Pediatric Adrenocortical Neoplasms On the Road to Some Clarity
Louis P. Dehner, M.D.
In as many years of surgical pathology practice prob- ably reflect that many adrenal cortical tumors (ACTs) I have seen in children and most of these in consultation with the same question: benign or malignant? This issue contains a clinicopathologic study of 83 ACTs present- ing in the first two decades of life with manifestations of a hormonally functioning neoplasm in most cases.18 Al- though the subject of ACTs in children and adults has been thoroughly explored in any number of earlier stud- ies, the current report has the authority and possible pri- macy in terms of the number of cases with complete clinical follow-up. Only from the Armed Forces Institute of Pathology can we expect such a study, which again demonstrates the uniqueness of this invaluable national and international resource whose very existence is too often called into question at federal budget time. That issue aside, there are few other comparable experiences with ACTs in children and with the careful attention to pathologic details.3
The basic approach to the pathologic evaluation of these 83 cases is similar in many respects to previous investigations with regard to various gross and micro- scopic features that have been modified and adapted from those applied to ACTs presenting in adults.4 One of the facts of life about ACTs in children, which is re- flected in their clinicopathologic outcome groups, is that an adrenal cortical neoplasm may have pathologic fea- tures, more often of a microscopic nature, that by all other conventions qualify for an interpretation of malig- nancy, but whose prognosis is otherwise in terms of a durable disease-free interval after complete surgical re-
section. The critical focus of this study is the pathologic discrimination between their group B (clinically benign, histologically malignant) and group C (clinically and his- tologically malignant). On the basis of their pathologic criteria, without the incorporation of clinical outcome, almost 90% of ACTs were adrenocortical carcinomas (ACCs). The latter value compares with 80% ACCs in the Brazilian experience, and it appears generally that a majority of ACTs in children are interpreted pathologi- cally as malignant in various studies.3,13,16 However, the prognosis of ACC in children is clearly more favorable when compared with adults.10,1 10,15
It is at least reassuring from this study that a patho- logically benign ACT, although constituting only nine cases, behaved appropriately in a benign fashion. How- ever, there were more than twice as many ACTs in group B (51 cases) than in group C (23 cases): those neoplasms that not only had malignant pathologic features but be- haved accordingly. Younger children, typically <5 years of age, with pathologically malignant ACTs, had a sig- nificantly better prognosis than older children and ado- lescents whose tumors are more like ACCs in adults whose 5-year survival ranges from 10% to 35% and is only 50% for those with stage I disease.10,15 Tumors in excess of 10.5 cm, weighing >400 g, and invading into the periadrenal soft tissues and/or the inferior vena cava were significant univariate indicators of a poor progno- sis, but only the latter, vena caval invasion was an inde- pendent predictor of an unfavorable outcome when sub- jected to multivariate analysis. Some of the ACTs in infants we have seen over the years have had impres- sively bizarre pleomorphic nuclei. In the present study, nuclear pleomorphism had no predictive value, whereas increased mitotic activity or necrosis alone was prognos- tically unfavorable in multivariate analysis. It is fair to conclude from their findings that a child <5 years of age at diagnosis with a completely resectable ACT, which
From the Lauren V. Ackermann Laboratory of Surgical Pathology, Barnes-Jewish and St. Louis Children’s Hospitals, Washington Uni- versity Medical Center, St. Louis, Missouri, U.S.A.
Address correspondence and reprint requests to Louis P. Dehner, MD, Campus Box 8118, 660 S. Euclid Ave., St. Louis, MO 63110, U.S.A .; e-mail: dehner@path.wustl.edu
weighs <400 g, has <15 mitotic figures per 20 high power microscopic fields, and has minimal necrosis, should have an excellent clinical outcome. Very clearly, the smaller ACT, whether <200 or <400 g, in a child has the superior prognosis.9,17 Adrenocortical carcinoma in younger children whose lethal pathologic counterpart in adults is seemingly a fundamentally different disease in terms of its clinical presentation and behavior according to this study.18 As the age at diagnosis of an ACC ap- proaches adulthood, so the prognosis trends toward the poorer outcome associated with this neoplasm in older individuals.
The point is well taken by Weineke et al. to avoid the overdiagnosis or underdiagnosis of an ACT, and they leave us with Tables 8 and 9 with the nine pathologic features of malignancy and the correlation between the number of these features in a particular neoplasm and clinical outcome.18 Three or less unfavorable pathologic features would appear to be the breakpoint or threshold between the clinically benign and malignant ACT. The question remains whether an ACT with a few “malig- nant” pathologic features should be diagnosed at all as ACC or as something else. One approach to this dilemma is proposed by Bugg et al.2 who differentiated ACCs in children into a low-grade or high-grade category on the basis of the pathologic features. Another avenue that we have resorted to on occasion is the one acknowledging the uncertainty principle of “atypical adrenocortical neo- plasm” or “adrenocortical neoplasm of uncertain or in- determinate malignant potential” for the completely re- sected tumor. The recommendation of clinical follow-up with appropriate hormonal monitoring is made in these cases. If the ACT is an unequivocally ACC, then that is the diagnosis. A diagnosis of ACC in the borderline case will haunt that child in one way or another throughout life, especially in terms of insurability.
As a final note, Wieneke et al.18 indirectly and briefly touch upon some of the molecular and genetic aspects of ACTs in children. There are several syndromic associa- tions1 but apparently no known examples in their own patient population. Koch et al.8 have thoroughly re- viewed the molecular pathogenesis of ACTs. Some in- teresting observations have emerged from the studies of ACC in children from southern Brazil where the inci- dence of this disease is 10-15 times higher than else- where in the world.11,13 Not entirely a surprise, Ribeiro et al.12 have reported that 35 of 36 Brazilian children with ACCs had germline point mutations of p53 (17p13.1) encoding an Arg337His amino acid substitu- tion. Adrenocortical carcinoma is one of the constituent neoplasms in the Li-Fraumeni syndrome with its point mutations in chromosome locus 17p13.1,8 Yet these Bra- zilian children and their families do not have the other associated neoplasms of the classic Li-Fraumeni syn- drome. Using comparative genomic hybridization,
Figueiredo et al.º have demonstrated a number of chro- mosomal gains and losses in both benign and malignant ACTs in children from southern Brazil. The most con- sistent finding was the presence of copy number gains in chromosomal region 9q34.5 There were no consistent differences in chromosomal gains or losses between the adrenal adenomas and carcinomas in children. Both p57 and insulin-like growth factor 2 encoded on chromosom- al region 11p15.5 have engendered interest because the Beckwith-Wiedemann syndrome is associated with uni- parental paternal isodisomy for the insulin-like growth factor 2 locus.19 Despite the number of recent studies bearing on the molecular biology of ACTs in children and adults, there are still many unanswered questions about a neoplasm that has the potential for spontaneous regression of metastatic disease in an infant yet is a con- sistently lethal neoplasm in an adult.7,14
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