Diagnostic and Prognostic Impact of Progesterone Receptor Immunohistochemistry: A Study Evaluating More Than 16,000 Tumors

Viehweger, Florian; Tinger, Lisa-Marie; Dum, David; Gorbokon, Natalia; Menz, Anne; Uhlig, Ria; Büscheck, Franziska; Luebke, Andreas M.; Hube-Magg, Claudia; Hinsch, Andrea; Höflmayer, Doris; Fraune, Christoph; Lebok, Patrick; Weidemann, Sören; Lennartz, Maximilian; Jacobsen, Frank; Clauditz, Till S.; Krech, Rainer; Krech, Till; Marx, Andreas H.; Simon, Ronald; Burandt, Eike; Steurer, Stefan; Sauter, Guido; Minner, Sarah; Bernreuther, Christian

doi:https://doi.org/10.1155/2022/6412148

Analytical Cellular Pathology

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Abstract Introduction Methods Results Discussion Data Availability Ethical Approval Conflicts of Interest Authors’ Contributions Acknowledgments Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2022 | Article ID 6412148 | https://doi.org/10.1155/2022/6412148

Diagnostic and Prognostic Impact of Progesterone Receptor Immunohistochemistry: A Study Evaluating More Than 16,000 Tumors

Florian Viehweger,¹Lisa-Marie Tinger,¹David Dum,¹Natalia Gorbokon,¹Anne Menz,¹Ria Uhlig,¹Franziska Büscheck,¹Andreas M. Luebke,¹Claudia Hube-Magg,¹Andrea Hinsch,¹Doris Höflmayer,¹and Christoph Fraune¹ et al.

Academic Editor: Carmela Ricciardelli

Received29 Mar 2022

Accepted22 Jun 2022

Published08 Aug 2022

Abstract

Progesterone receptor (PR) is a member of the nuclear/steroid hormone receptor family of ligand-dependent transcription factors. It plays an important role in reproduction and mammary gland development and has various tissue-specific effects in nonreproductive organs. In diagnostic pathology, positive PR immunostaining is used to support a diagnosis of breast or gynecologic origin in a tumor. In this study, the expression of PR was analyzed by immunohistochemistry in 18,176 (interpretable: 16,445) samples from 147 different tumor types and subtypes in a tissue microarray format. PR immunostaining was detected in 57.4% of breast tumors, 28.6% of other gynecological tumors, and 1.8% of nongynecological and nonmammary tumors. Among the group of nongynecological and nonmammary tumors, particularly high rates of PR positivity were seen in neuroendocrine tumors (54.3%) and neuroendocrine carcinomas (35.7%) of the pancreas. A comparison with clinico-pathological parameters showed that reduced PR immunostaining was significantly associated with adverse histopathological and clinical features in breast carcinoma, endometrioid endometrial carcinoma, and pancreatic neuroendocrine tumors. In summary, our analysis of 147 different tumor types for PR immunostaining provides a ranking list of tumor entities according to their prevalence of PR positivity, helps to better understand the diagnostic utility of PR, and highlights the distinct PR positivity among neuroendocrine neoplasms of pancreatic origin.

1. Introduction

Progesterone receptor (PR) is a member of the nuclear/steroid hormone receptor family of ligand-dependent transcription factors. PR mediates the physiological effects of progesterone which plays an important role in the establishment and maintenance of pregnancy, hence the hormone’s name, which comes from the Latin pro gestationem. In addition to its effects in reproduction and mammary gland development [1], PR is involved in the regulation of various genes, affects cellular proliferation and differentiation in various nonreproductive tissues, exerts a neurosteroid activity in the central nervous system (reviewed in [2]), inhibits smooth muscle contractile activity in the gastrointestinal tract [3], and plays a role in development and maturation of the lung [4].

In diagnostic pathology, immunohistochemical detection of PR supports the diagnosis of a carcinoma of breast or gynecologic origin if cancers of unknown primary (CUP) are being evaluated [5]. However, many studies have shown that nonbreast and nongynecological tumors can also express estrogen and/or progesterone receptor. Data on PR immunostaining in the literature typically lacks associations with patient age, gender, or stage in cancer [6–14] and is overall highly variable. For example, the reported range of PR positivity ranges from 0 to 76% in colorectal cancer [6–8], from 0 to 52% in adenocarcinoma of the gall bladder [9, 10, 15, 16], from 0 to 85% in prostate cancer [11, 17, 18], from 0 to 63% in non-small-cell lung cancer [12, 19, 20], from 38.7 to 75.8% in papillary thyroid carcinoma [13, 14, 21–24], and from 15.2 to 100% in angiomyolipoma of the kidney [25–27]. These conflicting data are likely to be caused by the use of different antibodies, staining protocols, and interpretation criteria in these studies.

To better understand the diagnostic impact of PR immunohistochemistry, a comprehensive and highly standardized study analyzing a large number of tumors, especially from nongynecological and nonbreast tissues, is needed. Therefore, PR expression was successfully analyzed in more than 16,000 tumor tissue samples from 147 different tumor types and subtypes as well as 76 different nonneoplastic tissue types by immunohistochemistry in a tissue microarray (TMA) format in this study.

2. Material and Methods

2.1. Tissue Microarrays (TMAs)

The normal tissue TMA was composed of 8 samples from 8 different donors for each of 76 different normal tissue types (608 samples on one slide). The tumor TMAs contained a total of 18,176 primary tumors from 147 tumor types and subtypes. Detailed histopathological data on grade, pT, and pN status (HER2 status for breast cancer) were available from 2,139 breast cancers, 259 endometrial cancers, 192 neuroendocrine neoplasms, and 524 ovarian tumors. Clinical follow-up data were available from 877 patients with breast cancer. In these patients, the median follow-up time was 43 (range 1-88) months. The composition of both normal and tumor TMAs is described in detail in the results section. All samples were from the archives of the Institutes of Pathology, University Hospital of Hamburg, Germany; the Institute of Pathology, Clinical Center Osnabrueck, Germany; and Department of Pathology, Academic Hospital Fuerth, Germany. Tissues were fixed in 4% buffered formalin and then embedded in paraffin. One tissue spot (diameter: 0.6 mm) was transmitted from a tumor containing donor block in an empty recipient paraffin block. The use of archived remnants of diagnostic tissues for manufacturing of TMAs and their analysis for research purposes as well as patient data analysis has been approved by local laws (HmbKHG, §12) and by the local ethics committee (Ethics commission Hamburg, WF-049/09). All work has been carried out in compliance with the Helsinki Declaration.

2.2. Immunohistochemistry (IHC)

Freshly prepared TMA sections were immunostained in one day in one experiment. Slides were deparaffinized with xylol, rehydrated through a graded alcohol series, and exposed to heat-induced antigen retrieval for 5 minutes in an autoclave at 121°C in pH 7.8 buffer. Endogenous peroxidase activity was blocked with Dako Peroxidase Blocking Solution™ (Agilent, CA, USA; #52023) for 10 minutes. Primary antibody specific against PR (rabbit recombinant, MSVA-570R, #3332-570R; MS Validated Antibodies GmbH, Hamburg, Germany) was applied at 37°C for 60 minutes at a dilution of 1 : 50 (final concentration: 4 μg/ml). Bound antibody was then visualized using the EnVision Kit™ (Agilent, CA, USA; #K5007) according to the manufacturer’s directions. The sections were counterstained with haemalaun. For the purpose of antibody validation, immunohistochemical staining of the normal tissue TMA was performed with a different antiprogesterone antibody (mouse monoclonal, PgR636, Agilent, CA, USA; # IR068) on the DAKO autostainer system. Only nuclear staining was scored. For normal tissues, the staining intensity of positive cells was semiquantitively recorded (+, ++, +++). For tumor tissues, the percentage of PR positive tumor cells was estimated, and the staining intensity was semiquantitatively recorded (0, 1+, 2+, 3+). For statistical analyses, the staining results were categorized into four groups as follows: negative: no staining at all, weak staining: staining intensity of 1+ in ≤70% or staining intensity of 2+ in ≤30% of tumor cells, moderate staining: staining intensity of 1+ in >70%, staining intensity of 2+ in >30% but in ≤70% or staining intensity of 3+ in ≤30% of tumor cells, and strong staining: staining intensity of 2+ in >70% or staining intensity of 3+ in >30% of tumor cells.

2.3. Statistics

Statistical calculations were performed with JMP 14 software (SAS Institute Inc., NC, USA). Contingency tables and the chi²-test were performed to search for associations between PR and tumor phenotype. Survival curves were calculated according to Kaplan-Meier. The log-rank test was applied to detect significant differences between groups. A value of ≤0.05 was defined as significant.

3. Results

3.1. Technical Issues

An interpretable result was found in 16,445 (90.5%) tumors. Noninterpretable samples were due to lack of unequivocal tumor cells or loss of the tissue spot during technical procedures for one or both of the markers. A sufficient number of samples of each normal tissue type was evaluable.

3.2. Progesterone Receptor Immunostaining in Normal Tissues

In normal tissues, PR was expressed in various organs of the female reproductive organs, such as ovarian stroma, corpus luteum of the ovary, epithelial and stromal cells of the fallopian tube, stromal cells and basal cell layer of the squamous epithelium of the ectocervix, stromal and epithelial cells of the endocervix, stromal and epithelial cells of the endometrium, and decidual cells. In the female breast, some epithelial cells showed a moderate to strong staining. A positive immunostaining was also observed in islets of Langerhans of the pancreas, in a subset of epithelial cells of the adenohypophysis, a subset of adrenocortical cells, in a small number of epithelial cells of the submandibular gland, in subsets of glomerular, tubular and stromal cells of the kidney, in epithelial cells of the cauda epididymis, and a fraction of smooth muscle cells of the ileum, esophagus, and aorta. In some organs, only stromal cells showed a positive immunostaining. This included the prostate gland, the seminal vesicle, and the urinary bladder. PR staining was completely absent in skeletal muscle, heart muscle, fat, skin (including hair follicle and sebaceous glands), oral mucosa of the lip, oral cavity, surface epithelium of the tonsil, and transitional mucosa of the anal canal, squamous epithelium of the esophagus, urothelium of the renal pelvis and urinary bladder, corpus spongiosum of the penis, placental trophoblastic cells, mucosa of the stomach, duodenum, ileum, appendix, colon, rectum and gall bladder, liver, parotid gland, sublingual gland, Brunner gland of the duodenum, testis, respiratory epithelium and glands of bronchi and sinus paranasales, lung, thyroid and parathyroid gland, spleen, lymph node, thymus, cerebellum, and cerebrum. Images of PR staining in normal tissues are shown in Figure 1. By using the antibody PgR636, all positive stainings described above were confirmed. An additional staining of occasional mast cells, intracellular mucin within goblet cells in the tubular gut, and colloid of the thyroid gland was only seen by this antibody and was considered a tolerable antibody-specific cross-reactivity (Supplementary Figure 1).

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3.3. Progesterone Receptor Immunostaining in Neoplastic Tissues

A PR immunostaining was found in 1,856 (11.3%) of 16,445 cases (573 weak, 333 moderate, 950 strong; Table 1). 55 of 147 (37.4%) different tumor entities included at least one PR-positive case and 31 (21%) entities contained at least one tumor with strong PR staining. PR immunostaining was detected in 57.4% of breast tumors, 28.6% of other gynecological tumors, and 1.8% of nongynecological and nonmammary tumors. A ranking of tumor categories according to the rate of PR positivity is given in Table 2. Particularly, high rates of PR positivity were seen in neuroendocrine tumors (54.3%) and neuroendocrine carcinomas (35.7%) of the pancreas. The group of nonbreast and nongynecological tumors expressing PR in at least 10% of cases included also Leydig cell tumor of the testis (36.7%), medullary thyroid carcinoma (20.4%), small cell neuroendocrine carcinoma of the prostate (16.7%), small cell carcinoma of the lung (12.5%), angiomyolipoma (12.5%), adrenal cortical carcinoma (11.5%), follicular thyroid carcinoma (11.3%), and papillary thyroid carcinoma (10.6%). Images of progesterone receptor staining in “nonmammary” and “nongynecological” tumors are shown in Figure 2.

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3.4. Progesterone Receptor Immunostaining, Tumor Phenotype, and Prognosis

Reduced PR immunostaining was significantly associated with adverse histopathological and clinical features in breast carcinoma, endometroid endometrial carcinoma, and pancreatic neuroendocrine tumors (Table 3). In breast carcinomas of no special type, reduced PR immunostaining was linked to advanced tumor stage (), lymph node metastasis (), high tumor grade (), distant metastasis (), positive HER2 status (), and shorter overall survival (negative vs. any positivity, HR 1.8, 95% CI 1.3-2.5, ; Supplementary Figure 2). In endometroid endometrial carcinoma, low PR immunostaining was linked to lymph node metastasis (). In 49 pancreatic neuroendocrine tumors, low PR immunostaining was linked to lymph node metastasis (). PR staining was unrelated to histopathological features in 343 serous ovarian carcinomas. Within nonmammary, nongynecological, and nonprostate tumors, PR positivity was more common in tumors from female (3.2% of 3,085) than from male patients (1.6% of 4,752; ).

4. Discussion

Our successful analysis of more than 16,000 tumors revealed PR expression in 57.4% of breast tumors, 28.6% of other gynecological tumors, and 1.8% of nongynecological and nonmammary tumors.

Given the large size of our study, particular emphasis was placed on the validation of our reagents and protocols. The International Working Group for Antibody Validation (IWGAV) has proposed that antibody validation for immunohistochemistry on formalin fixed tissues should include either a comparison of the findings obtained by two independent antibodies or a comparison with expression data obtained by another independent method [28–30]. Both methods were applied in this project. A comparison of our IHC data with RNA data provided from three independent publicly available databases (Human Protein Atlas (HPA) RNA-seq tissue dataset [31], FANTOM5 project [32, 33], and Genotype-Tissue Expression (GTEx) project [34]) revealed IHC positivity in all tissues with unequivocal RNA expression such as the organs of the female genital tract, prostate, seminal vesicle, epididymis, and the pituitary gland. RNA expression had previously not been recorded for several tissues with a positive PR immunostaining such as the aortic wall, pancreatic islet cells, kidney, duodenum, adrenal gland, stroma cells of urinary bladder and pyelon mucosa, smooth muscle cells of gastrointestinal tract, or salivary glands. These tissues had previously either not been analyzed on the RNA level (aortic wall, Brunner glands of the duodenum) or the PR positive cells constitute such small fractions of their respective organs total number of cells that their PR RNAs may not have occurred at detectable quantities. True PR expression in all these cell types is supported by identical stainings obtained by the antibody PgR636 (Supplementary Figure 1). Additional positivity obtained by PgR636 in goblet cells of the gut and of thyroidal colloid was considered an antibody cross-reactivity specific to PgR636 because these tissues remained unstained by MSVA-570R.

The PR immunostaining results in breast and other gynecological tumors were in the range of most previous studies which is another confirmation of our experimental approach. The slightly lower PR positivity rate of breast tumors in our study (57.4%) compared to the 60-70% positivity rate described in previous studies (reviewed in [35]) may reflect a TMA effect. TMAs generally result in slightly lower positivity rates than seen in large section analysis. In a highly standardized study comparing PR immunostaining between TMAs and traditional sections in more than 500 breast cancers, Torhorst et al. [36] had found a PR positivity of 41-53% in multiple TMAs and 60% PR positivity in large sections. Although progesterone receptors are widely expressed in ovarian cancers, their distribution varies significantly by histology. Particularly, sex cord stromal tumors showed high PR positivity (50-81%), which fits well with previous studies [37–39]. PR positivity was found in 62% of endometroid but only in 32% of high grade serous ovarian carcinomas. This is in line with earlier studies describing 41-67% PR positivity in endometroid [40–43] but only 25-50% PR positivity in high-grade serous carcinomas of the ovary [43, 44]. In the uterus, endometrioid carcinomas (67%) also showed a much higher rate of PR positivity than serous carcinomas (21%). Consistent with these data, earlier reports have described PR positivity in 62.3-81.3% of endometroid [45–47] but only in 20-46% of serous carcinomas of the endometrium [48, 49]. As expected from previous studies (reviewed in [35, 50]) an absent or low expression of PR in breast and endometrium cancer was linked to unfavorable patient outcome. This observation seemingly reflects a loss of PR expression during cellular dedifferentiation as part of tumor progression.

Positive PR immunostaining was found in 239 tumors from 30 different categories in nonbreast and nongynecological tumors. In this group, a particularly high rate of PR positivity was observed in sex cord stromal tumors of the testis and in several neuroendocrine neoplasms. Among neuroendocrine tumors, there was a noticeable accumulation of positive cases among tumors originating from the pancreas. PR positivity was found in 54% of neuroendocrine tumors and in 36% of neuroendocrine carcinomas of the pancreas which is consistent with earlier studies describing PR positivity in 58-82% of pancreatic neuroendocrine tumors [51–53]. Given that only 0-6% of intestinal and none of the neuroendocrine tumors of the lung showed PR immunostaining, immunohistochemical PR analysis appears to represent a relevant diagnostic tool to determine the origin of metastases from neuroendocrine tumors. In concordance with our results, PR immunostaining has thus been proposed in the differential diagnosis between metastasis of small bowel neuroendocrine tumor and pancreatic neuroendocrine tumor [54]. The high rate of PR positive neuroendocrine tumors of the pancreas corresponds to the strong nuclear PR immunostaining in islets of Langerhans in normal pancreatic tissue [55, 56]. It is therefore not surprising that reduced PR staining, potentially a sign of dedifferentiation, was associated with the presence of lymph node metastasis in our pancreatic neuroendocrine tumors. Viale et al. also found reduced PR positivity associated with presence of metastases [53]. Another rare tumor entity of the pancreas, solid pseudopapillary neoplasm (which was not analyzed in this study), also was shown to express PR and therefore could come into differential diagnosis when evaluating a PR positive pancreatic tumor [51].

Other neuroendocrine neoplasms that showed PR expression in a significant fraction of cases predominantly included poorly differentiated small-cell neuroendocrine carcinomas from various sites of origin and medullary carcinoma of the thyroid. It is of note that various other tumors of the thyroid gland also showed PR immunostaining in 7-12% of cases. Other investigators have reported even higher rates of PR positivity in 39-76% of papillary thyroid carcinoma [13, 14, 21–23] and 17% of follicular thyroid carcinoma [57]. A dependency of PR in the pathogenesis of at least some thyroid cancers could explain why thyroid cancer is more than twice as common in women compared to men [58] and is the second most common type of cancer in pregnancy [59]. Bertoni et al. have demonstrated a direct effect of progesterone on thyroid cells, upregulating genes involved in thyroid function and growth [60]. Furthermore, patients receiving mifepristone, a PR blocker, had a decrease in thyroid hormone levels [61]. Interestingly, among 7,657 nonmammary and nongynecological tumors, significantly, more PR-positive tumors were seen in women (3.2%) than in men (1.6%), although there are no great quantitative differences in the progesterone serum levels between women and men outside the luteal phase [62].

In summary, our analysis of 147 different tumor types for PR immunostaining provides a ranking list of tumor entities according to their prevalence of PR positivity. Given the highly discordant literature data, such a ranking order would have been difficult to extract from the existing literature (summarized in Supplementary Figure 3). These data help to better understand the diagnostic utility of PR IHC. The distinction of neuroendocrine neoplasms derived from the pancreas appears to represent a particularly strong and poorly known application of PR IHC.

Data Availability

All data generated or analyzed during this study are included in this published article.

Ethical Approval

The usage of archived diagnostic left-over tissues for manufacturing of TMAs and their analysis for research purposes as well as patient data analysis has been approved by local laws (HmbKHG, §12,1) and by the local ethics committee (Ethics commission Hamburg, WF-049/09). All work has been carried out in compliance with the Helsinki Declaration.

Conflicts of Interest

The progesterone receptor antibody clone MSVA-570R was provided from MS Validated Antibodies GmbH (owned by a family member of GS).

Authors’ Contributions

FV, SM, RS, GS, and CB contributed to the conception, design, data collection, data analysis, and manuscript writing. LMT, VC, DD, NG, AM, AH, CH-M, DH, CB, SS, PL, and SM participated in pathology data analysis and data interpretation. ML, VC, SW, NG, AM, FB, DH, CB, PL, GS, SS, EB, DD, TK, SM, FJ, TSC, AML, AH, and RK contributed to the collection of samples; RS, CH-M, FV, and CB for data analysis; and FV, CB, and GS for study supervision. All authors agree to be accountable for the content of the work.

Acknowledgments

We are grateful to Melanie Witt, Laura Behm, Inge Brandt, Maren Eisenberg, and Sünje Seekamp for excellent technical assistance.

Supplementary Materials

Supplementary 1. Supplementary Figure 1: (A–D) PR staining with antibody MSVA-570R. (E–H) PR staining with antibody PgR636. Absent staining in mucosa of the ileum (A) and thyroid gland (B) with MSVA-570R and moderate to strong staining with PgR636 in goblet cells in the mucosa of the ileum and in colloid of the thyroid gland. Identical staining of both antibodies in islets of Langerhans in the pancreas (C and G) and endometrium (D and H).

Supplementary 2. Supplementary Figure 2: PR positivity and overall survival in patients with invasive breast carcinomas of no special type.

Supplementary 3. Supplementary Figure 3: graphical representation of PR data from this study (marked with a cross) in comparison with the previous literature (marked with a dot). In order to simplify the figure the percentage of weak, moderate and strong staining was merged. Red dots are used for studies from previous studies involving 3-10 cases, yellow dots for studies involving 11-25 cases, and green dots for studies involving >25cases. All studies are quoted in the supplementary material.

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Copyright © 2022 Florian Viehweger et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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