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J Thorac Cardiovasc Surg 1994;108:153-157
© 1994 Mosby, Inc.

GENERAL THORACIC SURGERY

Sex hormone receptors in non-small-cell lung cancer in human beings

Madison, Wis., and Lebanon, N.H.

Received for publication Oct. 13, 1993. Accepted for publication Dec. 12, 1993. Address for reprints: Charles C. Canver, MD, Division of Cardiothoracic Surgery, University of Wisconsin-Madison Medical School, H4/352 Clinical Science Center, 600 Highland Ave., Madison, WI 53792.

Abstract

To investigate whether sex hormone receptors exist in the resected non-small-cell lung cancer in human beings and to determine a link between the pulmonary carcinogenesis and the sex receptor status of the lung cancer tissue, we reviewed the case histories of 64 patients who underwent resectional therapy for non-small-cell lung cancer between 1988 and 1990 (38 men and 26 women, mean age 65 years). Mouse monoclonal immunoglobulin G antibodies were used for immunohistochemical detection of estrogen receptors and progesterone receptors in the acetone-fixed specimen. The control group consisted of normal lung tissue from the patients with and without bronchogenic carcinoma and breast cancer tissue from the patients with estrogen and progesterone receptor immunoreactivity. No evidence of estrogen and progesterone receptor immunoreactivity was present in the normal lung tissue. All but two patients had immunoreactivity (97%) for estrogen receptors in the lung cancer tissue (p < 0.001). Immunoreactivity for progesterone receptors was absent or weak in the majority (p > 0.05). The differences for sex and for histologic subtypes were not statistically significant. Observed actuarial survival at 3 years was 83% for all patients with estrogen receptor immunoreactivity: 94% for women and 75% for men (p < 0.05). We found no correlation between the hormone receptor status and the type, clinical features, or prognosis of the non-small-cell lung cancer. We conclude that an abundance of estrogen receptors is hosted only in cancerous tissue, not in normal pulmonary tissue. Improved identification and definition of estrogen receptors in the nontarget lung cancer tissue offer a possibility of antiestrogen therapy for patients with advanced bronchogenic carcinoma. (J THORACCARDIOVASCSURG1994;108:153-7)

Lung cancer is the leading cause of cancer death in both women and men. Although in the past this neoplasm occurred primarily in men, it is rapidly becoming more prevalent in women. Carcinoma of the lung recently surpassed breast carcinoma as the most common cancer killer in women. ¹ The exact reason for this is unknown. It is plausible to consider that a sex-specific factor, such as steroid receptors, may play a role in the distribution of bronchogenic cancer in men and women. In the past it was believed that sex hormones such as estrogens and progesterones exert their known function primarily on target organs—the breast, uterus, and pituitary gland. ^2,3 However, the demonstration of steroid receptors in a host of neoplastic tissues has generated a growing interest in focusing at the nontarget tissue level, as the estrogen receptor and progesterone receptor assays become widely used.

Steroid receptors are widely distributed in normal nontarget tissues such as skin, ⁴ bone, ⁵ and thyroid. ⁶ The existence of steroid receptors was also demonstrated in a wide array of malignant tissues, such as hepatocellular carcinoma, ⁷ colorectal cancer, ^8,9 osteosarcoma, ¹⁰ meningioma, ¹¹ and malignant melanoma. ^{12, 13} Whereas estrogen receptors have been identified in normal lung tissue of certain animals, ¹⁴ sex hormone receptors have never been demonstrated in human lung cancer tissue.

The purpose of this study was to investigate whether sex hormone receptors exist in non-small-cell lung cancer tissue and to determine any clinical significance of the sex hormone receptor status for the patient with lung cancer.

PATIENTS AND METHODS

Representative tissue material for the immunohistochemical analysis of estrogen and progesterone receptors was obtained from 64 patients who had undergone resectional therapy for primary non-small-cell carcinoma of the lung between 1988 and 1990. The mean age of the patients was 62 years, with a range between 36 and 85 years. There were 26 women (41%) and 38 men (59%). The records of these patients were studied to assess presenting preoperative signs and symptoms, chest roentgenographic findings, diagnostic studies, indications for operation, operations performed, postoperative complications, the operative mortality (defined as death within the first 30 days after operation), postoperative adjuvant therapy, and long-term outcome. Histologically, there were 25 adenocarcinomas, 18 squamous cell carcinomas, 14 poorly differentiated carcinomas, 6 large cell carcinomas, and 1 bronchoalveolar carcinoma. Patients with small-cell lung cancer and benign lung tumors were excluded from the study. Perioperative data were obtained from the patients' hospital records. Follow-up information was collected through direct patient contact, from the patient's personal physician, or by telephone interview with surviving patients or family members.

All tumors were histologically confirmed. Using the avidin-biotin-peroxidase complex method ¹⁵ and mouse monoclonal immunoglobulin G antibodies, we examined paraffin-embedded sections from the formalin-fixed tumors. Because of the retrospective nature of this study, none of the cases included had been subjected to analysis for estrogen receptors by the dextran-coated charcoal method. Normal lung tissue from the patients with and without bronchogenic carcinoma and breast cancer tissue from the patients with estrogen and progesterone receptor immunoreactivity were used as control groups. Immunostains were reviewed in a blinded fashion by two authors (V.A.M. and P.L.V.). Tumors were interpreted as "positive" only if both observers agreed on the presence of definitive immunoreactivity in at least 10% of the neoplastic cells.

Follow-up data were available in all patients and averaged 38 months, ranging between 11 and 48 months. Patient survival is expressed by actuarial analysis according to the method of Kaplan and Meier ¹⁶ and is plotted at semiannual intervals with the day of operation used as the starting time. Parametric data analysis was done by the use of Student's t and ² tests. The log-rank test was used for the comparison of survival curves. Differences resulting in a p value of less than 0.05 were considered significant.

RESULTS

The cancer was located in the right lung in 48 patients (75%) and in the left lung in 16 (25%). The operations performed were lobectomy in 45 patients (67%), pneumonectomy in 12 (18%), wedge excision in 5 (8%), and combined lobectomy and wedge resection in 2 patients (3%). The histologic diagnoses of lung cancer are listed in Table I. Ipsilateral hilar lymph nodes were involved histologically in 14 patients (22%) and uninvolved in 44 patients (68%); their involvement was not specified in 6 (10%). The clinical and surgical stage varied from stage I to stage IIIa.

View larger version (123K): [in this window] [in a new window]   Fig. 1. Nonneoplastic lung parencyhma with no evidence for estrogen receptor activity (avidin-biotin complex immunostain, original magnification x 200).

View larger version (141K): [in this window] [in a new window]   Fig. 2. Immunoreactivity for estrogen receptor protein in a squamous cell lung carcinoma, manifested by nuclear staining. Note lack of staining inadjacent normal bronchial mucosa (avidin-biotin complex immunostain, original magnification x 200).

There were nine deaths, occurring in one woman and eight men. The cause of death was tumor recurrence and distant metastasis in five patients (56%), followed by cardiac failure in two (22%) and multiple organ failure in two (22%). Postoperative radiation therapy was given to three patients; combined chemotherapy and irradiation were administered in two patients. Observed overall survival for patients with estrogen receptor reactivity at 3 years was 83% (Fig. 3): 94% for the women and 75% for the men (p < 0.05).

View larger version (23K): [in this window] [in a new window]   Fig. 3. Survival curves of patients with immunoreactive estrogen receptors. Number of patients alive at a specific time point is shown in parentheses.

Immunocytochemical staining with specific monoclonal antibodies is the most commonly accepted method to provide conclusive evidence of the presence of estrogen and progesterone receptors in the neoplastic tissue of a target organ such as the human breast, prostate, and endometrium. ^17,18 The level of sex hormone receptors in the cancer tissue often is considered as an indicator for the selection of appropriate treatment. ³ The finding of steroid receptors in a wide array of nontarget neoplastic tissues may be indicative of their common role in the regulation of cancer growth irrespective of the organ involved.

Recently, it has been shown that steroid hormone receptors are a part of the steroid-thyroid-vitamin D₃ receptor superfamily. ¹⁹ A ligand-binding domain at the carboxylterminus and a deoxyribonucleic acid–binding domain in the middle portion of the molecule are characteristic for these receptors. The amino acid sequence for corticosteroids, sex steroids, thyroid hormone, vitamin D, and retinoic acid receptors is highly specific at these two regions. Each of these hormones is crucial in tissue differentiation and organ development. Despite the fact that the lung is an endocrine organ, the presence of estrogen and progesterone receptors have been reported in only a few cases of rare benign pulmonary neoplasms such as lymphangioleiomyomatosis, epithelioid hemangioendothelioma, and sclerosing pulmonary hemangioma. ^20,21 In the present work, immunocytochemical staining demonstrated the presence of estrogen receptors and absence of progesterone receptors in the target cell nuclei of non-small-cell lung cancer tissue. Estrogen receptors could not be demonstrated in the normal human lung tissue. Although the proteins found in estrogen and progesterone receptors share similar properties, the exact reason for their discordance in lung cancer tissue requires further investigation.

The functional role of sex hormone receptors in various nontarget neoplastic tissue is unclear. Because mutation of the receptor in the neoplastic tissue can cause altered function, it is controversial whether simply measuring the receptors by immunocytochemical staining represents the presence of genuine functional receptor. Our study is unable to determine whether the abundant amount of estrogen receptors in non-small-cell lung cancer are functional. Our efforts are now directed toward characterizing the roles of receptor steroid–binding proteins in other neoplastic lesions of the lung such as small-cell-lung cancer and metastatic bronchogenic cancer. A prospective study of estrogen receptor status on fresh lung cancer tissue is currently underway.

The distribution of sex receptors in non-small-cell lung cancer does not appear to be sex-specific; survival analysis of men and women is confounded by heterogeneous characteristics of the patient population, different histologic subtypes, and surgical stages. Nevertheless, this study clearly demonstrates the presence of estrogen receptors in non-small-cell lung cancer tissue, and this may lead to a new and beneficial avenue for adjuvant therapy in a disease with limited therapeutic options. If future investigations prove that sex receptors in lung cancer tissue are functional, a clinical trial that considers an antiestrogen preparation such as tamoxifen in the treatment of patients with lung cancer or in the control of recurrent bronchogenic cancer may be appropriate.

Acknowledgments

We thank Thomas Ausfeld, CBET, for statistical assistance.

Footnotes

From the Division of Cardiothoracic Surgery, University of Wisconsin-Madison Medical School, Madison, Wis.,^a and the Section of Pathology, Darmouth-Hitchcock Medical Center, Lebanon, N.H.^b

Read at the Forty-seventh Annual Meeting of the Society of Surgical Oncology, Houston, Tex., March 17-20, 1994.

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This Article Abstract 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): Charles C. Canver Robert M. Mentzer, Jr. Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Canver, C. C. Articles by Mentzer, R. M. Search for Related Content PubMed PubMed Citation Articles by Canver, C. C. Articles by Mentzer, R. M., Jr.