A 36-year-old woman presents to her primary care physician with vague abdominal pain. After a thorough physical exam and workup, she is found to have a blood pressure of 189/122 mm Hg and a large mass in her left hepatic lobe. Of note, four years ago she underwent a left adrenalectomy. She undergoes a partial left hepatectomy.

Master List of Diagnoses

  • Cholangiocarcinoma
  • Fibrolamellar hepatocellular carcinoma
  • Metastatic adrenal cortical carcinoma
  • Metastatic melanoma
  • Metastatic pheochromocytoma
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 17, and is metastatic pheochromocytoma of the liver.

Criteria for Diagnosis and Comments

Histologically the liver is non-cirrhotic with an irregular mass composed of pleomorphic cells that are nested in nature. The cells have various shapes with some being polygonal, round, or epithelioid. The tumor cells have large vesicular nuclei, and many are multilobated. Some nuclei are quite pleomorphic and hyperchromatic. Only a few mitoses are present. The tumor cell cytoplasm is abundantly granular and varies in color from basophilic to amphophilic. Scattered cytoplasmic hyaline globules are present. In many of the slides the tumor cells can be seen percolating in sinusoids and within vessels. The histomorphology in conjunction with the clinical history are diagnostic of metastatic pheochromocytomas.

Pheochromocytomas arise from chromaffin cells of the adrenal medulla. Most pheochromocytomas are sporadic and benign (approximately 90%). They typically occur in the 4th to 5th decades of life, affecting men and woman equally. Pheochromocytomas are rare tumors with only around 0.4 - 9.5 cases per million per year. However, this may be an underestimation as many autopsy series reveal a higher prevalence.

Malignancy is reported in up to 13% of pheochromocytomas with a 5-year mortality rate of less than 50%. Unilateral tumors are more likely to be sporadic while bilateral tumors tend to be familial. Approximately 50% of patients with pheochromocytomas have clinical symptoms which include sweating, intense headaches, palpitations, abdominal, and chest pains. Many also have hypertension which can present either as primary hypertension or paroxysmal hypertension. Symptomatology is not a good discriminator between malignant and benign pheochromocytomas; hypertension may be more elevated in metastatic disease.

Histologically, pheochromocytomas are composed of cells that are basophilic to amphophilic. They tend to have abundant cytoplasm with large vesicular nuclei and are nested. Cytoplasmic globules are often present. Mitoses should be rare. By immunohistochemistry these tumors are positive for neuroendocrine markers such as synaptophysin and chromogranin with the intervening sustentacular cells being S100 protein positive.

Predicting metastasis is the critical question in pheochromocytomas. Histology can suggest potential malignant behavior. These findings include capsular invasion, vascular invasion, necrosis, extension into periadrenal adipose tissue, macronucleoli, increased and atypical mitoses, decreased hyaline globules, increased cellularity, and marked pleomorphism. There have been scoring systems proposed based on some of these histopathologic findings. One is the pheochromocytoma of the adrenal gland scaled score (PASS) system. It tallies histologic features and if the score is greater than or equal to 4 there is a high probability of malignancy. However, these findings have not been validated by others. Another study out of Japan proposed a grading system for adrenal pheochromocytoma and paraganglioma (GAPP). The tumor score is based on histologic pattern, cellularity, comedonecrosis, capsular/vascular invasion, Ki-67 labeling index, and catecholamine type. Ki-67 has also been shown independently to be of use in pheochromocytomas for delineating benign from malignant in some studies; however, the sensitivities of these studies have not been great. Despite all these efforts, unfortunately, metastasis remains the most reliable marker of malignancy.

Pheochromocytomas can cause significant morbidity and mortality related to their secretion of catecholamines with the cardiovascular system being the most commonly involved. Currently there is no effective curative treatment; but surgery, chemotherapy, and radiotherapy have all demonstrated benefits in some individuals. Metastasis has been reported to occur up to 20 years after the primary resection. Worse outcomes are associated with older age and synchronous metastasis.

Pheochromocytomas and paragangliomas both originate from the neural crest. Both secrete catecholamines and peptides in response to neural stimulation. Therefore, they are quite similar in nature (morphology, immunohistochemistry, and ultrastructure) but there are some molecular differences. RET mutations are much more common in pheochromocytomas while paragangliomas more commonly have SDHx abnormalities. There appears to be two distinct pathways in the tumor genesis of pheochromocytomas. One involves the kinase receptor singling cluster (TMEM127, MAX, RET, NF1, and KIF1B) while the other involves pseudo-hypoxic gene cluster associated with genes VHL, SDHx, and PHD2.

Some of the genetic syndromes/diseases that have been associated with pheochromocytomas include multiple endocrine neoplasia 2 (MEN2), von Hippel-Lindau (10% - 30%), neurofibromatosis type 1 (1% - 4%), hereditary pheochromocytoma/paraganglioma syndrome, and Sturge-Weber disease. MEN2 is characterized by pheochromocytomas in addition to multicentric adrenal medullary hyperplasia, hyperparathyroidism, and medullary thyroid carcinoma. This syndrome is due to mutations in the RET gene. About 50% of MEN2 patients develop pheochromocytomas. Pheochromocytomas in hereditary pheochromocytoma/paraganglioma syndrome have specific gene mutations in succinate dehydrogenase. These specific mutations characterize distinct types of this syndrome. Individuals with these mutations all can develop pheochromocytomas and/or paragangliomas but will present different clinically and pathologically.

SDHB/SDHA protein immunohistochemistry on pheochromocytomas or paragangliomas can be a way of preliminary screening for pheochromocytoma/paraganglioma syndrome. Testing can help determine what mutation is present and potential aggressiveness. Good inter-observer correlation has been demonstrated with absent SDHB staining being seen in SDHB/C/D/AF2 germline mutations. If SDHB immunohistochemistry is negative, there is also a higher tendency for the tumor to behave in a malignant fashion.

Metastatic pheochromocytoma can be a very challenging diagnosis if one does not have the clinical history or if the primary diagnosis has not been made.

Due to the marked pleomorphism one can always think of metastatic melanoma especially because some pheochromocytomas have a melanin-like pigment. However, the tumor cells of pheochromocytomas are negative for melanoma markers.

Adrenal cortical carcinoma also is in the differential diagnosis in light of the patient’s history. Adrenal cortical tumors are positive for EMA, alpha inhibin, and keratins (weakly), while pheochromocytomas are positive for chromogranin and negative for keratins.

Fibrolamellar hepatocellular carcinoma may be a consideration as well, due to the tumor’s pleomorphism and the presence of a noncirrhotic liver. Those tumors however are positive by immunohistochemistry for hepatocellular markers (most commonly HepPar1) and have a translocation DNAJB1-PRKACA which is specific for the tumor.

A poorly-differentiated cholangiocarcinoma is also in the differential based on site. Cholangiocarcinomas do not typically have the pleomorphism of the current tumor and express keratin, which pheochromocytomas do not.

  1. Which of the following features is the only definitive diagnostic finding of malignancy in the pheochromocytoma?
    1. Capsular invasion
    2. Increased mitotic activity
    3. Marked pleomorphism
    4. Metastasis
    5. Vascular invasion
  2. Which of the following mutations has been found in pheochromocytomas?
    1. BRAF
    2. c-MYC
    3. DNAJB1-PRKACA
    4. MET
    5. RET
  3. Immunohistochemistry testing for which of the following proteins can be used to screen pheochromocytomas for genetic syndromes and aggressiveness?
    1. BRAF
    2. EGFR
    3. EMA
    4. PHD2
    5. SDHB

References

  1. Guo Z, Lloyd RV. Pheochromocytomas and paragangliomas: an update on recent molecular genetic advances and criteria for malignancy. Adv Anat Pathol. 2015;22(5):283-293.
  2. Graham R, Long J, Knutson D, et al. DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 2015;28:822–829.
  3. Kimura N, Takayanagi N, Takizawa N, et al. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer. 2014;21:405-414.
  4. Lack E. Tumors of the Adrenal Gland and Extra-Adrenal Paraganglia. AFIP Fascicle. No. 19. Third Series. Washington DC: American Registry of Pathology; 1997.
  5. Lloyd, R. Adrenal cortical tumors, pheochromocytomas and paragangliomas. Mod Pathol. 2011;24:S58–S65.
  6. Papathomas TG, Oudijk L, Persu A, Gill AJ, et al. SDHB/SDHA immunohistochemistry in pheochromocytomas and paraganglioma: a multicenter interobserver variation analysis using virtual microscopy: a multinational study of the European network for the study of adrenal tumors. Mod Pathol. 2015;28(6):807-821.
  7. Sadlow PM, Hartford NM, Nosé V. Familial Endocrine Syndromes. Surg Pathol Clin. 2014;7(4):577-598.
  8. van Nederveen FH, Gaal J, Favier J, et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009;10:764-771.

Author

William V. Chopp, MD FCAP
Surgical Pathology Committee
Michigan Pathology Specialists
Grand Rapids, MI


Answer Key

  1. Metastasis (d)
  2. RET (e)
  3. SDHB (e)