ELSEVIER
NEOPLASTIC DISEASE
Adrenal Cortex Carcinomas with Distant Metastases in Beef Cattle at Slaughter
J. F. Edwards” and K. E. Ralston™
* Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A& M University, College Station and P.O. Box 432, Castroville, TX, USA
Summary
Ten cases of adrenal cortex carcinomas with distant metastases were collected as subclinical lesions at slaughter of approximately 14,000 adult cattle. The primary lesion in the adrenal gland and the distant metastases, to either the lung or liver, were characterized by light microscopy and immunohistochemistry. Carcinomas were usually detected by noting metastases in the lungs as polypoid, soft, red or red and yellow masses. All ad- renal tumours were unilateral and none were seen in bulls. In six of 10 carcinomas there was gross evidence of invasion of the vena cava via the adrenal vein. Normal bovine adrenal cortex labelled positively with S100, calretinin, o. inhibin and melan-A; however, adenomas and seven of 10 carcinomas were labelled best by melan-A and a inhibin. Three carcinomas, grossly identical to the other seven, had numerous calcific granules and a slightly different microscopical appearance. In addition to melan-A and a-inhibin, these variant carci- nomas labelled with S100. This variant may be derived from a different layer of the adrenal cortex. Because of the similarity of the bovine and human adrenal cortices, cultures of spontaneously arising bovine adrenal tumours may be a useful resource for study of human neoplasia.
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Keywords: adrenal; carcinoma; cattle; immunohistochemistry
Introduction
The bovine adrenal gland has become important to the biomedical community. The ease of obtaining and culturing cortical cells from different portions of the cortex or medullary chromaffin cells from bovine adrenal glands taken at slaughter, and the similarity of the physiology of the bovine adrenal gland to that of the human adrenal gland has resulted in a body of literature concerned with the physiology, toxicology and neoplasia of this tissue (Hornsby and Gill, 1977; Livett et al., 1983; Waterman and Simpson, 1985; Hornsby et al., 2003; Meizhen et al., 2004; Romero et al., 2006). Indeed, because the inci- dence of human adrenal carcinomas is low, use of cul- tured bovine adrenal cells has become an important tool for study of human adrenal carcinogenesis (Cardoso et al., 2009).
While bovine adrenal tumours are diagnosed at slaughter, they are not a cause of morbidity and mor- tality. They are seen infrequently by diagnostic labo- ratories and veterinary teaching hospitals. We are unaware of a report involving a functional bovine ad- renal tumour or an adrenal-induced paraneoplastic endocrinopathy. Single-case reports of phaeochromo- cytomas (Head and West, 1955; West, 1975), a tera- toma (Ladds et al., 1990), a ganglioneuroblastoma (Riley and Forsyth, 1976) and a cortical carcinoma (Hamir, 1984) found incidentally in bovine adrenal glands are in the literature. The multiple endocrine tumour syndrome of phaeochromocytoma, thyroid C-cell carcinoma and pituitary chromophobe ade- noma in bulls constitutes the only bovine endocrino- logical condition studied (Wilkie and Krook, 1970; Black et al., 1973; Sponenberg and McEntee, 1983; Seimiya et al., 2009). No report of lethal bovine adre- nal neoplasia was found. Although cattle arrive at slaughter with no clinical history, it is possible that malignant adrenal tumours cause lower production,
Correspondence to: J. F. Edwards (e-mail: jedwards@cvm.tamu.edu).
weight loss or infertility that result in animals being culled. Therefore, the best source of information on bovine adrenal neoplasia is from slaughter material. Because cattle with these tumours pass ante-mortem inspection, clinical data from slaughtered cattle with adrenal neoplasia also are non-existent, and the le- sions are seen only during viscera inspection.
Based on slaughterhouse survey data (Monlux et al., 1956; Cotchin, 1960; Brandley and Migaki, 1963; Sandison and Anderson, 1968; Wright and Conner, 1968; Dukes et al., 1982), veterinary text- books state that in domestic species, adrenal cortical neoplasia is seen frequently in cattle (Appleby, 1976; Capen, 2002, 2007; La Perle and Capen, 2007). Most reports describe tumours that invade the vena cava, but distant metastases are not usually described (Schofield, 1949; Sandison and Anderson, 1968; Wright and Conner, 1968; Hamir, 1984; Kuipel et al., 2008). Distant metastasis is mentioned in passing in one survey (Misdorp, 1967). The present study characterizes the immunohistochemistry (IHC) of the bovine adrenal gland as well as the histology and IHC of ten bovine adrenal cortical carcinomas with distant metastases that were diagnosed at slaughter.
Materials and Methods
During multiple visits to a slaughter facility over a 4-year period, samples of adrenal tumours were col- lected from primary and metastatic lesions. The cattle population examined at this facility consisted of
culled beef cattle, including approximately 5% bulls and 95% mature cows, of Bos taurus and Bos indicus lin- eages. When large adrenal adenomas were identified without obvious metastases, the lungs were examined closely for metastases and the second adrenal gland was inspected. If suspicious red nodules were noted in the lungs, both adrenal glands were then examined for a possible primary adrenal lesion. Normal adrenal gland, adrenal cortical adenomas without vena cava invasion and a phaeochromocytoma were collected for use as control tissues. Some adenomas were associ- ated with gross evidence of invasion of the vena cava, but only adenomas without venous invasion were used as controls. Sections (5 um) of formalin-fixed and paraffin wax-embedded tissues were prepared for staining by haematoxylin and eosin (HE) or Von Kossa’s stain or IHC.
IHC was performed by incubating primary anti- bodies for 1 h at 20℃ with dewaxed and rehydrated sections using an automated immunostainer (Dako Autostainer, Dako, Carpinteria, California, USA). The primary antibodies used are listed in Table 1. Bound mouse primary antibodies were detected with a polymer labelled with horseradish peroxidase (HRP) (ImmPress anti-mouse Ig, HRP, Vector Lab- oratories, Burlingame, California, USA) with 3, 3’-di- aminobenzidine (DAB) as the chromogen (Dako). Bound rabbit polyclonal antibodies were detected with a HRP-conjugated polymer (Mach2, Biocare Medical, Concord, California, USA). For melan-A and a-inhibin antibodies, an alkaline phosphatase system was used (goat anti-mouse secondary antibody
| Table 1 Reagents used for immunohistochemistry | ||||
|---|---|---|---|---|
| Antibody | Pretreatment | Dilution | Clone | Manufacturer |
| Calretinin | HIER | 1 in 300 | Polyclonal rabbit | Cell Marque, Rockline, California, USA |
| Chromogranin A | HIER | 1 in 1,000 | Polyclonal rabbit | Dako, Carpentaria, California, USA |
| Cytokeratin | Proteinase K | 1 in 500 | Mouse MNF116 | Dako |
| Neuron specific enolase | HIER | 1 in 500 | Mouse BBS/WC/V1-H 14 | Dako |
| S100 | HIER | 1 in 1,000 | Polyclonal rabbit | Dako |
| Synaptophysin | HIER | 1 in 400 | Mouse SY-38 | Dako |
| Tryosine | HIER | 1in 400 | Mouse MAGH/AP2 | Affinity BioReagents, |
| hydroxylase | Golden, Colorado, USA | |||
| Vimentin | HIER | 1 in 500 | Mouse V9 | Dako |
| a inhibin | None | 1 in 300 | Mouse R-1 | Biocare Medical, Concord, California, USA |
| Melan-A | None | 1 in 40 | Mouse A103 | Vector Laboratories, Burlingame, California, USA |
HIER, heat-induced epitope retrieval.
and streptavidin phosphatase label; KPL, Gaithers- burg, Maryland, USA). Warp-red (Biocare Medical) was used as the chromogen. Sections were counter- stained with Gill’s haematoxylin. Sections of normal mature bovine adrenal gland, bovine adrenal ade- noma and bovine phaeochromocytoma on the same slide served as controls. Test samples with replace- ment of the primary antibody with universal negative control antibody (Biocare Medical) were used as neg- ative controls. Neither the S100 nor the NSE reactions required antigen retrieval pretreatment and the cyto- keratin reaction required only a 2-min enzyme pre- treatment with ready-to-use proteinase K (Dako). For all other antibodies, a heat-induced epitope re- trieval system (HIER, Reveal Decloaker, Biocare Medical) using citrate buffer (pH 6.0) for 20 min was used. Endogenous peroxidase activity was blocked by incubation for 10 min in H2O2 3% in methanol followed by 20 min in a protein block (Background Sniper, Biocare Medical).
Results
Seventeen days of collection, during which approxi- mately 14,000 cattle were inspected, were necessary to accumulate 10 cases of adrenal cortical carcinoma with pulmonary metastases. The animals had not been identified as having clinical disease following ante-mortem inspection and the animals were not emaciated. The contralateral adrenal glands were normal. No bulls had adrenal carcinomas. The pri- mary adrenal carcinomas were unilateral with three being in the left adrenal gland and seven in the right. A normal portion of adrenal gland could usually be seen at a margin of the tumour (Fig. 1). Carcinomas were spherical or slightly ovoid and ranged from 9 x 5 x 5 cm to 29 × 21 x 21 cm. They were adhered firmly to the vena cava and when on the left side they
TTTTTITIT
were often adherent to the hepatic renal impression (Fig. 2). All tumours were soft and mottled yellow-red in colour (Figs. 3 and 4). In all tumours some foci of mineral were noted when incised, but three tumours were particularly gritty and difficult to section smoothly. In all cases, the thin capsule of the tumour was readily torn when manipulated. In six carcinomas, the primary lesion exited via the adrenal vein into the vena cava as a smooth, yellow or yellow-red, slightly elongated and nodular projection with a fibrous capsule 1-2 mm thick (Fig. 2). The projections were directed cranially along the vena cava and ranged in size from 2 x 3 to 7 x 3 cm, each slightly thicker than 1 cm. The ve- nous surface was roughened adjacent to the projec- tions, but no thrombi were identified on the surface of the intravascular projections.
In nine cases metastases were present in the lungs. These were soft, variably red or mottled yellow-red,
and large growths often protruded from the pulmo- nary parietal pleura (Figs. 5 and 6). In two cases, small metastases were detected by close examination of the lungs from animals that had what initially were considered typical adrenal adenomas; that is, the metastases were not seen during routine inspection or noted by inspectors on the inspection line. These metastases were red and <1 cm in diameter (Fig. 7). They grossly resembled haemal no- des embedded in lungs. In three cases when pulmo- nary metastases were numerous and large, the tumours also had metastasized to the tracheobron- chial lymph nodes. One case only had 1-2-cm diam- eter metastases concentrated in the hilus of the liver, presumably representing local invasion.
One or two adrenal adenomas were collected on each collection day for use as controls. Of these, six were noted to have vena caval invasion without dis- tant metastases. Histologically, these adenomas were
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similar to the seven non-gritty carcinomas in all re- spects. Adrenal adenomas only differed from carcino- mas by having slightly less haemorrhage. By incising many grossly normal adrenal glands, two phaeochro- mocytomas were collected for use as controls. These lesions were pink in colour and were <1 cm in diam- eter.
Neoplastic carcinoma cells in the primary tumours and in the metastases were subtended and packeted by a fine, fibrovascular stroma on which the cells pali- saded. In seven of the tumours, the cells had finely vacuolated, pale eosinophilic cytoplasm and a round to oval, hyperchromatic nucleus with 1-2 prominent nucleoli (Fig. 8). Mitoses were rare and anisokaryosis was mild to moderate. Granules stained positively by Von Kossa’s method were seen in all tumours, but three tumours had many of these calcific granules, which disrupted sections in the primary lesions and
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the metastases. These neoplastic cells had abundant, lacey cytoplasm and an oval hyperchromatic nucleus (Fig. 9). Large, blood-filled spaces without severe ne- crosis were common in both types of tumour. Haemosiderin-laden macrophages were seen individ- ually or in scattered groups. The surface of invasions into the vena cava had a slightly thicker fibrous cap- sule with an endothelial cover that was continuous with the venous surface and had no adherent fibrin.
Normal mature adrenal cortical cells had expressed S100, a calcium receptor protein (Zimmer et al., 1997), in the nucleus and cytoplasm, but adrenal cor- tical neoplasms without numerous calcific granules were S100 negative (Fig. 10). Primary and metastatic tissue from three carcinomas that had numerous cal-
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cific granules also expressed S100 (Fig. 11) and the adrenal adenoma controls on the same slide were neg- atively labelled. Cells from normal adrenal cortex and adrenal adenomas expressed a-inhibin, melan-A, cal- retinin and vimentin. Calretinin was expressed less strongly by normal adrenal glands in the zona glo- merulosa than in the zona fasiculata and labelled the tumours unevenly. Vimentin always labelled both the adrenal cortex and medulla. Thus, calretinin and vimentin were not useful for the identification of cortical carcinomas and their metastases. The normal
medulla and the phaeochromocytoma controls were immunolabelled for vimentin, tyrosine hydroxylase, chromogranin-A, synaptophysin and neuron-specific enolase (NSE) and were not labelled by the other markers. Cytokeratin did not reliably label the adre- nal cortex or medulla or the adrenal tumours. With all primary and metastatic cortical carcinomas, «-in- hibin and melan-A labelled >70% of neoplastic cells with a finely granular, cytoplasmic pattern (Figs. 12 and 13).
Discussion
The incidence of adrenal carcinomas with distant me- tastases in mature beef cattle from subtropical USA (Texas) is approximately 0.07%. None of these lesions were seen in bulls, but given the low incidence of the tumour, had a larger population of old bulls been studied, it is presumed that these tumours would have been found. Because extra-adrenal metastases to other organs have not been described before, it is not possible to compare our findings to previous stud- ies. However, adrenal tumours that were classified as carcinomas based on vena caval invasion in previous publications (Misdorp, 1967; Wright and Conner, 1968; Monlux and Monlux, 1972; Hamir, 1984; Gil, 2005) were seen in six animals in our study. These were similar grossly and microscopically to the 10 ad- renal cortical carcinomas with metastases. It would seem that adrenal neoplasia with vena caval invasion would progress and presumably would have metasta- sized to distant sites if given more time. It is not ex- plained why, given the large number of malignant adrenal tumours reported in surveys, that distant me- tastases have not been described more frequently.
Determining the incidence of neoplasia from slaughter material has certain limitations and associ- ated variables. Surveys done in different geographical areas reflect differences due to variations in produc- tion systems, genetic diversity and epigenetic influ- ences. For example, information from facilities slaughtering dairy cows would be different from that derived from facilities slaughtering culled beef cattle that are older, are raised primarily on grass and consist of purebred and crossbred animals from many breeds. Because of industry pressures resulting from bovine spongiform encephalopathy, younger animals are now slaughtered and presumably a youn- ger population would have fewer tumours. Published surveys regarding the incidence of bovine neoplasia and quoted in textbooks are several decades old and were conducted in facilities primarily in northern Eu- rope, Australia and North America. In most surveys, much if not all data are derived from material sent to diagnostic services. Trained inspectors recognize and correctly diagnose most tumours grossly; therefore, cases sent for diagnosis often represent a subset of all tumours that inspectors see because of time con- straints and the personal interest of Veterinary In- spectors (Dukes et al., 1982).
It is interesting to compare the lesions in cattle to those of man (Lack, 2007; Mezhir et al., 2008). Hu- man malignant cortical carcinomas are rare, and ap- proximately 40% are non-functional and only become clinically significant once they become large masses that cause weight loss or abdominal pain. Of- ten, they are diagnosed by imaging examinations per- formed for non-adrenal-associated complaints. Most are associated with the right adrenal gland, and at di- agnosis the tumours may have invaded locally into
the inferior vena cava and display tumour-associated caval thrombosis. Some have local or lymph node in- volvement without distant metastases. Treatment involves thrombectomy and vena caval resection or en-bloc resection of the vena cava, kidney and any local metastases. Distant metastasis is rare. The reported, post-resection survival time ranges from 4 to 45 months. Microscopical criteria associated with the highest probability of metastasis include the pres- ence of broad fibrous bands (P <0.0001), widespread tumour necrosis (P <0.0001), vascular invasion (P <0.001), cellular pleomorphism (P <0.001) and a diffuse (solid) growth pattern (P <0.001). These tumours express synaptophysin, NSE, melan-A, a-inhibin and calretinin.
The bovine tumours invaded via the adrenal vein into the vena cava without inducing thrombosis. By design, cases were selected in which the tumour had metastasized to other organs, and only one tumour had invaded locally into the liver. The lung was the favoured site for metastasis. The neoplastic cells had morphology similar to that of steroid producing cells of the zona reticularis and zona fasiculata, lacking the eosinophilic granules seen in cells of the zona glo- merulosa. The carcinomas were solid growths, but unlike their human counterpart, they showed rela- tively little fibrosis or cellular pleomorphism. It is felt by some that the microscopical features of bovine neoplasia are not reliable guides to malignancy (Wright and Conner, 1968).
The bovine adrenal carcinomas studied were pre- sumably non-functional, and all came from mature cows. Lesions indicating adrenal endocrinopathies, such as cachexia or dermatopathy were not noted, and contralateral adrenal cortical atrophy was not noted. The lack of clinical signs was expected given the lack of reports of bovine adrenal endocrinopathies in the literature. A subgroup of the carcinomas had numerous calcific granules and, unlike the other car- cinomas and adenomas, expressed S100 indicating that the carcinomas that do metastasize may not be a homogeneous group.
IHC was studied as an adjunct technique for diag- nosis and the labelling of the normal bovine adrenal gland and cortical carcinomas correlated well with each other, with the exception of S100 labelling. The bovine adrenal cortex has its origin in the meso- derm of the gonadal ridge, while the medullary chro- maffin cells are derived from the neural crest ectoderm (Wrobel and Süß, 1999). Therefore, the uniform and intense labelling of the normal bovine adrenal cortex for S100 and the lack of labelling in the chromaffin cells of the adrenal medulla were un- expected findings. That result prompted hope that S100 would be a diagnostic label for adrenal cortical
carcinomas. However, S100 did not label the adrenal cortical adenomas and most cortical carcinomas. In- stead, melan-A and a-inhibin were the most useful markers for the carcinomas because calretinin anti- body labelled the cortex unevenly and vimentin anti- body intensely labelled all adrenal components, including vessels and connective tissue of the cortex and medulla. Bovine adrenal tissues have similar im- munolabelling properties to human adrenal tumours. Human adrenal carcinomas label for melan-A, a-in- hibin and calretinin. Although all the carcinomas in the present study appeared grossly identical, the his- tomorphometry, calcific granule excess and S100 ex- pression of three of the carcinomas suggests that these represented a different neoplastic cell popula- tion, presumably from a different zone of the adrenal cortex. This variant has not been reported in other species.
Textbooks report that of domestic animal species, phaeochromocytomas are more commonly seen in cattle at slaughter (Capen, 2007; La Perle and Capen, 2007), and they are known to be a component of a multiple endocrine neoplasia syndrome in aged bulls (Wilkie and Krook, 1970; Sponenberg and McEntee, 1983). Because some human adrenal corti- cal carcinomas are reported to be difficult to distin- guish from malignant phaeochromocytomas because their labelling for neuroendocrine markers such as synaptophysin and NSE (Lack, 2007), the adrenal medullary labelling of bovine adrenal glands and bo- vine phaeochromocytomas was also investigated. Ad- ditionally, the haemorrhagic nature of some adrenal cortical tumours might cause confusion in diagnosis. As for human tissues, the bovine phaeochromoctyo- mas used as controls in this study were immunola- belled for tyrosine hydroxylase, synaptophysin, chromogranin-A and NSE, while adrenal adenomas and carcinomas did not. We did not try to quantify the prevalence of phaeochromocytomas at slaughter. During the study, large or malignant phaeochromo- cytomas were not encountered, and in order to obtain the phaeochromocytoma controls, many adrenal glands of normal gross appearance were examined. The gross and histological description in the report of one phaeochromocytoma (West, 1975) is identical to that of the cortical carcinomas of our study. The re- port predates the use of IHC, and one wonders if hae- morrhagic cortical carcinomas have been occasionally misdiagnosed as phaeochromocytomas.
Adrenal cortical carcinomas have a characteristic appearance grossly and microscopically in mature cattle. They appear to be non-functional and unilat- eral. With time, they metastasize via the vena cava primarily to the lung and sometimes invade the liver, but presumably in early stages, they may be noted as
intraluminal vena caval projections without distant metastases. Melan-A and a-inhibin are useful immu- nohistochemical markers for confirming a diagnosis of the primary and metastatic lesions. More studies should be done to clarify if differences in S100 label- ling represent tumours derived from different areas of the cortex or a variation in differentiation or neo- plastic progression. Bovine adrenal cortical carcino- mas are similar to adrenal cortical carcinomas in man, and cultures derived from these tumours may be valuable for study of human adrenal neoplasia.
Acknowledgments
The authors acknowledge the technical assistance of Dr. A. Ambrus in immunolabelling the tumours and funding support provided by the Texas Agricultural Experimental Station.
Conflict of Interest Statement
The authors have no financial or personal relation- ships with other people or organizations that could in- appropriately influence this work.
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[ Received, April 11th, 2012 Accepted, September 24th, 2012 ]