Patient report
A rare case of isolated Cushing syndrome in a 3-month-old boy
Saurabh Garge1,a, Monika Bawa1,a,*, Ravi P. Kanojia1,a, Kirti Gupta2,a and Kattragadda Laxmi Narain Rao1,a
1 Department of Pediatric Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
2 Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy in chil- dren. Most of these are endocrinologically active tumors, with virilizing features being typically dominant. Its presentation with isolated Cushing syndrome is rare. We report a 3-month- old infant with Cushing syndrome without the clinical fea- tures of androgen or mineralocorticoid excess consequently diagnosed with ACC. We discuss the different presentations, diagnosis, and management of this rare tumor with a rarer presentation.
Keywords: adrenocortical carcinoma; Cushing syndrome; virilizing tumors.
Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy accounting for only 0.2% of all cases of childhood cancer. This rare malignancy is associated with a high rate of recur- rence and mortality, with a reported 5-year event-free survival estimate of 54.2% in children. The single best prognostic fac- tor is when a “localized” (stage 1, 2) tumor can be subjected
a Authors’ contribution: Saurabh Garge, literature search and drafting of the manuscript; Monika Bawa, finalizing of the manuscript and caring for the patient; Ravi P. Kanojia, drafting of the manuscript; Kirti Gupta, histopathological workup; and K.L.N. Rao, operating surgeon.
*Corresponding author: Dr. Monika Bawa, Assistant Professor, Department of Pediatric Surgery, Advanced Pediatric Center, Postgraduate Institute of Medical Education and Research (PGIMER), Sector 12,
Chandigarh 160012, India Phone: +91 172 2755352
E-mail: monikabawa@hotmail.com
Received July 7, 2011; accepted October 29, 2011; previously pub- lished online February 15, 2013
to “complete” removal (“curative” surgery), hence the critical importance of an early diagnosis. These tumors are classi- fied as either benign or malignant and range in clinical sig- nificance. Most adrenocortical tumors (ACTs) in children are endocrinologically active tumors and present with viriliza- tion, precocious puberty, or Cushing syndrome (1). The path- ological features of these tumors as they relate to prognosis have been debated in the literature, and as yet, there is little consensus. Isolated Cushing syndrome is rare (2). We report an infant with Cushing syndrome without the clinical features of androgen or mineralocorticoid excess consequently diag- nosed with ACC.
Case report
A 3-month-old male child was referred to us by a pediatric endocrine clinic with a history of sudden weight gain in the last 15 days. He was born at term with a birth weight of 3.06 kg; pregnancy and delivery were uncomplicated. There was no history of any drug intake or any use of steroids during preg- nancy. The perinatal period was uneventful. He had a history of progressive puffiness of face, acne, and irritability for the last 15 days. His weight at presentation was 5.5 kg (>95th percentile) and length was 54.1 cm (<5th percentile). Blood pressure was 120/70 mm Hg (>96th percentile). Physical examination showed cushingoid facies, buffalo hump, facial acne, and poor muscle tone (Figure 1A,B). There were no signs of virilization. Family history was non-contributory.
Laboratory evaluation revealed serum cortisol of 1240 µg/dL (normal range, 4.5-22.7 ug/dL), total testosterone of 185 ng/dL (normal range, 6-77 ng/dL), and dehydroepi- androsterone sulfate (DHEA-S) of 251 µg/dL (normal range, 16-96 µg/dL). Serum adrenocorticotropic hormone (ACTH) was <5 pg/mL (normal range, 0-60 pg/mL).
An ultrasound of the abdomen showed a well-defined, hypoechoic, solid mass in right adrenal region of 2.5×2.4×1.8 cm in size (Figure 2). A computed tomography (CT) scan of the abdomen confirmed the presence of a well-defined spin- dle-shaped uniform soft tissue attenuation mass arising from the right adrenal measuring 3.1×1.9x2.0 cm without calcifi- cation or any cystic changes (Figure 3). Magnetic resonance imaging (MRI) of the abdomen showed a heterogeneous right adrenal mass measuring 2.6×2.4×2.3 cm, causing mild inferior displacement of the upper pole of the right kidney (Figure 3). There were no metastases seen in the liver or lungs on MRI.
Keeping a clinical diagnosis of an ACT, the patient was taken up for surgical resection of the mass. Amlodipine was
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started before surgery due to moderately elevated blood pressure.
Intraoperatively, there was a well-circumscribed mass in the right adrenal gland measuring 3.2×2.4x2.5 cm mass that was not invading the liver, kidney, or other surrounding soft tissues. The adrenal mass removed en bloc weighed 20 g and was sent for histopathological examination. Microscopic examination revealed a well-encapsulated tumor with periph- erally compressed adrenal gland (Figure 4A,B). The tumor cells were arranged in nests separated by fibrous septa (Figure 4C). The neoplastic cells were round to oval with vesicular nuclei, conspicuous nucleoli, and abundant granu- lar cytoplasm (Figure 4D). Few foci of necrosis were seen.
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There was no increase in mitosis, sheeting pattern, or clear cell change. The surgical margins were negative.
Hydrocortisone in stress doses was given during and after surgery and was gradually reduced to physiological replace- ment dose by 15 days postoperatively. Postoperative labora- tory investigations were also normal. DHEA value was 3.94 ng/ml, serum cortisol was 5.5 µg/dL, and serum ACTH was 54 pg/mL. The patient has been symptom-free at follow-up at 3 months (Figure 1C).
He was considered to have stage 1 ACC based on the relatively small tumor size, complete surgical resection, lack of metastases, and normalization of hormonal markers postoperatively. The tumor cells demonstrated a low mitotic count (<1-2 per 50 high-power fields and no atypical mito- ses). In addition, the MIB-1 index (proliferative index) was low at <1%-12% with regional variability. Tumor immu- nohistochemistry for p53 protein was negative. In a sub- sequent follow-up at 6 months, the patient has improved symptomatically and the hormonal levels are within the normal range.
Discussion
Epidemiology
ACC is a rare malignancy comprising only about 0.2% of all childhood cancers and has a bimodal age distribution, with a peak occurring in the first decade, although some report its peak at younger than 5 years (2, 3). Girls predom- inate over boys (5.3:1) until 4 years old, and thereafter, the distribution is reported to be similar (0.8:1) for both sexes, suggesting different disease etiologies for each age group.
Clinical features
The clinical features of sporadic ACC are provoked by hor- mone hypersecretion and/or tumor mass and spread. The most common presentation associates features of combined
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glucocorticoid and androgen oversecretion by the tumor, and Cushing syndrome, feminization, and hypertension are less common.
The tendency for ACTs to occur in younger age groups and to be predominantly androgen producing can be attributed to the two different zones of the fetal adrenal cortex, with the outer definitive zone being steroidogenically quiescent until late gestation and the inner zone producing steroid hor- mones throughout gestation. The inner fetal zone makes up 85%-90% of the total fetal adrenal cortex at birth, from which time it begins to undergo apoptosis. The primary steroid prod- uct of the fetal adrenal cortex is DHEA-S, which is the pre- cursor of placental estrogen (4). Thus, the derivation of ACTs
of infants, and young children from the fetal zone of the adre- nal cortex could help to explain their preferential elaboration of androgens.
Our case is unique as his presentation with Cushingoid fea- tures alone is unusual, especially at such a young age. Although, biochemically, he demonstrated elevations in both androgens and cortisol, he had no evidence of virilization on physical examination. Michalkiewicz et al. (2) found in a registry of 254 pediatric patients with ACTs that 55% presented with viriliza- tion alone. Twenty-nine percent presented with mixed overpro- duction of adrenal hormones. Only 5.5% of this group presented with isolated Cushing syndrome, and this tended to occur in older children (median age, 12.6 years). Therefore, our patient is
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remarkable in that he presented with Cushingoid features alone during infancy.
Other common presentations are the manifestations of the tumor burden in the form of local symptoms (pain, palpable lump) or distant metastases (liver, lung, bones). Fever may occur, concomitant to tumor necrosis. It is, however, seen that the frequency of palpable abdominal mass is less nowadays, possibly due to increasing awareness, by pediatricians, of the possibility of adrenal tumor in young children with preco- cious puberty.
Although most ACCs are of sporadic origin, they may also be part of congenital and/or familial diseases. Association of ACT with abnormalities, such as hemihypertrophy, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome has been reported (3). Our patient did not have any associated abnormalities.
Imaging
Imaging is an essential diagnostic step. Ultrasound is the ideal modality to screen the adrenal region and to assess the tumor recurrence postoperatively. However, it cannot reliably identify smaller lesions as accurately as CT (5), which has been reported to be superior in the imaging of tumors mea- suring 0.5-1 cm, assessment of tumor thrombi in the adrenal or renal vein, regional invasion, and distant metastasis. MRI appears to be accurate in imaging ACTs and has the added ability to show coronal slices, which allows better distinction from adjacent tissues. MRI may replace CT as a diagnostic choice in the evaluation of ACTs (6). Adrenal renography and arteriography are invasive and not usually used in children (3). Apart from the radiology, routine endocrinological inves- tigations look for oversecretion of various adrenal cortical steroids.
Staging
The staging system presently in vogue is based on the size of tumor, presence or absence of metastasis, hormonal activity, complete resection, and spill during surgery. Based on these criteria, ACTs are staged in four categories. Our case was a stage 1 tumor based on the staging system (7).
Prognosis
There has been much debate about which tumor character- istics are the best prognosticators. Among the various prog- nostic factors, grading using the Weiss system, size of tumor, and completeness of resection are the most consistent ones (8-12). Our patient has a favorable prognosis, given complete surgical resection, small tumor size, lack of metastasis, and young age.
Treatment
Surgical Complete resection of tumor and local lymph nodes is the single most important procedure in the successful treatment of ACT. En bloc resection, which may include the
adjacent structures invaded by the tumor, is required in cases of large and invasive tumors. Surgery requires careful and precise perioperative planning. All patients with a functioning tumor are assumed to have suppression of the contralateral adrenal gland; thus, steroid replacement therapy should be given to these patients. Special attention to electrolyte balance, hypertension, surgical wound care, and infectious complications is imperative.
Laparoscopic adrenalectomy is not indicated for malig- nant adrenal lesions because of large tumors, which are technically difficult to remove and are also vulnerable to breakage or incomplete resection. Also, the tumors may invade adjacent organs or regional lymph nodes, which will also require resection. Unfortunately, it is impossible to preoperatively know the malignant nature of the lesion. Certain criteria, such as size, have been considered by some to be a possible preoperative indicator of malignancy but are refuted by others. Often, this only becomes evident when tumor spread is demonstrated beyond the confines of the adrenal capsule. Laparoscopic adrenalectomy has clear applicability in the management of patients with benign adrenal neoplasms.
Chemotherapy Chemotherapy is advocated as the mainstay of treatment of end-stage or unresectable disease. Review of the literature reports a range from 5% to 64% of patients present with stage IV disease at diagnosis. Most published support for chemotherapy has advocated mitotane in adults, with response rates ranging from 10% to 60%. Other agents, such as cisplatin, taxol, cyclophosphamide, doxorubicin, 5-fluorouracil, have been used, but results are equally varied (1, 3). Most series in the pediatric literature do not report favorable results with mitotane (1, 3). In the largest reported series, of the 55 with follow-up, the overall survival was 46%. The survival was 83% in those younger than 2 years compared with 36% in those older than 2 years. Survival was 67% was achieved if there was a total excision of the tumor. Although this series found no relationship to size, other smaller series have noted lower survival with larger tumors (13-16).
Chemotherapy with mitotane has been frequently utilized with varying response rates (34%-61%) (17, 18). Other reports have noted success with use of cisplatin, carbopla- tin, and etoposide (VP-16), some in combination with mito- tane (19, 20). Studies have shown diploid and near-diploid tumors to have a good outcome regardless of tumor weight and also noted that malignant tumors were aneuploid with reactivity to p53 protein and had a poor prognosis (21). Also, in the aneuploid cases, small tumors (<100 g) had a good outcome, probably due to surgical treatment earlier in the disease process, whereas large tumors (>750 g) had a poor prognosis.
Our patient’s tumor was negative for p53 mutation which is estimated to occur in 80%-90% of all pediatric ACTs. Several characterized TP53 polymorphisms have shown altered regulation of p53 protein posttranslational modifica- tions, protein stability, nuclear localization, and downstream signaling. Restoration of TP53 functions, in particular TP53-
dependent apoptosis, is an attractive cancer therapeutic strategy.
Conclusion
In conclusion, although rare, ACTs should be considered in the differential diagnosis of Cushing syndrome in the pediat- ric age group. Although virilizing features are typically domi- nant, ACTs may present with isolated Cushing syndrome. Early diagnosis, adequate perioperative management with specific emphasis on postoperative glucocorticoid replace- ment, complete excision of tumor, and close follow-up for recurrence and metastases are crucial to improve survival.
Acknowledgments
The authors thank the Departments of Pathology and Pediatric Endocrinology of PGIMER.
Conflict of interest statement
Authors’ conflict of interest disclosure: The author stated that there are no conflict of interest regarding the publication of this article.
Source of support: None.
Competing interest: None.
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