THE AMERICAN JOURNAL OF SURGICAL PATHOLOGY
D. Wolters Kluwer
Immunoreactivity for A103, an Antibody to Melan-A (Mart-1), in Adrenocortical and Other Steroid Tumors
Busam K. J. M.D .; Iversen, K. B.A .; Coplan, K. A. M.Sc .; Old, L. J. M.D .; Stockert, E. Ph.D .; Chen, Y-T. M.D .; McGregor, D. M.D .; Jungbluth, A. M.D.
The American Journal of Surgical PathologyAmerican Journal of Surgical Pathology. 22:p 57-63, January 1998.
Author Information
From the Department of Pathology, Memorial Sloan-Kettering Cancer Center (K.J.B.), Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center (K.I., K.A.C., L.J.O., E.S., Y-T.C., A.J.), and Department of Pathology, Cornell Medical College (Y-T.C.), New York, New York, USA; and Ludwig Institute for Cancer Research, Melbourne Branch, Melbourne, Australia (D.M.).
Address correspondence and reprint requests to Dr. K.J. Busam, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA.
Abstract
The Melan-A (MART-1) gene encodes an antigen recognized by cytotoxic T cells. It has been said to be restricted in its expression to melanocytes. However, here we report the presence of immunoreactivity for A103, an antibody to Melan-A, in five adrenocortical adenomas, 16 primary and 13 metastatic adrenocortical carcinomas, four Leydig cell tumors of the testis, and three Sertoli-Leydig cell tumors of the ovary. To evaluate the potential diagnostic role of this antibody, we studied immunoreactivity for A103 in 111 carcinomas, 40 germ cell tumors, and 33 miscellaneous nonmelanocytic epithelioid tumors. All of them were negative for A103. Our findings suggest that once melanoma is excluded, A103 can aid in the recognition of steroid hormone-producing tumors and may be particularly useful in the diagnosis of adrenocortical carcinoma. The presence of immunoreactivity for A103 practically excludes any other carcinoma that may enter into the differential diagnosis of adrenocortical tumors.
In an attempt to develop immunotherapy for malignant melanoma, a number of melanoma-associated antigens have been identified and characterized.3,4,7,15,17,27,34-36 Melan-A (MART-1) is such an antigen, which is recognized by autologous cytotoxic T cells.6,9,17,18 Its gene was cloned from the human melanoma cell line SK-Mel-29.2 The same gene was independently cloned and designated MART-1.17
Analysis of messenger RNA (mRNA) in normal human tissue and cells showed that Melan-A expression is limited to melanocytes in the skin and the retina but is not found in other normal tissues tested.9,17 Evaluation of tumor tissues confirmed specificity for melanocytes: Melan-A mRNA has been found in most melanoma specimens tested to date, but not in any other human cancer. 2,6,9-11,17,21
Monoclonal antibodies against recombinant Melan-A protein have since been generated by two separate groups: A103 by Chen et al.6 and M2-7C10 by Fetsch et al. 10 Initial studies with the antibodies appear to confirm restriction of this protein to melanocytes.2,6,10,11,18,21 However, using the antibody A103, we have observed immunoreactivity for Melan-A also in a limited number of other cell types, including cells of the adrenal cortex, Leydig cells of the ovary and testis, Sertoli cells, theca and granulosa cells of the mature ovarian follicle, and luteal cells of the corpus luteum (Jungbluth et al., manuscript in preparation).
Based on this observation, we investigated the potential diagnostic use of immunoreactivity for A103 focusing on the recognition of adrenocortical tumors. We studied five adenomas (ACA), 16 adrenocortical carcinomas (ACCs), and 13 metastases from ACC. We also examined immunoreactivity for A103 in other steroid hormone-producing tumors, including Leydig cell tumors (LCTs) of the testis and Sertoli-Leydig cell tumors (SLCTs) of the ovary, and in 111 carcinomas, 40 germ cell tumors, and 33 other nonmelanocytic epithelioid tumors.
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MATERIALS AND METHODS
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Case Selection
Five ACAs, 16 ACCs, 13 metastatic ACCs (13 tumor nodules of eight patients), 4 LCTs, 4 SLCTs, and 184 other tumors (Table 1), were retrieved from the archives of the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York. The
majority of the tumors listed in Table 1 were studied on multitissue blocks (10 different tumor types with four different examples of each type present on one block).
| Tumor type | No. of tumors | Staining for A103 |
|---|---|---|
| Leydig cell tumor of testis | 4 | 4 |
| Sertoli-Leydig cell tumor of ovary | 4 | 3 |
| Renal cell carcinoma (clear cell type) | 14 | None |
| Hepatocellular carcinoma | 5 | None |
| Adenocarcinoma of the lung | 4 | None |
| Adenocarcinoma of the stomach | 4 | None |
| Adenocarcinoma of the colon | 4 | None |
| Adenocarcinoma of the pancreas | 4 | None |
| Adenocarcinoma of the endometrium | 4 | None |
| Serous adenocarcinoma of the ovary | 4 | None |
| Endometrioid adenocarcinoma of the ovary | 4 | None |
| Mucinous adenocarcinoma of the ovary | 4 | None |
| Adenocarcinoma of the prostate | 4 | None |
| Ductal carcinoma of the breast | 4 | None |
| Lobular carcinoma of the breast | 4 | None |
| Thyroid carcinoma, follicular type | 4 | None |
| Thyroid carcinoma, papillary type | 4 | None |
| Thyroid carcinoma, anaplastic type | 4 | None |
| Thyroid carcinoma, Hurthle cell type | 4 | None |
| Thyroid carcinoma, medullary type | 4 | None |
| Parathyroid carcinoma | 4 | None |
| Urothelial carcinoma of the bladder | 4 | None |
| Squamous cell carcinoma of the lung | 4 | None |
| Squamous cell carcinoma of the head and neck* | 4 | None |
| Squamous cell carcinoma of the cervix | 4 | None |
| Basal cell carcinoma | 4 | None |
| Salivary gland adenocarcinomat | 4 | None |
| Mesothelioma | 4 | None |
| Pleomorphic adenoma of the parotid | 4 | None |
| Angiosarcoma | 4 | None |
| Giant cell tumor of soft tissue | 4 | None |
| Granular cell tumor | 4 | None |
| Islet cell tumor | 4 | None |
| Pituitary adenoma | 4 | None |
| Seminoma of testis | 4 | None |
| Dysgerminoma of ovary | 4 | None |
| Embryonal carcinoma of testis | 4 | None |
| Yolk sac tumor of testis | 4 | None |
| Mature teratoma of testis | 4 | None |
| Immature teratoma of ovary | 4 | None |
| Immature teratoma of testis | 4 | None |
| Nongestational choriocarcinoma | 4 | None |
| Gestational choriocarcinoma | 4 | None |
| Implantation site trophoblastic tumor | 4 | None |
| Pheochromocytoma | 5 | None |
* Two tongue and two laryngeal carcinomas.
t Two polymorphous low grade adenocarcinomas, one carci- noma ex pleomorphic adenoma and one mucoepidermoid carci- noma.
Immunoreactivity for A103 in various tumors
All cases were rereviewed histologically. All primary adrenocortical tumors were classified as ACA or ACC according to previously defined criteria.37,38 The ACAs in this series ranged in weight from 9 g to 55 g (mean 31.5). The ACCs ranged in weight from 170 to 2,600 g (mean 600). All metastatic adenocortical tumors had documented primary carcinoma. The slides of those primary lesions were reviewed to confirm the diagnosis. All LCTs of the testis and all SLCTs of the ovary were benign. All renal cell carcinomas (RCCs) had a classic gross and microscopic appearance with a pure clear cell cytology. They were graded according to the criteria of Fuhrmann. 13 Six RCCs were of grade II, three of grade III, and one of grade IV.
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Antibodies
A103, a mouse monoclonal antibody (mAb) against recombinant human Melan-A, has been described before.6 The antibody was diluted in 2% (wt/vol) bovine serum albumin at a final concentration of 7.5 µg/ml. HMB-45, an mAb reactive with melanoma antigen glycoprotein 100 was obtained commercially from Dako. It was applied at a dilution of 1:50 (wt/vol). The mAb to S-100 protein was obtained from Biogenics and used at 1:5,000 (vol/vol). Cam 5.2 was obtained from Becton-Dickinson in a prediluted solution and further diluted 10-fold. AE1/AE3 was purchased from Boehringer Mannheim and used at a final dilution of 1:1,000 (vol/vol). Epithelial membrane antigen (EMA) and vimentin were obtained from Dako and applied at a dilution of 1:1,000 (vol/vol). Isotype control antibodies (Becton-Dickinson) were run as negative controls in parallel at the same concentration as the test antibodies.
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Immunohistochemistry
Sections were taken from paraffin blocks. They were deparaffinized in xylene and rehydrated in a series of graded alcohols. An antigen retrieval technique was used for the antibodies A103, HMB-45, and anti-S-100 protein. The slides were incubated in 10 mM citrate buffer, pH 6.0, at 121°℃ for 10 minutes in a steam autoclave.
Immunohistochemistry was performed with an ABC (Vector) system, using horse antimouse secondary antibodies (Vector, 1:200, vol/vol) and DAB (Sigma) as the chromogen. The slides were counterstained with Mayer’s hematoxylin (Sigma) and dehydrated.
RESULTS
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A103 Immunoreactivity in Adrenocortical Tumors
Five adrenocortical adenomas, 16 primary adrenocortical carcinomas, and 13 metastatic adrenocortical tumors were examined for immunoreactivity for A103, anti-S- 100 protein, and HMB-45. Although the tumor cells lacked staining for anti-S-100 and HMB-45, A103 immunoreactivity was present in every single adenoma, carcinoma, and metastasis (Table 2). All ACAs (Fig. 1), and all ACCs showed strong and diffuse ☒ granular cytoplasmic staining in all or the majority of cells (Fig. 2), except for one, in which staining was only focal. In selected cases of primary or metastatic ACC, in which the diagnosis was difficult, additional immunohistochemistry was performed for cytokeratins (Cam 5.2, AE1/AE3), EMA, and vimentin. All four of these cases were positive for vimentin and completely negative for cytokeratins and EMA.
| Antibody | ACA | ACC primary | ACC metastatic |
|---|---|---|---|
| A103 | 5/5 | 16/16 | 13/13 |
| S-100 | 0/5 | 0/5 | 0/16 |
| HMB-45 | 0/5 | 0/5 | 0/16 |
Immunohistochemical staining of adrenocortical tumors
Immunoreactivity for A103 in adrenocortical adenoma.
Immunoreactivity for A103 in adrenocortical carcinoma metastatic to liver.
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A103 Immunoreactivity in Leydig Cell Tumors and Sertoli-Leydig Cell Tumors
Four LCTs of the testis and four SLCTs of the ovary were examined for the presence of immunoreactivity for A103. All LCTs of the testis and three of four SLCTs of the ovary were positive for this antibody (Table 2). A103 immunoreactivity resulted in granular cytoplasmic staining in LCTs (Fig. 3), and SLCTs (Fig. 4). Although in SLCTs, positive immunohistochemical staining was predominantly seen in Leydig cells, a few Sertoli cells were also positive (Fig. 4). The one SLCT that was completely negative for A103 was poorly differentiated, displaying almost exclusively a spindle cell morphology.
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Lack of Immunoreactivity for A103 in Other Carcinomas or Epithelioid Tumors
One hundred eleven carcinomas, mainly adenocarcinomas and squamous cell carcinomas from various organs and sites, including 14 renal cell carcinomas and five hepatocellular carcinomas, were examined for the presence of immunoreactivity for A103. They were all negative for A103 (Table 1). Furthermore, 40 germ cell tumors and 33 additional nonmelanocytic epithelioid tumors were analyzed and found to be negative for A103 (Table 1).
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DISCUSSION
Melan-A expression has been thought to be entirely restricted in its expression to melanocytes based on mRNA expression and immunohistochemical studies.2,6,9- 11,17,18,21 However, our results demonstrate immunoreactivity of benign and malignant adrenocortical tumors, LCTs, and SLCTs for A103, an antibody that recognizes Melan-A. Most studies investigating the expression of Melan-A by
immunohistochemistry had not included examination of adrenocortical tissue. No previous study has examined LCTs or SLCTs. In the one study by Fetsch et al.,11 in which among other normal tissue and tumors six normal adrenal glands and six adrenocortical carcinomas were analyzed for the presence of MART-1, no immunoreactivity was detected for the murine monoclonal IgG2 antibody M2-7C10. A direct comparison of M2-7C10 and A103 would resolve this tissue, and such analyses are currently ongoing. The difference between A103 and M2-7C10 may be due to the difference in antigenic epitopes recognized by these two antibodies. Differences in immunohistochemical methodology also may play a role. 10,11
Although we clearly demonstrate immunoreactivity for A103 in adrenocortical tissue, we are aware of the fact that this observation does not prove the presence of true Melan-A protein in adrenocortical cells. Coulie et al. did not detect Melan-A mRNA in normal adrenal tissue by reverse-transcriptase polymerase chain reaction, 2 and our own preliminary attempts to identify the gene in adrenocortical tissues and normal testes have so far been unsuccessful (data not shown). These findings suggest that the immunoreactive epitope recognized by the antibody A103 in adrenocortical and other steroid hormone-producing cells may be an immunologically crossreacting but genetically different product from Melan-A. The finding that M2-7C10 did not react with normal adrenal gland also suggests this interpretation.
However, irrespective of whether the antibody recognizes exclusively Melan-A or also another protein, the positive immunoreactivity is a consistent finding, which we explored for its potential diagnostic use focusing on adrenocortical tumors. As our findings indicate, A103 does not discriminate between benign and malignant adrenocortical cells: both ACA and ACC are A103-positive. Thus, the diagnostic role of A103 can only be to aid in the recognition of adrenocortical histogenesis and not to predict the clinical behavior of an adrenocortical tumor.
The main challenge for the pathologist with regard to the differential diagnosis of adrenocortical tumors is to distinguish them from other carcinomas, 12,20,25,31,32,39 especially RCCs and HCCs, and malignant melanoma.20,25,39 In such cases, immunohistochemical studies may be required for a more definitive diagnosis. Because ACCs are negative for S-100 protein and HMB-45, the presence of immunoreactivity for these markers excludes ACCs and leads to a diagnosis of melanoma instead.5,14,20,25,32 The distinction of ACCs from other carcinomas or epithelioid tumors is more problematic, and it is this diagnostic problem for which A103 seems to be most valuable.
ACCs lack a pathognomonic immunohistochemical profile.20 ACCs are negative for EMA and variably positive for cytokeratins (CK).8,14,20,23,24,29,30,39 The presence
of CK 18 and 19 in ACCs has been confirmed by Western immunoblot analysis and on occasion can be demonstrated immunohistochemically if fresh-frozen tissue is used or if the sections are pretreated with a protease. 14 However, most tumors are negative for CK in routinely fixed, paraffin-embedded tissue.20,29,39 Vimentin is said to be positive in many ACCs, but the frequency reported in the literature varies considerably.20 A significant number of ACCs also may be positive for synaptophysin. 16 Despite the variable results, the immunohistochemical absence of CK and EMA expression in fixed sections, combined with positivity for vimentin, support a diagnosis of ACC if the histologic and clinical findings suggest ACC.20,39 However, there is sufficient immunophenotypic overlap with other tumors that diagnostic certainty cannot always be achieved. For example, not all RCCs are positive for CK and EMA,14,20,22 and some melanomas are negative for S-100 protein and HMB- 45.1,5,32 Because differentiation between some carcinomas, such as RCC versus ACC or melanoma versus ACC, may not be possible in an individual case, there is a need for additional markers that can recognize adrenocortical cells more distinctly.
RCCs and HCCs are probably the two carcinomas whose distinction from a steroid hormone-producing tumor, in particular ACC, is diagnostically most problematic.20,25,31,39 The distinction may be difficult not only because of overlapping histologic and immunohistochemical findings,12,22,31,39 but also because of confusing clinical situations. RCCs, for example, may present as solitary adrenal metastasis, 12,25 and ACCs may present with direct extension into the renal parenchyma.20,25 Likewise, ACC metastatic to the liver can mimic HCC, and vice versa, HCC metastatic to the adrenal can mimic ACC.20,25 Our findings suggest that immunohistochemical studies using the antibody A103 may be decisive in such diagnostic dilemmas. Positivity for A103 practically excludes any extra-adrenal carcinoma.
Although A103 can clearly be of help in excluding extra-adrenal carcinomas, it needs to be emphasized that A103 fails to discriminate between adrenocortical tumors and other tumors of steroid hormone-producing cells as illustrated for LCTs and SLCTs. Therefore, adrenocortical tumors need to be distinguished from extra-adrenal steroid tumors on histologic and clinical grounds 19,20,26,40 Primary adrenocortical tumors and LCTs, for example, can be distinguished from each other based on the clinical setting of a testicular versus adrenal mass and histologically on the basis of pathognomonic crystalloids of Reinke, which are present in approximately 25-40% of LCTs.26 Conversely, extratesticular or metastatic LCTs may be exceedingly difficult to distinguish from ACC. Fortunately, however, such LCTs are exceedingly rare and the clinical setting is usually distinctly different from ACC.
Although we probed a large spectrum of epithelial or epithelioid malignancies for possible immunoreactivity for A103 (Table 2), there are still other tumor types, which we did not study, such as mesenchymal, lymphoid, or neuroendocrine tumors. We did not analyze them in this study because in practical terms they are easily distinguished histologically and immunohistochemically from ACC. Furthermore, examination of various types of tissue by Jungbluth et al. failed to show immunoreactivity for A103 in mesenchymal, lymphoid, or neuroendocrine tissues, including the adrenal medulla (Jungbluth et al., manuscript in preparation). The only mesenchymal tumor that reacted with A103 was angiomyolipoma (Jungbluth et al., manuscript in preparation). Because angiomyolipomas can easily be distinguished morphologically from adrenocortical tumors, their immunoreactivity for A103 does not diminish the diagnostic value of A103 in the recognition of adrenocortical tumors. Among neuroendocrine tumors, pheochromocytoma was the only tumor that we examined because this tumor type may indeed enter into the differential diagnosis of ACC. All five pheochromocytomas tested in this study were negative for A103 (Table 2). With regard to other steroid tumors, such as granulosa cell tumors, the-comas, and luteomas, which may be A103-positive, we did not include them in this study. Their clinical and pathologic presentation is quite different from ACC so that diagnostic confusion between these lesions and ACC should practically not occur.
There is one other antibody that has previously been reported to aid in the recognition of adrenocortical tumors: D11, which was reported to be specific for adrenocortical cells.28 This monoclonal antibody recognizes several 59-kDa proteins capable of binding apolipoprotein E. In contrast to A103, which stains the cytoplasm, immunoreactivity for D11 typically results in nuclear staining of adrenocortical cells. However, the potential immunohistochemical expression of this marker in Leydig cells or other steroid hormone-producing cells was not investigated. Furthermore, subsequent studies showed that this antibody was not entirely specific for ACC. Immunoreactivity for D11 also was seen in all 20 hepatocellular carcinomas examined, as well as in one RCC and in three of five lung carcinomas. 33
Thus, the antibody A103 currently seems to be the most discriminating tool to distinguish between ACC, RCC, HCC, and other carcinomas. Our proposed role then for A103 in the differential diagnosis of adrenocortical tumors is illustrated and summarized in Fig. 5. If an epithelioid malignancy is A103 positive, the main tumor that needs to be excluded immunohistochemically is melanoma. If melanoma is ruled out, the presence of A103 immunoreactivity practically excludes an epithelial or epithelioid malignancy other than ACC. As mentioned before, the only other epithelioid tumor that may have to be considered is LCT.
Extra-adrenal carcinoma
Other neoplasms
CK +
CK -
EMA +
EMA -
A103 -
A103 +
S-100 -
S-100 +
HMB-45-
HMB-45 +
Adrenocortical carcinoma*
Melanoma
Proposed algorithm for the use of A103 in the diagnosis of ACC. Malignant Leydig cell tumor needs to be excluded.
Acknowledgment: We thank Dr. J Rosai for valuable comments and for help with the multitissue tissue blocks.
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Keywords:
Melan-A; MART-1; Steroid tumors; Adrenocortical tumors; Melanocytes C Lippincott-Raven Publishers