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Ann Thorac Surg 2002;73:403-406
© 2002 The Society of Thoracic Surgeons

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Original article: general thoracic

Detection of estrogen receptor by immunohistochemistry in pulmonary adenocarcinoma

^a Department of Pathology, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
^b Division of General Thoracic Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA

* Address reprint requests to Dr Dabbs, Department of Pathology, St. Agnes Healthcare, 900 Caton Ave, Baltimore, MD 21229, USA
e-mail: d.dabbs{at}att.net

Presented at the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.

	Abstract

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Background. The distinction between primary adenocarcinoma and metastatic breast carcinoma in the lung is important for therapeutic purposes. There is a good deal of morphologic overlap between primary pulmonary adenocarcinoma and breast carcinoma metastatic in the lung. Many diagnosticians rely upon the presence of estrogen receptor (ER) in tumors of the lung in women in order to make a pathologic diagnosis of metastatic breast carcinoma. There are conflicting data in the literature regarding the presence of ER in lung carcinomas. In this study, we examined primary lung adenocarcinomas with monoclonal antibodies to two different clones to ER (clone 6F11 and clone 1D5), and progesterone receptor by the immunoperoxidase method in order to ascertain if ER is detectable in primary lung adenocarcinomas.

Methods. Twenty-five resected solitary pulmonary nonmucinous bronchioalveolar carcinomas (15 female, 10 male) and 20 resected solitary pulmonary adenocarcinomas of no special type (12F, 8 mol/L) were studied by the immunohistochemical method using heat-induced epitope retrieval. Immunostaining was semiquantitated, and positive results included nuclear staining for ER and progesterone receptor. All of these tumors were documented as primary pulmonary adenocarcinomas clinically and pathologically.

Results. Nuclear ER was seen only with the 6F11 clone, in 56% of the bronchioalveolar type and 80% of the no special type. No nuclear ER was seen in carcinomas utilizing the 1D5 clone. There was no progesterone receptor detectable in carcinomas.

Conclusions. Estrogen receptor is present in the majority of lung adenocarcinomas, and detection of ER in lung adenocarcinomas is dependent upon the antibody clone that is used. Epitope recognition may account for the differences in immunoreactivity between these two antibodies, although a cross-reactive antibody reaction cannot be completely excluded. Further study is warranted to discern the nature of the 6F11 clone immunoreactivity with nuclei of lung adenocarcinomas. The clinical significance and ramifications of ER in pulmonary adenocarcinomas remain unknown. Caution should be exercised by clinicians and pathologists in accepting a diagnosis of metastatic breast carcinoma in lung based on the presence of ER detected by clone 6F11.

	Introduction

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Breast carcinoma is the neoplasm of highest prevalence in women, and lung carcinoma is the neoplasm with the highest incidence. As a result, it is not uncommon to encounter women who present with a lung mass and who have a history of breast carcinoma. The correct diagnosis is crucial because of the differences in treatment and prognosis. Breast carcinomas are often estrogen receptor (ER) positive, and clinicians and pathologists alike often assume that an ER-positive carcinoma is breast carcinoma. However, the literature cites numerous different types of tumors from origins in traditionally nonestrogen ("nontarget") responsive tissues that may express ER in the neoplastic state. In this study, we examine primary lung adenocarcinomas with two different antibodies to ER by the immunohistochemical technique in order to determine whether ER is present in pulmonary adenocarcinoma and to what degree these tests would be useful to delineate primary lung adenocarcinomas from ER-positive metastatic breast carcinoma in the lung.

	Material and methods

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Forty-five resected primary adenocarcinomas of the lung were studied for this study. Twenty-five tumors were of the nonmucinous bronchioalveolar type (15 female, 10 male), and 20 were moderately differentiated and of the not otherwise specified type (12 female, 8 male). Paraffin blocks were deparaffinized, rehydrated, and subjected to boiling in 0.01 mol/L citrate buffer (heat-induced epitope retrieval [HIER]) before incubating with antibodies to estrogen receptor clone ER1D5 (Dako, Carpinteria, CA) and clone 6F11 (Ventana Medical Systems, Tucson, AZ). Antibody localization was performed using the labeled streptavidin biotin method with diaminobenzidine. Positive immunostaining was recorded for ER and progesterone receptor as nuclear staining: 1+ (10% of cells positive), 2+ (11% to 50% positive), and 3+ (greater than 50% positive). Appropriate positive and negative controls were tested simultaneously with the test slides.

	Results

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All 45 cases of lung adenocarcinoma were negative for ER with the ER1D5 clone. The same tumors showed a positive intranuclear immunostaining with clone 6F11 in 16 of 20 (80%) adenocarcinomas of no special type, and 14 of 25 (56%) in bronchioalveolar adenocarcinomas (Figs 1, 2). The majority of ER-positive carcinomas were greater than 1+ nuclear immunostaining (Table 1).

View larger version (133K): [in this window] [in a new window]   Fig 1. Histologic section of bronchioalveolar cell carcinoma showing nuclear positivity (arrow) for estrogen receptor 6F11 clone. (Original magnification, 250x).

View larger version (158K): [in this window] [in a new window]   Fig 2. Histologic section of adenocarcinoma of lung, not otherwise specified type, showing nuclear positivity (arrow) for estrogen receptor with 6F11 clone. (Original magnification, 400x).

	Comment

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This observation is important because the immunohistochemical techniques were uniform and utilized the most effective antigen retrieval method (HIER). To date, no ER immunoreactivity has been documented in lung adenocarcinomas with antibody clone 1D5, and we confirm this in our study. We also demonstrated the presence of ER using antibody clone 6F11 in the majority of pulmonary adenocarcinomas. As a result, antibody 6F11 should not be used in the pathologic differential diagnosis of pulmonary adenocarcinoma versus metastatic breast carcinoma.

ER immunoreactivity in tumors of so-called "nontarget" tissues (ie, tissues that are not normally responsive to circulating estrogens), have been described, and include the stomach [1], liver [1], gallbladder [1], pancreas [2], colon [3], lymphoma/leukemia [4–6], thymoma [6], few squamous cancers of the head and neck [7], central nervous system (gliomas and meningiomas) [8], thyroid [9], kidney [9], and lung [10–13]. In addition to carcinomas of the lung, sclerosing hemangioma and lymphangioleiomyomatosis of the lung are also ER positive [14]. Despite the presence of ER receptors in these tissues, hormonal manipulation in patients with these tumors has not proved fruitful in affecting prognosis [15, 16].

It is difficult to make comparisons between all of these studies because of the different methods used in tissue preparation, fixation times, antibodies utilized, and the wide variation in immunohistochemical techniques used without HIER. The studies include a mix of estradiol binding studies, dextran-coated charcoal assay, and immunohistochemistry. However, the weight of the evidence from these studies strongly supports the presence of some form of estrogen-related receptors in nontarget tissues, including the lung.

Caltagirone and associates [17] reported inhibition of growth of lung carcinoma cells in culture to tamoxifen and the antiestrogen quercetin. These investigators attributed the blockade of estrogen effect to binding of type II estrogen binding sites by the antagonists.

Vargas and associates [18] reported the presence of ER-related protein p29 in 98% of non-small cell carcinomas by immunohistochemistry, despite being unable to demonstrate ER receptors using antibody ER1D5 by immunohistochemistry.

Nunno and associates [19], in a study of 248 patients with non-small cell carcinoma, did not find ER receptors by immunohistochemistry using antibody ER1D5. Interestingly, ER has been detected with clone ER1D5 in tumors of other nontarget tissues [14].

The diagnosis of primary pulmonary adenocarcinoma is usually made by using a combination of clinical and pathologic studies; and in most cases, the diagnosis is straightforward. However, women with a history of breast carcinoma who present with a lung mass offer the most challenging situation to make a correct tissue diagnosis.

The patients in this study all had adenocarcinomas that were documented by clinical (no evidence of breast carcinoma) and pathologic (morphology and pathologic staging of resection specimens) methods. There was no appreciable difference in the presence of ER with antibody 6F11 between males and females, as immunoreactivity was present in males and females in approximately equal numbers.

There are other antibodies in the diagnostic armamentarium that may be used to distinguish primary lung from metastatic breast carcinoma in the lung, and some of these include CEA D14, gross cystic disease fluid protein 15, and TTF-1 [20]. When the pathologic differential diagnosis is between breast and lung carcinomas, CEA D14 clone and TTF-1 antibodies have a specificity for lung carcinoma near 95%, with sensitivities of 95% and 67%, respectively, for pulmonary non-small cell carcinomas. Gross cystic disease fluid protein is not observed in lung cancers, having a specificity for breast carcinoma of 95% and a sensitivity of 55%. The appropriate use of an ER antibody would be to use it to assay a known case of breast carcinoma, diagnosed with the aforementioned antibodies.

Because small biopsies or fine needle aspiration biopsy specimens are often used to obtain tissue in women with a lung mass and history of breast carcinoma, caution must be used interpreting the above-mentioned antibodies, because positive immunostaining for any of these antibodies may be regional within a tumor, resulting in the possibility of false-negative diagnoses.

In summary, there is substantial evidence for the presence of ER or ER-related proteins in pulmonary adenocarcinomas. The ER should not be used as a diagnostic tool to distinguish primary lung adenocarcinoma from metastatic breast carcinoma, because both tumors may be positive for ER, especially the ER 6F11 clone. The clinician and diagnostic pathologist need to be aware of the profound differences in immunoreactivity between the ER1D5 and 6F11 clones when examining tumors in the lung that are suspected of being a metastasis, especially from the breast.

	Discussion

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DR JOSHUA R. SONETT (Baltimore, MD): I enjoyed your presentation, Dr Landreneau. In regards to therapeutic efficacy and other receptors, did you look at HER-2/neu?

DR LANDRENEAU: We have not looked at that yet in lung cancer. We are seeing HER-2/neu expression in some of the work we are doing, in about 30% of the patients that we will resect with primarily adenocarcinomas, less than the squamous cells.

DR SONETT: It might be interesting, the ones that are estrogen receptor positive, because that is at least an easy target for clinical studies with HER-2/neu treatment. Thanks.

DR HIRAM C. FERNANDO (Pittsbugh, PA): I enjoyed the presentation. Have you thought about biopsying these patients beforehand to help you decide whether you would be doing a lobectomy in someone with a prior history of breast cancer?

DR LANDRENEAU: No, we have not. This is a retrospective review of just experience over the last year or so. With this information in mind, I think that if a patient was positive for the CEA D16, then I think I would be much more inclined to take a more anatomical resection approach, leading me to believe that this was a primary adenocarcinoma of the lung.

DR MALCOLM M. DeCAMP (Cleveland, OH): Rod, I enjoyed that very much. As you know, there appear to be significant gender differences in outcomes in non-small cell lung cancer. As you looked at the estrogen receptor expression, even though it was qualitatively equivalent across genders, in terms of the intensity of expression, did the women that were ER positive have greater expression?

DR LANDRENEAU: There really was not any trend there, Mal. There are other studies, however, that have documented a more favorable survival among women with adenocarcinoma, and it may have something to do with these hormonal issues, but we could not see a trend in this small data set.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Rodney J. Landreneau Richard H. Maley Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dabbs, D. J. Articles by Silverman, J. F. Search for Related Content PubMed PubMed Citation Articles by Dabbs, D. J. Articles by Silverman, J. F. Related Collections Lung - cancer