Spontaneously Regressing Adrenocortical Carcinoma in a Newborn
A Case Report With DNA Ploidy Analysis
SONIA SARACCO, MD, CARLOS ABRAMOWSKY, MD, SUZANNE TAYLOR, MD, PHD, ROBERT A. SILVERMAN, MD, AND BRIAN W. BERMAN, MD
Adrenal cortical carcinoma is an uncommon neoplasm in children. Only a handful of congenital adrenal cortical carcinoma cases have been described. A newborn who had metastatic adrenal cortical carcinoma (skin metastases and cerebral lesions) is described. This patient underwent surgical resection of the right adrenal primary, but no further treatment was given. Hemihypertrophy developed in this patient by 2 months of age, and at 4 months of age spontaneous regression of all skin nodules and central nervous system (CNS) lesions was observed. Follow-up at 1 year shows the patient to be alive, well, and disease-free. Evaluation of the tumor included DNA ploidy analysis that showed the tumor to be polyploid, a pattern recently associated with nonmetastasizing adrenal cortical neoplasm. The observa- tion of apparent metastatic disease that regressed spontaneously highlights the prognostic value of DNA ploidy analysis and raises the possibility of an adrenal tumor with properties similar to those of Stage IV-S neuroblastoma.
Cancer 62:507-511, 1988.
Case Report
A 1-day-old male newborn experiencing episodes of brady- cardia was transferred to Rainbow Babies and Children’s Hos- pital. At 42 weeks gestation, he was delivered by cesarean sec- tion for transverse lie and failure to progress. At birth, he weighed 3750 g with normal Apgar scores. During periods of bradycardia, his heart rate decreased to 60 to 80 beats per minute without cyanosis or color change.
Physical examination showed approximately 20 cherry red, slightly violaceous 3-mm to 10-mm papular and nodular le- sions distributed predominantly over the upper back, neck, and scalp (Fig. 1). These lesions blanched minimally, and were believed to be hemangiomas. The chest was unremarkable and no visceromegaly or abdominal masses were noticed. There were no physical signs of hypercortisolism, virilization, or fem- inization. Cardiac evaluation showed no structural abnormali- ties or rhythm disturbances and the patient eventually ceased
From the Institute of Pathology, Departments of Dermatology and Pediatrics, University Hospitals of Cleveland, Cleveland, and the Case Western Reserve University, Cleveland, Ohio; and the Department of Pathology, Children’s Hospital and the University of Pittsburgh, Pitts- burgh, Pennsylvania.
The authors thank J. Bruce Beckwith, MD, from the Children’s Hospital in Denver, Colorado for reviewing the renal specimen.
Address for reprints: Carlos Abramowsky, MD, Institute of Pathol- ogy, Case Western Reserve University, 2085 Adelbert Road, Cleve- land, OH.
Accepted for publication January 14, 1988.
to have episodes of bradycardia. Given the possibility of dis- seminated neonatal hemangiomatosis syndrome, abdominal ultrasound and computed tomography scans were obtained showing a mass in the right adrenal region. Computed tomog-
raphy of the head showed enhancing areas in the right frontal and left parietal lobes suggestive of metastatic tumor. Biopsy of a skin lesion showed a tumor consistent with an adrenocortical neoplasm (Fig. 2). The differential diagnosis in this age group includes neuroblastoma, congenital leukemia, and histiocy- tosis X. All of these were easily ruled out on the basis of tumor cytomorphology and by pertinent negative immunohisto- chemical staining. Routine laboratory tests, including electro- lytes, hemogram, renal, and liver function tests, were unre- markable. Urine catecholamines were slightly elevated and in- terpreted as being secondary to stress. Urine ketosteroid fractionation showed mild elevations in dehydroepiandroste-
| Patient results | Reference values for patient age | |
|---|---|---|
| U pregnanediol | 0.8 mg/12 h | ≤0.1 mg/24 h |
| U androsterone | 0.1 mg/12 h | <0.1 mg/24 h |
| U etiocholanolone | 0.1 mg/12 h | <0.1 mg/24 h |
| U dehydroepiandrosterone | 0.2 mg/12 h | <0.1 mg/24 h |
| U delta 5-pregnanetriol | 0.1 mg/12 h | <0.1 mg/24 h |
| U 11-ketoetiocholanolone | 0.2 mg/12 h | <0.1 mg/24 h |
| U 11-hydroxyandrosterone | 0.7 mg/12 h | <0.3 mg/24 h |
| U 11-hydroxyetiocholanolone | 0.6 mg/12 h | <0.1 mg/24 h |
| U 11-ketopregnanetriol | 0.2 mg/12 h | <0.2 mg/24 h |
| U free cortisol | 41 ug/24 h | 2-30 µg/24 h |
| U norepinephrine and epinephrine | 0.08 µg/mg Cr | <0.05 µg/mg Cr |
| U VMA | 18.78 µg/mg Cr | 12.06 µg/mg Cr |
| U normetanephrine | 0.93 µg/mg Cr | 0.36 ug/mg Cr |
| U dopamine | 0.73 µg/mg Cr | 0.54 µg/mg Cr |
| U DOPA | 0.12 µg/mg Cr | 0.07 ug/mg Cr |
| U HVA | 9.57 µg/mg Cr | 8.0 µg/mg Cr |
| S 17-hydroxyprogesterone | 976 ng/dl | ≤70 ng/dl |
| S DHEA sulfate | 746 ug/dl | 10-90 µg/dl |
U: urine; S: serum; VMA: vanillylmandelic acid; DOPA: dihydroxy- phenylalanine; HVA: homovanillic acid; DHEA: dehydroepiandroste- rone; Cr: creatinine.
rone (DHEA), pregnanediol, 11-ketoetiocholanolone, 11-hy- droxyandrosterone, and 11-hydroxyetiocholanolone, which were difficult to interpret. Serum levels of DHEA sulfate and 17-hydroxyprogesterone were significantly elevated (Table 1).
On the 22nd day of life, the patient underwent surgery for excision of the abdominal mass and a wedge liver biopsy. Pathologic examination of the mass showed a 35-g, well-en- capsulated, tan-colored adrenal neoplasm. Microscopically, the tumor was similar to the one seen in the skin and included tumor cells arranged in typical endocrine fashion as nests sepa- rated by prominent vascular spaces. Fifty percent of its cell population consisted of large hyperchromatic pleomorphic cells with prominent nucleoli and abundant eosinophilic granular cytoplasm (Fig. 3). Mitoses were seen in approxi- mately 1 per 10 high-power fields, but there was no capsular or vascular invasion. The results of the liver biopsy were normal.
In view of the patient’s age, antitumor therapy was not started and the patient was observed closely. Right hemihy- pertrophy was noticed at 2 months of age. Initial regression of cutaneous nodules was observed in the second month. By 4 months of age, all skin lesions had resolved spontaneously. Magnetic resonance imaging of the head showed no residual brain lesions. One year after diagnosis, the patient shows no evidence of tumor and he is developing appropriately.
Results
DNA Quantitation by Image Analysis
DNA quantitation was performed using slides, re- agents, instrumentation, and software (Cell Analysis Systems [CAS], Lombard, IL). Nuclei were isolated from an aliquot of the primary tumor frozen at -70℃ using the procedure of Vindelov et al.1 Direct smears were prepared on CAS slides containing control cells and were air-dried and fixed in 10% buffered formalin for 10 minutes. The fixed preparations were hydrolyzed
in 5 (normal) hydrochloric acid (5N HCI) before stain- ing with azure A. Analysis was performed on the CAS 100 system with the Quantitative DNA Analysis soft- ware program. The instrument was calibrated indepen- dently for each slide using the predeposited control cells. On each of two slides 300 cells were evaluated.
The histograms from the two slides were virtually identical. Four distinct populations of nuclei with dif- fering DNA contents were detected, with the modes of the first three peaks occuring at 2N, 4N, and 8N (Fig. 4). The fourth population, although slightly asymmetric, had an apparent mode at 16N. Of the 300 cells analyzed, 14 cells had DNA contents greater than 64 pg and were off-scale. Whether or not these cells represent the tailing fraction of the population at 16N or higher multiples cannot be determined. It is clear, however, that there were essentially no cells with DNA contents outside of the modes and the tumor must be interpreted as poly- ploid rather than heteroploid-aneuploid.
Discussion
Adrenocortical carcinoma is an uncommon malig- nancy representing approximately 0.2% of all cancers.2,3 Although the peak incidence in many series is in the fifth decade,2,3 adrenocortical carcinoma also is seen in children and represents 6% of all pediatric adrenal tumors.4 It is uncommon for adrenocortical carcinoma to present in the newborn or early infancy period. Table 2 is a partial list of some recent cases.5-8
Presenting symptoms of adrenocortical carcinoma can include virilization, feminization, hypercortisolism, and occasionally hyperaldosteronism. Approximately 58% of patients have functioning tumors,2 with in-
creased levels of dehydroepiandrosterone, dehydroepi- androsterone sulfate, testosterone, cortisol, urine 17-ke- tosteroids, and urine 17-hydroxycorticosteroids. Carci- nomas are usually nonresponsive to exogenous corticotropin (ACTH) administration.9 According to Henly,2 functional tumors have a female-male ratio of 3 to 1, whereas nonfunctional tumors have a male pre- dominance of 2 to 1. Nonfunctional tumors have been associated with increased levels of pregnenolone.2,10 Hemihypertrophy11 developed in our patient but he did
DNA Index
1
2
.
150
120
Il Count
90
3
60
30
0
0
16
32
48
64
DNA Mass (Picograms)
| Reference | Year | Sex | Condition at birth | Comments |
|---|---|---|---|---|
| Burrington and Stephens5 | 1969 | F | Hirsutism | Enlarged clitoris at 2 wk of age, pubic hair at 3 mo, acne at 11 mo; died of metastases 6 mo after resection of carcinoma of the right adrenal gland |
| Artigas et al.6 | 1976 | F | Hypertrophy of clitoris, left abdominal mass | Surgery at 24 d of life showed left ACC; recurrence of ACC at 4 yr of age at site of initial neoplasm requiring left nephrectomy; alive and well 5 yr after diagnosis |
| F | Hypertrophy of clitoris, left abdominal mass | Surgery at 5 d of life showed a left ACC adherent to left kidney, spleen, and diaphragm; died immediately after resection | ||
| Mann et al.7 | 1983 | F | Two masses on head at 2 mo of age | Right adrenal mass; widespread subcutaneous nodules; lymphadenopathy, pulmonary, and skeletal metastasis; diagnosis of ACC made at 5.5 mo of age by lymph node biopsy; died at 17 mo |
| Pigeon et al.8 Current case | 1985 | F M | Hypertrophy of clitoris Skin nodules, right adrenal mass, brain lesions | Surgery at 16 mo of age showed a right adrenal cortical tumor; died at 24 mo of age of pulmonary metastases Spontaneous regression of metastatic nodules |
ACC: adrenocortical carcinoma.
not have clinical evidence of virilization, despite ele- vated urine and serum levels of dehydroepiandrosterone and serum 17-hydroxyprogesterone.
Hogan et al.12 studied a series of patients with adreno- cortical carcinoma and divided them into the following two groups based on histologic condition: (1) anaplastic if 50% or more of the tumor was composed of large pleomorphic cells and (2) differentiated if only a few pleomorphic cells were detected. Based on this classifi- cation, it was found that seven of 21 patients had ana- plastic tumors. Most were male patients, had more cuta- neous metastases, and lacked clinical or laboratory evi- dence of hormone production. The outcome of patients with anaplastic adrenocortical carcinoma was dismal, with a median survival of 5 months. The remaining 66% of the patients with differentiated adrenocortical carci- noma were mostly female and had clinical or laboratory evidence of hormone excess. Median survival in this latter group was significantly longer at 40 months.
The distinction between adrenocortical adenoma and carcinoma is often difficult. The weight of the tumor is considered by many to be helpful in predicting neo- plasm behavior.13,14 Cagle et al.14 studied 23 pediatric and 42 adult adrenocortical tumors. They found that size was the only predictor of malignancy in the pediat- ric group. In their study, tumors greater than 500 g be- haved in a malignant fashion. In contrast, those weigh- ing less than 100 to 500 g were benign. However, other authors have reported tumors weighing 39 and 40 g15,16 in which metastases occurred. Mitotic activity greater than 2 per 10 or 5 per 50 high-power fields is reported to
have discriminating value in predicting malignant be- havior.13,17 In a study by Cagle et al., 14 this did not hold for the pediatric population. Thus, it appears that tech- niques other than histologic evaluation will have to be used to assess the biologic potential of these neoplasms.
Quantitative DNA analysis has been applied to these tumors in an effort to objectively measure their biologic potential. In several studies of tumors occurring in both adults18-22 and children,23,24 DNA aneuploidy has been associated with metastasizing tumors.
In the current case, polyploidy with DNA modal values at 2N, 4N, 8N, and 16N was demonstrated by image cytophotometry of Feulgen-stained isolated nu- clei. The lack of significant numbers of cells between the modal values implies a lack of mitotic activity and favors interpretation of the pattern as polyploid rather than heteroploid-aneuploid. Polyploidy may indicate a failure of normal progression of the cell cycle preventing tumor growth and resulting in tumor cell death.
Despite the seemingly malignant behavior with me- tastases in our patient, all cutaneous and brain lesions have resolved spontaneously. By many criteria, one would have expected benign behavior after examination of the adrenal primary (weight of only 35 g and low number of mitoses). Pleomorphism was present, but as previously stated,14 pediatric adrenocortical adenomas can have a significant degree of pleomorphism. Com- plete spontaneous regression of all metastatic disease is unexplained. However, the young age of this patient14 leads us to speculate on the possibility of a special cate- gory of self regressing pediatric adrenocortical carci-
noma akin to the IV-S group of neuroblastomas. Fur- thermore, the “benign” DNA ploidy study underscores the need for this type of analysis to understand the true biologic potential of these neoplasms.
Addendum
Since submission of the manuscript, the patient (at 1 year of age) was found to have a Stage I multicentric Wilm’s tumor (favorable histol- ogy) on the same side as the adrenal tumor. Although classical clinical and other renal pathological findings are lacking, this patient may represent an incomplete form of Beckwith-Wiedemann syndrome.25
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