FETAL AND NEWBORN ADRENOCORTICAL TUMORS
Hart Isaacs, Jr. n Departments of Pathology, Rady Children’s Hospital San Diego, San ☐ Diego, CA and University of California San Diego School of Medicine, La Jolla, CA, USA
✷ ☐ Adrenocortical tumors occur less often in the fetus and newborn than later in life. The purpose of this study was to focus on the fetus and newborn in an attempt to determine the various ways these tumors differ in their biologic behavior, pathology, clinical presentation and response to therapy from those occurring in the older child and adolescent. Twenty-five fetuses and newborns were diagnosed with ACTs prenatally (n = 3) and in the newborn period (n = 22). The study consisted of two main neoplasms: adrenocortical adenoma, 24%, and adrenocortical carcinoma, 76%. The most common presenting finding was an abdominal mass. Overall survival for patients with ACA and ACC were 33% and 53%, respectively.
Keywords adrenocortical tumors, adrenocortical adenoma, adrenocortical carcinoma, fetus, neonate, newborn.
INTRODUCTION
thcare ution
The adrenal cortex is the source of tumors and tumor-like condi- tions with unusual clinical manifestations in the fetus and newborn [1-25] (Table 1). Relatively few examples of adrenal cysts, adrenocortical adenomas (ACAs) and adrenocortical carcinomas (ACCs) have been described, some in association with the Wiedemann-Beckwith syndrome, hemihypertrophy, cancer family (Li-Fraumeni) syndrome or other tumors [10, 11, 22, 24, 27-30]. Adrenocortical tumors (ACTs) are rare in the pediatric age group occurring in fewer than 15 children per year in the U.S.A., less than 3 per year in England, and in 0.3 to 0.38 per million in children under age 15 years world wide [22, 23-27]. The recurrence and mortality rates associated with ACC are significantly high [20]. Pathology of the ACTs is described elsewhere in more detail [10, 18-20, 28, 30, 31-35, 37-39].
Address correspondence to Hart Isaacs, M.D., Department of Pathology, MC 5007, Rady Childrens Hospital San Diego, San Diego, CA 92123, USA. E-mail: hisaacs@ucsd.edu.
TABLE 1 Tumors and Tumor-like Conditions of the Adrenal Cortex in Fetuses and Newborns1
Adrenocortical hyperplasia
Congenital adrenal hyperplasia (adrenogenital syndrome) Adrenocortical hyperplasia associated with Cushing’s syndrome
Adrenocortical tumors
Adrenocortical adenoma Adrenocortical carcinoma
Adrenocortical cytomegaly Adrenal cyst Adrenal enlargement due to hemorrhage Adrenal enlargement due to infection or abscess
1 Source: Isaacs H Jr. [20].
METHODS
The author conducted a retrospective review of fetal and newborn ACTs reported in the literature and of patients in the Childrens Hospitals of San Diego and Los Angeles Department of Pathology files. Only fetuses and infants less than 4 months of age with adequate clinical and pathologic data were accepted for review. In addition those who presented with endocrine signs at less than 4 months of age but diagnosed later on were admitted to the study. The time period of patient accrual was from 1955 to 2005. Length of follow-up varied from one week to 21 years. Criteria used for the diagnosis of Cushing syndrome were clinical signs as moon facies, excessive weight gain, abdominal and upper dorsal distribution of fat, hypertension, and striae in addition to elevated urinary 17-ketosteroids and/or serum cortisol [17]. Virilization was defined as clitorimegaly or phallomegaly with premature appearance of pubic or axillary hair [17]. Patients were clinically staged according to the descriptions outlined by Stewart et al. and Sandrini et al. [28, 36] (Table 2). Weights and dimensions of the tumor were recorded
| Stage | Description |
|---|---|
| I | Complete surgical resection Tumor <100 g or <200 cm3 Normal hormone levels postoperatively |
| II | Microscopic residual tumor Tumor >100 g or >200 cm3 |
| Tumor spillage during surgery Abnormal hormone levels postoperatively | |
| III | Gross residual or inoperable primary tumor |
| IV | Metastatic tumor |
Adapted from 1 Stewart N, et al. [36] and 2Sandrini R, et al. [28]
4The above tumor weights were not applicable to fetuses and newborns in this study.
and the volume in cm3 was determined. Survival rates were based mostly on whether the patient survived or not.
RESULTS
Twenty-five patients including 3 fetuses and 22 newborns presented with ACTs (Tables 3 and 4). The study consisted of two main tumors: ACA (6 cases, 24%) and ACC (19 cases, 76%). The sex distribution for ACA was 1:1, 3 females and 3 males and for ACC 1.4:1, 11 females and 8 males. Most patients with adrenocortical tumors were born at term. The main presenting finding was an abdominal mass discovered either by antenatal sonography or by physical examination in the newborn period. Overall, virilization was next followed by Cushing syndrome and hypertension. Elevated urinary 17- ketosteroids were determined in half the newborns. Three patients (12%), 2 with ACC and 1 with ACA showed no clinical signs of tumor endocrine func- tion, i.e., they were classified as “non-functional” ACTs. Three newborns with
| Male/ female | 3/3 = 1:1 |
| Fetusª /Newbornb | -/6 |
| Gestation / Birth weight | 36 weeks (27-40)/ 3020 g (1240-5122) |
| Clinical presentation | |
| Cushing syndrome | 5 |
| Abdominal mass | 3 |
| Hypertension | 3 |
| Virilization | 1 |
| No clinical evidence of tumor endocrine | 1 |
| function | |
| Elevation of urinary 17-ketosteroids | 2 |
| Not mentioned | 4 |
| Stage I | 6 |
| Location | |
| Left/ right/ bilateral | 3 (50%)/ 2 (33%)/ 1 (16.7%) |
| Pathology | |
| Tumor dimensions/ volume/ weight | 5 cm (3-8)/ 91 (cm3)/ 33 g (2-61) |
| Treatment | |
| Patients treated | 4/6 (66.7%) |
| Patients untreated | 2/6 (33.3%) |
| Survival with surgical resectionb | 2/4 (50%) |
| Survival with surgical resection + | – |
| chemotherapy | |
| Outcome | |
| Recurrences | 0/6 |
| Fetus/ newborn survival | -/2/6 (33%) |
| Patients treated survived | 2/4 (50%) |
| Patients untreated survived | 0/2 |
| OVERALL SURVIVAL | 2/6 (33%) |
aPatients whose tumors were detected by prenatal imaging.
bFrom birth to 4 months of age.
ACC had associated malformation syndromes including hemi-hypertrophy, Wiedemann-Beckwith syndrome and trisomy 13 [3, 12, 32]. There was no definite relationship between the pathological findings, particularly tumor weight, volume and histology, and prognosis. All ACA patients were classi- fied as Stage I. Five of 6 ACA patients presented with Cushing syndrome and one fetus without endocrine signs. ACT locations and tumor mesurements varied considerably (Tables 3 and 4). Four of 6 ACA patients had surgical re- sections after 1980 resulting in 2 survivors (50%). Two non-treated patients
| Female/male | 11/8 = 1.4 |
| Fetus/newborn | 2/17 |
| Gestation /birth weight | 36 weeks (26-40) / 2963 g (1575-4100) |
| Clinical presentation | |
| Abdomnal mass | 13 |
| Virilization | 11 |
| Metastases | 6 |
| Hypertension | 5 |
| Cushings syndrome | 4 |
| No clinical evidence of tumor | 2 |
| endocrine function | |
| Other findings1 | 4 |
| Elevation of urinary 17-ketosteroids | 12 |
| Not elevated/not mentioned | 2/5 |
| Location | |
| Left/right/bilateral | 4 (21%)/ 10 (52%)/ 3 (16%) |
| Not specified | 2 (11%) |
| Pathology | |
| Tumor dimensions /volume/weight | 7 cm (3.5-18)/ 213 cm3 (7-1800)/ 68 g (2-125) |
Outcome
| Stage | Number | Survival |
|---|---|---|
| I | 1 (5%) | 1/1 (100%) |
| II | 1 (5%) | 0/1 |
| III | – | – |
| IV | 16 (85%) | 8/16 (50%) |
| Not specified | 1 (5%) | 1/1 (100%) |
| Patients treated | Number | Survival |
| 14 (74%) | 10/14 (71%) | |
| Surgical resection2 | 8 | 5 (62.5%) |
| Surgical resection + chemotherapy3 | 6 | 5 (83%) |
| Patients untreated | 5 | 0 |
| Recurrences | 3/19 (16%) | |
| Fetus/ Newborn survival | 1/2 (50%)/9/17 (53%) | |
| OVERALL SURVIVAL | 10/19 (53%) |
1Two examples of the incomplete form of the Beckwith-Wiedemann syndrome and 1each: Beckwith-Wiedemann syndrome, hemi-hypertrophy and trisomy 13.
2There were 8 patients who received surgical resection only: 3 of 6 (50%) with Stage IV, 1 with stage I and 1 not staged survived.
3 All 6 patients were classified as Stage IV, 5 survived.
died, one from infection and the other with intracranial hemorrhage before treatment could be started. Overall survival for ACA was 2 of 6 or 33% (Table 3).
Thirteen of 19 (68%) ACCs were classified as Stage IV and 1 each as Stages I and II; there were no examples of Stage III (Table 4). Stage was not specified for 4 patients. Six or 32% presented with metastases at the time of diagnosis, 3 to the skin and 3 to various other sites. Fourteen or 74% of ACC patients were treated, 8 with surgical resection alone and 6 with surgery plus chemotherapy resulting in 5/8 or 62.5% and 5/6 or 83% survival, re- spectively. Both fetuses with ACC had Stage IV disease; one received surgical resection plus mitotane chemotherapy and was cured and the other died shortly after birth. Of 14 ACC patients who were treated 10 or 71% survived. Five newborns who were not treated died; 1 was diagnosed at necropsy with Trisomy 13 and multiple congenital anomalies, and 4 had extensive metas- tases. There were 2 or 10.5% with abdominal recurrences who recovered after surgery and chemotherapy. The sites of metastases in the 11 Stage IV patients were lungs 5, liver 4, skin 3, brain 2 and 1 each in the lymph nodes, spleen, pancreas, mesentery, diaphram and bone. The overall survival for the 19 ACC patients, both treated and not treated, was 53% compared with 10 of 14 or 71% who were treated. The overall survival for the entire group of ACT patients in the study was 12 of 25 or 48%.
There were no examples of fetal or newborn ACTs listed in either the Los Angeles or Rady San Diego Childrens Hospital records.
DISCUSSION
ACTs rarely occur in the fetus or newborn. ACCs are more common than ACAs, 76% of the total in this study (Tables 3 and 4). The adrenal medulla is by far a more frequent site of origin of tumors in the young than is the cortex with an incidence ratio of 10:1 of neuroblastoma to ACTs [11]. Adrenocorti- cal hyperplasia associated with the adrenogenital and Cushing’s syndromes, occurs more often than true ACTs during the first year of life [17, 30, 31]. Neuroblastoma, adrenal cyst, adrenal enlargement due to hemorrhage, in- fection or abscess should be considered in the differential diagnosis of an adrenal mass detected in a fetus or newborn [19, 30] (Table 1). Although histological criteria for malignancy in adults are well established, definitive criteria for establishing malignancy in the fetus and newborn remain uncer- tain [34, 37, 41]. This is due in part, to the rarity of tumors as well as to the lack of clinical pathologic correlation of the patient’s outcomes [34]. Although newborn ACTs have similar histological appearances as those seen in tumors of older children and adults, the distinction between benign and malignant tumors is not always clear [11, 19, 38]. This problem makes pre- dicting prognosis on the basis of histology alone difficult [30, 38]. Obviously
the ACT is malignant if it recurs or spreads. The incidence of metastases at diagnosis here was significant for it occurred in a third of the fetuses and newborns with ACC [10, 14, 16, 21, 25] (Table 4). Size of the ACT was not always a reliable indicator of malignancy for small tumors metastasized whereas some of the larger ones did not [20]. It was not possible to apply weight or volume criteria for malignancy because tumor measurements of both ACAs and ACCs varied considerably (Tables 3 and 4). ACTs produce characteristic signs and symptoms in the newborn period [1-25] (Tables 3 and 4). Five of the 6 newborns with ACA presented with Cushing syndrome and a 6th with a “non-endocrine functioning” adenoma [1, 5-7, 11, 25]. The leading presentation of the 19 with ACC was an abdominal mass (13/19), while 11 showed virilization, 5 hypertension and 4 Cushing syndrome. An abdominal mass was more common than either virilization or Cushings syn- drome which is different from that described in adolescents or adults [13, 37-39]. ACTs were classified also as either functional (hormonally active) or non-functional [21]. More than 90% of newborn ACTs were classified as “functional” as compared to older individuals where they are less common [13, 22, 37-39]. Some patients with non-functioning ACCs presented also with widespread metastasizes as observed in the “blueberry muffin baby” with bluish skin tumor nodules [14, 16, 20].
Some childhood studies show that a young age at diagnosis is a favorable prognostic factor compared with patients older than age 5 years [18, 28, 30, 34-40]. For example, survival rates were reported as 70% for children less than 5 years compared with 7% for those older by Lack et al. [38], 53% for children less than 5 years compared with 17% for those older by Humphrey et al. [13A], and 53% for children less than 5 years compared with 17% for adolescents and adults by Medeiros et al. [39]. Our results are similar for treated ACC patients where the survival rate was 71% (Table 4). However, the outcome for ACA patients was much lower at 50% (Table 3). Most ACAs (4 of 6) were diagnosed prior to 1980. Perhaps a valid explanation for the high mortality would be that before the advent of adequate steroid replacement therapy, resection of functional ACTs often led to acute fatal adrenal insufficiency [37].
Stage IV ACC is associated with an unfavorable prognosis and a poor long term out come [2, 4, 8, 11, 14, 16, 18, 23, 25] (Table 4). However, not all newborns with metastatic disease died [12-15, 21, 23, 38]. Two Stage IV ACC patients had complete remissions after surgical resection as the only form of treatment of their primary tumors suggesting perhaps that “spontaneous regression” played a role [12, 14].
Complete surgical excision continues to be the treatment of choice for both ACAs and ACCs [11, 18, 21, 23, 36, 38, 42]. Generally children with small ACTs have a good prognosis with surgery as the only form of therapy [18]. Incomplete resection and lymph node involvement have an adverse effect on outcome [36, 41]. Because of this lymph nodes should be widely
sampled at the time of the initial surgery [36]. While the curative value of surgical resection in the absence of metastatic disease is proven, the role of effective chemotherapy after surgery remains unsettled [9, 36]. Chemother- apy generally is reserved for patients with inoperable tumors, recurrent or metastatic disease [36, 38]. Treatment with the insecticide mitotane has been tried with inconsistent results [36, 41-43]. Combinations with other agents such as eteposide and cisplatinum have produced some cures [9, 36, 43]. There is some convincing evidence that adjuvant therapy improves survival once the tumor has spread as seen by 5 Stage IV patients in the present study [9, 13, 16, 21, 23, 28, 41-43] (Table 4).
Congenital anomalies of the genitourinary tract, hamartomas and brain tumors are reported with increased frequency in patients with virilizing adrenocortical tumors [17, 20, 31]. Children with hemihypertrophy and/or Wiedemann-Beckwith syndrome should be followed closely with imaging studies for at least every 6 months to facilitate early diagnosis of an ACT, Wilms or other tumor formation. The same applies to patients with the autosomal dominant cancer family syndrome [28-30]. Moreover, there are reports of children with ACCs who have recurred and/or metastasized after a long interval as much as 6 years after the primary resection and therefore these patients should be followed closely for a long period of time [38].
CONCLUSION
ACTs in the fetus and newborn are both biologically and clinically dif- ferent from those occurring in older children and adults. Over 90% of newborn ACTs are hormonally active which is not the same for adolescents and adults. A third of fetuses and newborns with Stage IV disease had metas- tases at the time of diagnosis in addition to their abdominal mass. Newborns with treated Stage IV disease have better outcomes compared with older individuals. Although uncommon in the young, instances of spontaneous regression are not found later in life. Complete surgical excision continues to be the treatment of choice. Stage IV ACC newborns who were treated by surgical resection followed by chemotherapy had the best outcome. Survival rates were higher than those reported for adolescents or adults.
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