Friday 29 October 2004
Pheochromocytoma (PCC) in children is rare, genetically not well described, and often related to a poor prognosis.
PHEO is a relatively rare neoplasm whose annual inci-dence ranges from two to eight cases:1,000,000 population.
The term pheochromocytoma is derived from the brown color observed when the tumor is immersed in a dichromate solution.
Approximately 5% to 10% of incidentally-discovered adrenal masses, mainly in adults, are pheochromocytomas.
Although 10% to 15% of cases present in the ﬁrst two decades of life, some of the special clinical settings of PHEOs in children include the greater likelihood of a syndromic association, estimated at 15% to 25% of tumors:
bilaterality (commonly an association with one of the predisposing inherited disorders)
extraadrenal paraganglioma (25% to 40% of children).
These predisposing syndromes are:
von Hippel-Lindau syndrome
MEN 2a (50% of cases)
In patients with apparent sporadic PHEOs, 11% had germline mutations in VHL, RET SDHB and SDHD.
In a similar study of 271 patients with “sporadic” PHEOs, 24% had germline mutations in VHL, RET, SDHB, and SDHD.
Havekes et al. have recently reported that 40% of PHEOs (adrenal and extra adrenal) had a hereditary basis.
The WHO deﬁnes PHEO as a tumor of chromafﬁn cells of the adrenal medulla, and paraganglioma as a tumor arising from the extra-adrenal paraganglia; both tumors are neural crest in origin.
A number of studies, however, combine both adrenal medullary tumors and extra-adrenal tumors under the diagnosis “pheochromocytoma.”
When combined, 80% of these tumors arise in the adrenal medulla and the remainder in the extra-adrenal paraganglia (20%).
In a review of 520 PHEOs, 50 PHEOs (9.6%) occurred in children less than 16 years of age.
Among these 50 childhood cases, the male:female ratio was 2:1, bilaterality was present in 32% of cases and extra-adrenal location in 18% of cases.
A hereditary syndrome was identiﬁed in 7% of cases. Local recurrence or metastasis after initial excision occurred in 12% of children.
The major clinical signs and symptoms are related to the release of epinephrine with hypertension, paroxysms (headaches, palpitations and sweating) and either tachycardia (epinephrine) or reﬂex bradycardia (norepinephrine).
Cerebral infarction, cardiomyopathy, and catecholamine crisis have been observed in children.
A female predilection is seen in some studies and others report a male preference.
The average age at diagnosis in childhood is 12 to 15 years.
Sporadic PHEO is typically a solitary, well-circumscribed mass with either a true capsule or a pseudocapsule related to the tumor expansion and compression of adjacent connective tissue.
Most tumors range in size from 3 to 5 cm, and the average weight is about 100 g.
Periadrenal brown fat is often seen.
Because medullary tissue is concentrated in the head and body of the adrenal, the smaller PHEO arises in the latter locations.
On cut section, the tumor is ﬁrm and gray or dark red or is extensively hemorrhagic with cystic degeneration and friability.
The chromafﬁn reaction is a manifestation of the catecholamines in the tissue and is produced by exposure of the unﬁxed specimen to a dichromate solution, which leads to a deep brown coloration.
Three principal histological patterns are found in PHEO:
a trabecular pattern with anastomosing cords of cells,
an alveolar or nesting pattern with “zellballen” formation,
and a diffuse or solid growth pattern.
Spindle cells, angiomatoid foci, prominent interstitial and perivascular sclerosis, pseudopapillary formations and smallspaces ﬁlled with eosinophilic proteinaceous debris are focal or generalized features in any one tumor.
Nuclear pseudoinclusions and eosinophilic hyaline intracytoplasmic globules are common.
The individual tumor cells range from eosinophilic and granular to intense basophilia.
Immunohistochemistry has superseded many of the classic silver stains.
These tumors are typically immunoreactive for VIM, CHR, VIP, and, infrequently HMB-45.
Antibodies to S-100 protein stain the sustentacular cells.
Electron microscopy reveals cells with interdigitating borders and poorly formed cells junctions.
Membrane-bound dense-core neurosecretory granules are prominent; these granules appear to be norepinephrine with a prominent eccentric electron-lucent space surrounding the dense core.
The incidence of malignancy in childhood PHEOs is difﬁcult to ascertain due to the inclusion of paragangliomas in many studies; however, it is estimated that 2% to 12% of these tumors behave in a malignant fashion.
With inclusion of paragangliomas, the incidence is even higher, since paragangliomas especially in sites other than in the head and neck region are more prone to malignant behavior.
When paragangliomas are included in the assessment of prognosis, the incidence of malignancy approaches 50% in some series inclusive of pediatric series.
Except for the presence of metastasis, no single histological feature of the tumor itself including local invasion is predictive of malignant behavior.
Risk factors for malignancy include the diagnosis of paraganglioma and tumor size greater than 6 cm.
However, tumor size is not always predictive of malignancy.
The 5- and 10-year survival rates for malignant tumors is 78% and 31%, respectively.
In aggregate, extra-adrenal location, coarse nodularity, conﬂ uent necro-sis, and absence of hyaline globules are features associated with malignancy.
An increased MIB-1 index (nuclear immunopositivity) correlated with malignant behavior in some but not all studies.
+/- amyloid stroma
oncocytic pheochromocytoma (#11075859#)
composite adrenal pheochromocytoma/adrenal ganglioneuroma (MEN2A) (#8990146#, #3181953#, #10839612#)
pigmented paraganglioma (#8491482#)
gangliocytic paraganglioma (#15492999#)
von Hippel-Lindau disease (VHL)
losses of chromosomes
- 3p loss (72%)
- Chr.4 loss
- 11p loss (72%)
- 13q loss
- 15q loss
- 16p loss
- 17p loss
- Chr.18 loss
- partial gains of chromosome 7
Hering A, Guratowska M, Bucsky P, Claussen U, Decker J, Ernst G, Hoeppner W, Michel S, Neumann H, Parlowsky T, Loncarevic I. Characteristic genomic imbalances in pediatric pheochromocytoma. Genes Chromosomes Cancer. 2006 Jun;45(6):602-7. PMID: #16518846#
Maher ER, Eng C. The pressure rises: update on the genetics of phaeochromocytoma. Hum Mol Genet. 2002 Oct 1;11(20):2347-54. PMID: #12351569#
Clarke MR, Weyant RJ, Watson CG, Carty SE. Prognostic markers in pheochromocytoma. Hum Pathol. 1998 May;29(5):522-6. PMID: #9596278#