounded aggregates of cells (so called “zellballen” pattern) and presence of multifaceted cell nests surrounded by fibrovascular septa is the most common architectural growth pattern associated with these tumors. Cytoplasmic hyaline globules, melanin-like pigment, and presence of ganglion cells are frequently present. Mitotic figures are not commonly seen. Immunohistochemical studies show that the chief cells of the tumors are positive for chromogranin and synaptophysin, while the sustentacular cells which surround nests of chief cells are positive for S100 protein. Ultrastructural examination of these tumors shows presence of dense core secretory granules. Malignant pheochromocytomas comprise approximately 10% of all pheochromocytomas.
Adrenal cortical carcinomas are usually large tumors with areas of necrosis with tumor cells exhibiting large nuclei and prominent nucleoli. Adrenal cortical carcinomas are positive for Melan A, inhibin, and calretinin, and weakly positive for keratin; but negative for synaptophysin and chromogranin, whereas pheochromocytomas and paragangliomas are positive for synaptophysin and chromogranin and negative for Melan A and keratins.
Renal cell carcinomas (RCC) and melanomas can metastasize to adrenal gland. The former scenario needs consideration in patients with VHL. High grade RCC and melanoma can show tumor cells with nuclear pleomorphism and atypical mitoses. The negativity for epithelial membrane antigen (EMA), Melan A, HMB-45, as well neuroendocrine markers helps distinguish pheochromocytomas from RCC and melanoma.
- Tumor cells of pheochromocytoma will show positive immunostaining for which of the following markers?
- Which of the following statements is true regarding pheochromocytoma?
- Histopathological features of pheochromocytomas and paragangliomas are similar.
- Majority of the pheochromocytomas show metastasis at presentation.
- Pheochromocytomas are never associated with inheritable conditions.
- Prognosis depends on the size of the tumor.
- The frequency of succinate dehydrogenase B and succinate dehydrogenase D mutations in pheochromocytomas is about 50%.
- Pheochromocytomas are associated with which of the following syndromes?
- Beckwith-Wiedemann syndrome
- Multiple endocrine neoplasia type 1
- Multiple endocrine neoplasia type 2
- Multiple endocrine neoplasia type 3
- Peutz-Jeghers syndrome
- 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(3):405-414.
- Kimura N, Watanabe T, Noshiro T, Shizawa S, Miura Y. Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol. 2005;16:23–32.
- Lloyd RV. Adrenal cortical tumors, pheochromocytomas and paragangliomas. Mod Pathol. 2011; 24 Suppl 2:S58-S65.
- 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; 26:551–566.
Kirtee Raparia, MD
Surgical Pathology Committee
- Synaptophysin (e)
- Histopathological features of pheochromocytomas and paragangliomas are similar. (a)
- Multiple endocrine neoplasia type 2 (c)