AMERICAN ACADEMY
1948
PAPER
PATHOLOGY/BIOLOGY
Mark Pilla,1 B.Health.Sci .; John Gilbert,2 F.R.C.P.A .; Lynette Moore,1,3 F.R.C.P.A .; and Roger W. Byard,1,2 M.D.
Occult Adrenocortical Carcinoma and Unexpected Early Childhood Death
ABSTRACT: A four-year-old previously well boy collapsed unexpectedly and was taken immediately to hospital, where he developed sei- zures and cardiogenic shock with lethal, rapidly progressing multi-organ failure. At autopsy, the height was >90th percentile and there were indications of early virilization. Internally, a friable tumor of the left adrenal gland was identified that had invaded the left renal vein and infe- rior vena cava. Histology revealed typical features of an adrenocortical carcinoma with aggregated trabeculae of cells containing abundant eosi- nophilic cytoplasm and large pleomorphic nuclei. There was strong positive cytoplasmic staining for inhibin; mitochondria were shown on electron microscopy to contain prominent electron-dense granules. Death was due to massive pulmonary tumor embolism. Although adrenocor- tical carcinomas are very rare and are more commonly found in adults, the current case demonstrates that they may also occur in childhood and be responsible for unexpected death by the very unusual mechanism of tumor embolism.
KEYWORDS: forensic science, adrenocortical carcinoma, sudden death, tumor embolism, pulmonary embolism, virilization
Tumor embolism is a rare event which occurs when a friable, angioinvasive malignant tumor breaks up within the vasculature. Once in the bloodstream, pieces of tumor may then travel cen- trally or peripherally and wedge within such vessels as the pul- monary veins, cerebral blood vessels, and the femoral arteries, depending on the site of the primary tumor and/or the presence of right to left communication within the heart (1). Pulmonary tumor embolism may have significant immediate consequences with the development of pulmonary hypertension, cor pul- monale, and right heart failure, sometimes resulting in quite rapid death (2,3). The following case is reported to demonstrate a very rare cause of tumor embolism resulting in the rapid demise of a previously asymptomatic boy.
A four-year-old boy unexpectedly collapsed while playing and was admitted to hospital, where he experienced intermittent sei- zures, unstable blood pressure, and bradyarrhythmias. He then became severely acidotic and developed a coagulopathy, pul- monary hypertension, cardiogenic shock, and multi-organ failure and died 11 h after the initial episode.
There had been no previous illnesses, and he had been consid- ered to be completely healthy. External examination at autopsy revealed a tall boy (height > 90th percentile) with indications of early virilization (Tanner stage 4 genitalia). A major finding on internal examination was a large (95 × 85 × 65 mm) tumor of
the left adrenal gland (Fig. 1) with invasion into the left adrenal vein and inferior vena cava. The tumor had an intact capsule but on sectioning was markedly necrotic and focally cystic (Fig. 2). Plugs of cream-colored presumed tumor emboli were demon- strated on cross-sectioning of both lungs (Fig. 3).
Histologically, the primary tumor was composed of large eosi- nophilic cells, which were arranged in a trabecular pattern (Fig. 4). The cells contained abundant eosinophilic cytoplasm and had large pleomorphic nuclei with numerous atypical mitoses. Both lungs had extensive tumor emboli with no parenchymal metastases (Fig. 5). The liver and brain were simi- larly free of metastatic tumor. Immunohistochemically, the cells had strong positive cytoplasmic staining for inhibin with nega- tive staining for Melan A, chromogranin, cytokeratin, vimentin, calretinin, EMA, and S100. Electron microscopy also revealed characteristic features of adrenal cortical carcinoma with mito- chondria containing prominent electron-dense granules, as well as small stacks of rough endoplasmic reticulum, with no obvious neurosecretory granules (Fig. 6). Postmortem androgen studies revealed elevated testosterone levels (23 nmol/L; N < 6) and free androgen index (195%). Radiology and microbiology studies were normal.
Death was therefore due to massive pulmonary tumor embo- lism arising from a previously asymptomatic adrenocortical car- cinoma of the left kidney.
1School of Medicine, The University of Adelaide, Frome Rd, Adelaide 5005, Australia.
2Forensic Science SA, 21 Divett Place, Adelaide 5000, Australia.
3Department of Pathology, SA Pathology, Womens’ and Childrens’ Hospital, Adelaide 5006,Australia.
Received 3 Feb. 2016; and in revised form 25 April 2016; accepted 6 May 2016.
Discussion
Adrenal cortical carcinoma is a rare sporadic endocrine malig- nancy with an incidence of 0.7-2 cases per million population. It most commonly occurs between 40 and 50 years of age, although there is a biphasic pattern with a second peak in early
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childhood (4,5). In children (<15 years), the annual incidence is 0.3-0.38 cases per million, with most cases (65%) occurring under the age of 5 years (6). The prognosis is quite poor due to the aggressive nature of the malignancy, although some respond to surgical resection (4,7). The tumor also has a well-known propensity to invade the adrenal vein and adjacent vena cava (8). The histological appearance of large eosinophilic cells with a high mitotic rate is characteristic but not predictive of progno- sis; nuclear DNA analysis is also not always reliably associated with outcome (9).
Emboli represent material in the bloodstream that is trans- ported from the point of origin or entry into the vasculature to a distant location and may include thrombi, infective agents (sep- tic/mycotic), fat, foreign bodies, or fragments of tumors (1,10,11). While thromboembolism is well documented in adults, pediatric cases are rare, with an incidence of pulmonary throm- boembolism of 0.86 cases per 100,000 children admitted to hos- pital per year (12-14). Risk factors for thromboembolism in children are the same as for adults (15,16). Vessels that may be occluded by the effects of emboli range from the pulmonary ves- sels, as was seen in the current case, to smaller vessels such as
the coronary arteries and to larger vessels such as the aorta (17,18).
Tumor emboli are very rare in adults (3) and are even less common in childhood. Tumors that may embolize in adults include breast and gastric carcinomas, hepatoma,
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choriocarcinoma, chondrosarcomas, and renal cell carcinoma (19,20), with rare examples such as squamous cell carcinoma of the ureter (3). In children, most tumor emboli derive from nephroblastomas (Wilms tumor), with other less common tumors including pleuropulmonary blastomas and hepatoblastomas. Tumor embolism from adrenocortical carcinoma in childhood is thus extremely rare (1). A variety of mechanisms may result in embolism, which includes fragmentation of friable necrotic intravascular tumor, as in the current case, to saddle embolism with complete occlusion of the pulmonary outflow tract. The lat- ter occurs if angioinvasive tumor has extended a distance into the inferior vena cava, sometimes as far as the right atrium. An embolus, not including tumor, may also dislodge from a throm- bus attached to the tip of the intravascular tumor (8). Finally, tumor embolism may be a complication of surgery (11).
In the current case, there had been no prior health issues of concern although the height (>90th percentile) and early viriliza- tion were most likely due to hypersecretion of androgens by the tumor (confirmed on postmortem testing). For example, early puberty was reported in a five-year-old girl who had a functional adrenal cortical carcinoma causing an endocrinopathy (6). Indi- viduals with a functional adrenal cortical carcinoma may also develop Cushing’s syndrome (6,7,21).
In conclusion, this case demonstrates a very rare sequela to an uncommon childhood tumor. Although sudden death in the very young often has a cardiac etiology, on occasion an extraordinar- ily rare underlying disease and lethal mechanism may be identi- fied at autopsy, affirming its value in the evaluation of these types of cases.
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Additional information and reprint requests:
Prof Roger W. Byard, M.D. Discipline of Anatomy and Pathology The University of Adelaide Adelaide SA 5005 Australia