Rare Pediatric Adrenocortical Carcinoma with Oncocytic Change: A Cytologic Dilemma
Savita Agarwal · Kiran Agarwal
Published online: 22 December 2010 C Springer Science+Business Media, LLC 2010
Abstract Pediatric adrenocortical carcinoma is extremely rare with a prevalence of 0.3 per million. Adrenocortical neoplasms in children usually present with one of the endocrine abnormalities. Adrenocortical neoplasms cannot be easily diagnosed on cytopathology; hence, the cytomor- phological features posing diagnostic dilemmas are dis- cussed in a pediatric patient presenting with palpable abdominal mass and virilization. Fine-needle aspiration smears were cellular showing cells in cohesive clusters adhering to central core of capillaries exhibiting an endocrine vascular pattern along with single cells and stripped nuclei. Cells were polygonal in shape and had abundant cytoplasm with well-defined borders and round eccentric nuclei with prominent nucleoli. Marked anisonu- cleosis was also noted. Few cells showed abundant granular cytoplasm resembling oncocytes. Many bizarre and multi- nucleated cells, few mitotic figures, and necrosis were also seen. Hematoxylin and eosin-stained sections of tumor biopsy suggested possibility of adrenocortical neoplasm. A panel of immunohistochemical markers were used to exclude possibility of renal cell carcinoma (RCC) and pheochromocytoma that showed vimentin (+), cytokeratin (-), inhibin-« (+), neuron-specific enolase (focally +), and chromogranin (-). The Ki67 index was 15%, and P53 was strongly positive. It is difficult to distinguish adrenocortical neoplasm, RCC, and pheochromocytoma on cytology because of overlapping features; hence, important cytolog- ical features which help in distinguishing between the three are discussed.
Keywords Adrenocortical carcinoma . Renal cell carcinoma · Pheochromocytoma · Virilization · Endocrine vascular pattern
Introduction
Pediatric adrenocortical neoplasms (ACN) are rare and account for 0.2% of all neoplasms in children [1]. Adrenocortical carcinoma (ACC) is extremely rare and accounts for 0.3 per million [2]. ACC are known for hormonal syndromes like Cushing syndrome, Conn syndrome, virilization, and femini- zation. ACN in adults may present as an abdominal mass, but in children they usually manifest as one of the endocrine abnormalities and at times are associated with genetic syndromes like Li-Fraumeni syndrome and Beckwith- Weidemann syndrome [3].
ACN cannot be easily diagnosed on cytopathology; hence, the cytomorphological features posing diagnostic dilemmas are discussed in a 2.5-year-old female patient who presented with palpable abdominal mass and virilization.
Case History
A 2.5-year-old female child presented with a huge palpable abdominal mass with signs of virilization of external genitalia. There was no history of headache, and on examination there was no hypertension, lymphadenopathy, or ascites. Urinary VMA levels were normal. On contrast- enhanced CT scan of the abdomen, there was large heterogeneously enhancing well-circumscribed soft tissue mass with calcification and large areas of necrosis. The mass was arising from the left suprarenal region and was
S. Agarwal () . K. Agarwal Department of Pathology, Lady Hardinge Medical College and Smt S.K. Hospital, Shaheed Bhagat Singh Marg, New Delhi 110001, India
e-mail: savvymedico@gmail.com
supplied by suprarenal arteries. The mass displaced the adjacent organs, and the inferior vena cava showed a filling defect indicative of thrombus suggesting tumor extension into the inferior vena cava. The left kidney was displaced posteriorly. The right kidney and adrenal appeared normal. The possibility of neuroblastoma was suggested. A clinical diagnosis of neuroblastoma was kept, and ultrasound- guided fine-needle aspiration (FNA) was done.
FNA smears were cellular showing pleomorphic cells in cohesive clusters adhered to a central core of capillaries exhibiting an endocrine vascular pattern (Fig. 1). Many single cells and stripped nuclei were also present. Cells were polygonal in shape and had abundant cytoplasm with well-defined borders and round eccentric nuclei with prominent nucleoli. Marked anisonucleosis was also noted. Few cells showed abundant granular cytoplasm resembling oncocytes. Many bizarre and multinucleated cells, few mitotic figures, and necrosis were also seen. The possibility of adrenocortical neoplasm, renal cell carcinoma (RCC), and pheochromocytoma were considered, and biopsy was advised.
The patient underwent exploratory laparotomy that revealed a large suprarenal mass infiltrating into left kidney, pancreas, spleen, and diaphragm. Due to extensive infiltra- tion into adjacent organs, removal was considered impos- sible and abdomen was closed after taking small biopsy of the tumor.
Gross examination showed two tiny gray-brown frag- ments of tissue both measuring 0.7×0.5×0.3 cm were received. Hematoxylin and eosin-stained sections showed diffuse sheets of polygonal to round cells showing moderate anisocytosis and marked anisonucleosis. Cells had abundant eosinophilic homogeneous to vacuolated cytoplasm with admixture of cells with abundant dense eosinophilic granular cytoplasm resembling oncocytes. The
nuclei had granular to coarse chromatin and prominent nucleoli in most of them. A few large bizarre and multinucleated cells were also seen. Mitotic figures were 4-5/10 high power fields.
The possibility of adrenocortical neoplasm was consid- ered; however, the remote possibility of RCC and pheo- chromocytoma was also considered, and a panel of immunohistochemistry (IHC) markers were used that showed vimentin (+), cytokeratin CK (-), inhibin-« (+) (Fig. 2), neuron-specific enolase (NSE) (focally +), and chromogranin (-). The Ki67 index was 15%, and P53 was strongly positive. Inhibin positivity strongly suggested the adrenocortical origin, and CK and chromogranin negativity excluded the possibility of RCC and pheochromocytoma.
Considering the presence of large palpable mass with virilization, CECT showing large mass in left suprarenal region extending into inferior vena cava (IVC), infiltration of adjacent organs on exploratory laparotomy, and histopathological features combined with IHC findings, high Ki67 index, and strong P53 positivity, the diagnosis of ACC with oncocytic change was given out.
Discussion
ACC is an extremely rare neoplasm of pediatric age group with majority of the patients being less than 5 years of age [4], and most of them have endocrine abnormality in contrast to adult patients who usually have palpable abdominal mass. The presence of an abdominal palpable mass with coexistent endocrine abnormality favors malignant adrenocortical neoplasm. The present case had huge palpable abdominal mass with signs of virilization but no underlying genetic syndrome.
Adrenal tumors apart from neuroblastoma are relatively rare in infancy and childhood [5]. The combination of clinical features of hormone overproduction in child, supportive laboratory findings, and adrenal mass on imaging is virtually diagnostic of a functioning adrenocortical tumor [3].
Clinically, neuroblastoma typically affects young children, and its age of manifestation may overlap with that of childhood adrenocortical neoplasm. This tumor often produ- ces an increase in the serum and urinary catecholamine levels [3]. On imaging, it shows a retroperitoneal mass with punctate calcifications, and morphologically it is a small round cell tumor.
It is difficult to distinguish adrenocortical neoplasm, RCC, and pheochromocytoma on cytology because of overlapping features [6]. Important cytological features which help in distinguishing between the three are discussed in Table 1.
Pheochromocytoma occurs in older children (6-14 years) and presents with constant or paroxysmal headache caused by hypertension. Imaging shows a circumscribed suprarenal mass [3]. Cytologically, the cells are round to spindly with red cytoplasmic granularity. On histopathology, the most common pattern observed is zellballen, and it occasionally may show a solid pattern. IHC shows chromogranin positivity.
Large ACN may appear to invade or arise from the upper pole of the kidney at cross-sectional imaging, thus may mimic a primary renal tumor [3]. Cytologic features favoring RCC include cellular smears with cells forming sheets, acini, and papillary structures as well as lying singly and focal endocrine vascular pattern. Pleomorphism is uniformly observed throughout the smear. [6].
Several histological scoring systems have been evolved to differentiate between adrenocortical adenoma and ACC of which the Weiss criteria are most commonly used. However, it has been emphasized to take great care in applying these criteria to histological evaluation of pediatric adrenocortical neoplasms and adrenocortical oncocytomas, as they tend to overdiagnose malignancy in such cases [7]. Wieneke et al. proposed a criterion for discussing malignancy in pediatric ACN. Based on these, the following potential classification was proposed: 1, benign or adenoma when two or fewer criteria are met; 2, uncertain post operative clinical behavior when three criteria are met; and 3, malignant when four or more criteria are met [7].
Of the criteria mentioned by Wieneke et al., our case fulfilled four criteria (tumor size more than 14x12 cm, confluent necrosis, infiltration into adjacent organs, and IVC invasion), thus placing it in the malignant category.
IHC has become a standard procedure complementing classic histologic analysis, and assessment of cell proliferation is now a mainstay of clinical oncology. Inhibin-« and melan- A are useful markers of adrenocortical differentiation. Cote et al. concluded that undetectable expression of CK and strong vimentin positivity is associated with malignant ACN [8]. Many authors have studied the utility of Ki67 index in ACN. Christoph et al. in their study found that Ki67 staining index over 5% is a good marker for malignancy in ACN [9].
The present case was positive for inhibin-«, vimentin, and NSE (focally) but negative for CK and chromogranin. High Ki67 index (15%) and strong positivity for P53 favored malignancy.
A relatively poor prognosis has been assigned to children with ACN, and complete surgical removal results in best chance of survival [3].
| Features | Adrenocortical carcinoma | Renal cell carcinoma | Pheochromocytoma |
|---|---|---|---|
| Pattern | Moderately cohesive clusters of cells adhered to thin vascular cores (endocrine vascular pattern), stripped nuclei, and crushed spindle fragments | Sheet like, acinar, tubules, and papillary structures Cells adhered to pink hyaline material Focal endocrine vascular pattern. | Largely dispersed, +/- loosely acinar pattern |
| Cell shape | Polygonal to round cells with distinct cell border | Polygonal cells with defined borders | Round to spindle cells with indistinct cell border |
| Cytoplasm | Abundant vacuolated to dense | Abundant pale vacuolated to granular | Abundant fragile with fine to coarse red granularity |
| Anisokaryosis | Focal dramatic | Variable | Marked |
| Nuclei | Round, eccentric to central with coarse chromatin | Round vesicular to coarse chromatin | Oval or plump spindle, some round. Uniform granular chromatin |
| Nucleoli | Prominent | Macronucleoli | Single/multiple |
| Multinucleation | ++ | +/- | + |
| Intranuclear inclusion | +/- | Common | Common |
This case report emphasizes the rarity of malignant ACN in pediatric population and highlights its important diag- nostic cytological features along with contribution of IHC in discerning malignancy in adrenocortical neoplasm.
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