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. 2022 Aug 8;2022:6412148. doi: 10.1155/2022/6412148

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

Florian Viehweger 1, Lisa-Marie Tinger 1, David Dum 1, Natalia Gorbokon 1, Anne Menz 1, Ria Uhlig 1, Franziska Büscheck 1, Andreas M Luebke 1, Claudia Hube-Magg 1, Andrea Hinsch 1, Doris Höflmayer 1, Christoph Fraune 1, Patrick Lebok 1,2, Sören Weidemann 1, Maximilian Lennartz 1, Frank Jacobsen 1, Till S Clauditz 1, Rainer Krech 2, Till Krech 1,2, Andreas H Marx 1,3, Ronald Simon 1, Eike Burandt 1, Stefan Steurer 1, Guido Sauter 1, Sarah Minner 1,✉, Christian Bernreuther 1
PMCID: PMC9381849  PMID: 35992051

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 p 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).

Figure 1.

Figure 1

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PR immunostaining in normal tissues. Positive PR immunostaining in (a) stromal cells and epithelial cells in proliferative endometrium, (b) stromal cells and epithelial cell in endocervix, (c) luminal cells of breast epithelium, (d) islets of Langerhans in pancreas, (e) stromal cells of the prostate, and (f) stromal cells of seminal vesicle.

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.

Table 1.

PR immunostaining in tumors.

Tumor entity On TMA (n) PR immunostaining
Analyzable (n) Negative (%) Weak (%) Moderate (%) Strong (%)
Tumors of the skin (n = 410) Pilomatrixoma 35 34 100.0 0.0 0.0 0.0
Basal cell carcinoma 88 82 100.0 0.0 0.0 0.0
Benign nevus 29 29 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the skin 90 90 100.0 0.0 0.0 0.0
Malignant melanoma 46 46 100.0 0.0 0.0 0.0
Malignant melanoma lymph node metastasis 86 84 100.0 0.0 0.0 0.0
Merkel cell carcinoma 46 45 100.0 0.0 0.0 0.0
Tumors of the head and neck (n = 1,188) Squamous cell carcinoma of the larynx 60 54 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the pharynx 60 59 100.0 0.0 0.0 0.0
Oral squamous cell carcinoma (floor of the mouth) 80 80 100.0 0.0 0.0 0.0
Warthin tumor of the parotid gland 55 53 100.0 0.0 0.0 0.0
Adenocarcinoma, NOS (papillary cystadenocarcinoma) 14 11 100.0 0.0 0.0 0.0
Salivary duct carcinoma 15 13 100.0 0.0 0.0 0.0
Acinic cell carcinoma of the salivary gland 181 135 100.0 0.0 0.0 0.0
Adenocarcinoma NOS of the salivary gland 109 81 97.5 0.0 1.2 1.2
Adenoid cystic carcinoma of the salivary gland 180 126 100.0 0.0 0.0 0.0
Basal cell adenocarcinoma of the salivary gland 25 21 100.0 0.0 0.0 0.0
Basal cell adenoma of the salivary gland 86 66 100.0 0.0 0.0 0.0
Epithelial-myoepithelial carcinoma of the salivary gland 53 52 100.0 0.0 0.0 0.0
Mucoepidermoid carcinoma of the salivary gland 343 327 99.7 0.0 0.3 0.0
Myoepithelial carcinoma of the salivary gland 21 17 94.1 0.0 5.9 0.0
Myoepithelioma of the salivary gland 11 10 100.0 0.0 0.0 0.0
Oncocytic carcinoma of the salivary gland 12 8 100.0 0.0 0.0 0.0
Polymorphous adenocarcinoma, low grade, of the salivary gland 41 34 100.0 0.0 0.0 0.0
Pleomorphic adenoma of the salivary gland 53 41 100.0 0.0 0.0 0.0
Tumors of the lung, pleura, and thymus (n = 382) Adenocarcinoma of the lung 196 191 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the lung 80 75 100.0 0.0 0.0 0.0
Small cell carcinoma of the lung 16 16 87.5 6.3 6.3 0.0
Mesothelioma, epitheloid 39 30 100.0 0.0 0.0 0.0
Mesothelioma, other types 76 70 100.0 0.0 0.0 0.0
Tumors of the female genital tract (n = 1,534) Squamous cell carcinoma of the vagina 78 74 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the vulva 130 123 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the cervix 129 126 99.2 0.8 0.0 0.0
Adenocarcinoma of the cervix 21 21 90.5 4.8 4.8 0.0
Endometrioid endometrial carcinoma 236 197 33.5 21.8 13.7 31.0
Endometrial serous carcinoma 82 68 79.4 14.7 2.9 2.9
Carcinosarcoma of the uterus 48 41 87.8 4.9 0.0 7.3
Endometrial carcinoma, high grade, G3 13 12 83.3 8.3 0.0 8.3
Endometrial clear cell carcinoma 8 6 100.0 0.0 0.0 0.0
Endometrioid carcinoma of the ovary 110 92 38.0 18.5 14.1 29.3
Serous carcinoma of the ovary 559 520 67.9 22.1 4.2 5.8
Mucinous carcinoma of the ovary 96 77 94.8 0.0 0.0 5.2
Clear cell carcinoma of the ovary 50 45 88.9 6.7 2.2 2.2
Carcinosarcoma of the ovary 47 44 65.9 22.7 6.8 4.5
Granulosa cell tumor of the ovary 37 37 18.9 29.7 29.7 21.6
Leydig cell tumor of the ovary 4 4 50.0 50.0 0.0 0.0
Sertoli cell tumor of the ovary 1 1 100.0 0.0 0.0 0.0
Sertoli Leydig cell tumor of the ovary 3 3 33.3 66.7 0.0 0.0
Steroid cell tumor of the ovary 3 3 100.0 0.0 0.0 0.0
Brenner tumor 41 40 95.0 0.0 0.0 5.0
Tumors of the breast (n = 2,051) Invasive breast carcinoma of no special type 1764 1605 42.9 10.7 10.7 35.8
Lobular carcinoma of the breast 363 302 43.0 9.9 9.6 37.4
Medullary carcinoma of the breast 34 33 87.9 3.0 3.0 6.1
Tubular carcinoma of the breast 29 23 17.4 8.7 8.7 65.2
Mucinous carcinoma of the breast 65 51 23.5 7.8 7.8 60.8
Phyllodes tumor of the breast 50 37 27.0 0.0 18.9 54.1
Tumors of the digestive system (n = 3,911) Adenomatous polyp, low-grade dysplasia 50 50 100.0 0.0 0.0 0.0
Adenomatous polyp, high-grade dysplasia 50 50 100.0 0.0 0.0 0.0
Adenocarcinoma of the colon 2482 2146 99.9 0.0 0.0 0.0
Gastric adenocarcinoma, diffuse type 176 150 100.0 0.0 0.0 0.0
Gastric adenocarcinoma, intestinal type 174 157 100.0 0.0 0.0 0.0
Gastric adenocarcinoma, mixed type 62 49 100.0 0.0 0.0 0.0
Adenocarcinoma of the esophagus 83 83 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the esophagus 75 75 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the anal canal 89 88 100.0 0.0 0.0 0.0
Cholangiocarcinoma 50 50 100.0 0.0 0.0 0.0
Gallbladder adenocarcinoma 31 31 100.0 0.0 0.0 0.0
Gallbladder klatskin tumor 41 39 100.0 0.0 0.0 0.0
Hepatocellular carcinoma 300 299 100.0 0.0 0.0 0.0
Ductal adenocarcinoma of the pancreas 612 505 97.8 1.0 0.6 0.6
Pancreatic/ampullary adenocarcinoma 89 75 100.0 0.0 0.0 0.0
Acinar cell carcinoma of the pancreas 16 15 100.0 0.0 0.0 0.0
Gastrointestinal stromal tumor (GIST) 50 49 100.0 0.0 0.0 0.0
Tumors of the urinary system (n = 3,181) Noninvasive papillary urothelial carcinoma, pTa G2 low grade 177 170 100.0 0.0 0.0 0.0
Noninvasive papillary urothelial carcinoma, pTa G2 high grade 141 135 100.0 0.0 0.0 0.0
Noninvasive papillary urothelial carcinoma, pTa G3 219 195 100.0 0.0 0.0 0.0
Urothelial carcinoma, pT2-4 G3 735 636 99.7 0.0 0.0 0.3
Squamous cell carcinoma of the bladder 22 22 100.0 0.0 0.0 0.0
Small cell neuroendocrine carcinoma of the bladder 23 23 95.7 4.3 0.0 0.0
Sarcomatoid urothelial carcinoma 25 23 100.0 0.0 0.0 0.0
Urothelial carcinoma of the kidney pelvis 62 61 98.4 1.6 0.0 0.0
Clear cell renal cell carcinoma 1287 1179 99.9 0.1 0.0 0.0
Papillary renal cell carcinoma 368 329 99.7 0.3 0.0 0.0
Clear cell (tubulo) papillary renal cell carcinoma 26 24 95.8 0.0 4.2 0.0
Chromophobe renal cell carcinoma 170 153 95.4 3.3 0.0 1.3
Oncocytoma 257 231 93.1 6.5 0.4 0.0
Tumors of the male genital organs (n = 1,350) Adenocarcinoma of the prostate, Gleason 3 + 3 83 83 100.0 0.0 0.0 0.0
Adenocarcinoma of the prostate, Gleason 4 + 4 80 80 100.0 0.0 0.0 0.0
Adenocarcinoma of the prostate, Gleason 5 + 5 85 85 100.0 0.0 0.0 0.0
Adenocarcinoma of the prostate (recurrence) 258 257 99.6 0.4 0.0 0.0
Small cell neuroendocrine carcinoma of the prostate 19 18 83.3 16.7 0.0 0.0
Seminoma 621 586 100.0 0.0 0.0 0.0
Embryonal carcinoma of the testis 50 45 100.0 0.0 0.0 0.0
Leydig cell tumor of the testis 30 30 63.3 33.3 3.3 0.0
Sertoli cell tumor of the testis 2 1 0.0 100.0 0.0 0.0
Sex cord stromal tumor of the testis 1 1 0.0 0.0 100.0 0.0
Spermatocytic tumor of the testis 1 1 100.0 0.0 0.0 0.0
Yolk sac tumor 50 44 100.0 0.0 0.0 0.0
Teratoma 50 41 95.1 0.0 0.0 4.9
Squamous cell carcinoma of the penis 80 78 100.0 0.0 0.0 0.0
Tumors of endocrine organs (n = 1,171) Adenoma of the thyroid gland 114 112 92.9 4.5 2.7 0.0
Papillary thyroid carcinoma 392 379 89.4 9.0 1.1 0.5
Follicular thyroid carcinoma 154 151 88.7 5.3 3.3 2.6
Medullary thyroid carcinoma 111 108 79.6 16.7 1.9 1.9
Parathyroid gland adenoma 43 42 100.0 0.0 0.0 0.0
Anaplastic thyroid carcinoma 45 43 97.7 2.3 0.0 0.0
Adrenal cortical adenoma 50 44 95.5 2.3 0.0 2.3
Adrenal cortical carcinoma 26 26 88.5 11.5 0.0 0.0
Phaeochromocytoma 50 49 100.0 0.0 0.0 0.0
Appendix, neuroendocrine tumor (NET) 22 17 94.1 0.0 5.9 0.0
Colorectal, neuroendocrine tumor (NET) 12 11 100.0 0.0 0.0 0.0
Ileum, neuroendocrine tumor (NET) 49 49 100.0 0.0 0.0 0.0
Lung, neuroendocrine tumor (NET) 19 18 100.0 0.0 0.0 0.0
Pancreas, neuroendocrine tumor (NET) 97 94 45.7 17.0 9.6 27.7
Colorectal, neuroendocrine carcinoma (NEC) 12 10 100.0 0.0 0.0 0.0
Gallbladder, neuroendocrine carcinoma (NEC) 4 4 100.0 0.0 0.0 0.0
Pancreas, neuroendocrine carcinoma (NEC) 14 14 64.3 7.1 14.3 14.3
Tumors of haematopoetic and lymphoid tissues (n = 353) Hodgkin lymphoma 58 53 100.0 0.0 0.0 0.0
Small lymphocytic lymphoma, B-cell type (B-SLL/B-CLL) 50 44 100.0 0.0 0.0 0.0
Diffuse large B cell lymphoma (DLBCL) 113 103 100.0 0.0 0.0 0.0
Follicular lymphoma 88 80 100.0 0.0 0.0 0.0
T-cell non-Hodgkin lymphoma 25 24 100.0 0.0 0.0 0.0
Mantle cell lymphoma 18 17 100.0 0.0 0.0 0.0
Marginal zone lymphoma 16 14 100.0 0.0 0.0 0.0
Diffuse large B-cell lymphoma (DLBCL) in the testis 16 16 100.0 0.0 0.0 0.0
Burkitt lymphoma 5 2 100.0 0.0 0.0 0.0
Tumors of soft tissue and bone (n = 914) Tenosynovial giant cell tumor 45 45 100.0 0.0 0.0 0.0
Granular cell tumor 53 45 100.0 0.0 0.0 0.0
Leiomyosarcoma 38 37 89.2 2.7 0.0 8.1
Liposarcoma 132 130 100.0 0.0 0.0 0.0
Malignant peripheral nerve sheath tumor (MPNST) 13 13 100.0 0.0 0.0 0.0
Myofibrosarcoma 26 26 100.0 0.0 0.0 0.0
Angiosarcoma 73 66 100.0 0.0 0.0 0.0
Angiomyolipoma 91 88 87.5 9.1 0.0 3.4
Dermatofibrosarcoma protuberans 21 17 100.0 0.0 0.0 0.0
Ganglioneuroma 14 14 100.0 0.0 0.0 0.0
Kaposi sarcoma 8 5 100.0 0.0 0.0 0.0
Neurofibroma 117 104 95.2 4.8 0.0 0.0
Sarcoma, not otherwise specified (NOS) 74 70 98.6 0.0 0.0 1.4
Paraganglioma 41 41 100.0 0.0 0.0 0.0
Ewing sarcoma 23 18 100.0 0.0 0.0 0.0
Rhabdomyosarcoma 6 6 100.0 0.0 0.0 0.0
Schwannoma 121 112 100.0 0.0 0.0 0.0
Synovial sarcoma 12 11 100.0 0.0 0.0 0.0
Osteosarcoma 43 39 100.0 0.0 0.0 0.0
Chondrosarcoma 38 22 100.0 0.0 0.0 0.0
Rhabdoid tumor 5 5 100.0 0.0 0.0 0.0
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Table 2.

Ranking of PR immunostaining in tumors (only tumor entities with ≥3 evaluable tumors were included in the ranking. Mammary tumors are italicized. Gynecological tumors are in bold).

Ranking PR ≥ weak (%) ≥ mod (%) Strong (%)
Tubular carcinoma of the breast 82.6 73.9 65.2
Granulosa cell tumor of the ovary 81.1 51.4 21.6
Mucinous carcinoma of the breast 76.5 68.6 60.8
Phyllodes tumor of the breast 73.0 73.0 54.1
Sertoli Leydig cell tumor of the ovary 66.7 0.0 0.0
Endometrioid endometrial carcinoma 66.5 44.7 31.0
Endometrioid carcinoma of the ovary 62.0 43.5 29.3
Invasive breast carcinoma of no special type 57.1 46.5 35.8
Lobular carcinoma of the breast 57.0 47.0 37.4
Pancreas, neuroendocrine tumor (NET) 54.3 37.2 27.7
Leydig cell tumor of the ovary 50.0 0.0 0.0
Leydig cell tumor of the testis 36.7 3.3 0.0
Pancreas, neuroendocrine carcinoma (NEC) 35.7 28.6 14.3
Carcinosarcoma of the ovary 34.1 11.4 4.5
Serous carcinoma of the ovary 32.1 10.0 5.8
Endometrial serous carcinoma 20.6 5.9 2.9
Medullary thyroid carcinoma 20.4 3.7 1.9
Endometrial carcinoma, high grade, G3 16.7 8.3 8.3
Small cell neuroendocrine carcinoma of the prostate 16.7 0.0 0.0
Small cell carcinoma of the lung 12.5 6.3 0.0
Angiomyolipoma 12.5 3.4 3.4
Carcinosarcoma of the uterus 12.2 7.3 7.3
Medullary carcinoma of the breast 12.1 9.1 6.1
Adrenal cortical carcinoma 11.5 0.0 0.0
Follicular thyroid carcinoma 11.3 6.0 2.6
Clear cell carcinoma of the ovary 11.1 4.4 2.2
Leiomyosarcoma 10.8 8.1 8.1
Papillary thyroid carcinoma 10.6 1.6 0.5
Adenocarcinoma of the cervix 9.5 4.8 0.0
Adenoma of the thyroid gland 7.1 2.7 0.0
Oncocytoma 6.9 0.4 0.0
Myoepithelial carcinoma of the salivary gland 5.9 5.9 0.0
Appendix, neuroendocrine tumor (NET) 5.9 5.9 0.0
Mucinous carcinoma of the ovary 5.2 5.2 5.2
Brenner tumor 5.0 5.0 5.0
Teratoma 4.9 4.9 4.9
Neurofibroma 4.8 0.0 0.0
Chromophobe renal cell carcinoma 4.6 1.3 1.3
Adrenal cortical adenoma 4.5 2.3 2.3
Small cell neuroendocrine carcinoma of the bladder 4.3 0.0 0.0
Clear cell (tubulo) papillary renal cell carcinoma 4.2 4.2 0.0
Adenocarcinoma NOS of the salivary gland 2.5 2.5 1.2
Anaplastic thyroid carcinoma 2.3 0.0 0.0
Ductal adenocarcinoma of the pancreas 2.2 1.2 0.6
Urothelial carcinoma of the kidney pelvis 1.6 0.0 0.0
Sarcoma, not otherwise specified (NOS) 1.4 1.4 1.4
Squamous cell carcinoma of the cervix 0.8 0.0 0.0
Adenocarcinoma of the prostate (recurrence) 0.4 0.0 0.0
Urothelial carcinoma, pT2-4 G3 0.3 0.3 0.3
Mucoepidermoid carcinoma of the salivary gland 0.3 0.3 0.0
Papillary renal cell carcinoma 0.3 0.0 0.0
Adenocarcinoma of the colon 0.1 0.0 0.0
Clear cell renal cell carcinoma 0.1 0.0 0.0
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Figure 2.

Figure 2

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Moderate to strong PR immunostaining in “nonmammary” and “nongynecological” tumors. (a) Neuroendocrine tumor of the pancreas. (b) Neuroendocrine carcinoma of the pancreas. (c) Small cell carcinoma of the lung. (d) Leydig cell tumor of the testis. (e) Medullary thyroid carcinoma. (f) Follicular thyroid carcinoma. (g) Papillary thyroid carcinoma. (h) Angiomyolipoma.

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 (p < 0.0001), lymph node metastasis (p < 0.0001), high tumor grade (p < 0.0001), distant metastasis (p < 0.0001), positive HER2 status (p < 0.0001), and shorter overall survival (negative vs. any positivity, HR 1.8, 95% CI 1.3-2.5, p = 0.0127; Supplementary Figure 2). In endometroid endometrial carcinoma, low PR immunostaining was linked to lymph node metastasis (p = 0.0327). In 49 pancreatic neuroendocrine tumors, low PR immunostaining was linked to lymph node metastasis (p = 0.0345). 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; p < 0.0001).

Table 3.

PR immunostaining and tumor phenotype in breast carcinoma of no special type, endometrioid endometrial carcinoma, high-grade serous ovarian carcinoma, and pancreatic neuroendocrine tumors.

n Progesterone receptor IHC result p
Negative (%) Weak (%) Moderate (%) Strong (%)
Breast carcinoma of no special type Tumor stage pT1 749 36.7 9.9 11.9 41.5 <0.0001
pT2 613 44.5 11.4 11.4 32.6
pT3-4 122 54.9 11.5 4.1 29.5
Grade G1 183 23.0 10.9 12.6 53.6 <0.0001
G2 799 34.3 10.4 13.4 41.9
G3 543 59.7 10.7 7.2 22.5
Nodal stage pN0 682 40.2 8.8 9.8 41.2 <0.0001
pN1 325 38.2 14.5 14.2 33.2
pN2 114 47.4 13.2 10.5 28.9
pN3 68 63.2 13.2 5.9 17.6
Distant metastasis pM0 199 38.7 7.5 10.6 43.2 <0.0001
pM1 104 64.4 11.5 5.8 18.3
HER2 status Negative 850 37.8 10.5 11.1 40.7 <0.0001
Positive 120 63.3 12.5 6.7 17.5
Endometrioid endometrial carcinoma Tumor stage pT1 94 29.8 22.3 13.8 34.0 0.8885
pT2 23 34.8 17.4 8.7 39.1
pT3-4 29 34.5 24.1 17.2 24.1
Nodal stage pN0 43 20.9 25.6 18.6 34.9 0.0327
pN+ 25 56.0 16.0 8.0 20.0
Serous ovarian carcinoma Tumor stage pT1 33 51.5 18.2 9.1 21.2 0.0750
pT2 43 69.8 20.9 2.3 7.0
pT3 267 72.3 18.7 3.7 5.2
Nodal stage pN0 83 65.1 26.5 6.0 2.4 0.0534
pN1 171 76.0 15.8 2.3 5.8
Pancreatic neuroendocrine tumors Tumor stage pT1 10 40.0 10.0 20.0 30.0 0.0954
pT2 15 26.7 33.3 6.7 33.3
pT3 22 68.2 4.5 13.6 13.6
pT4 2 0.0 50.0 0.0 50.0
Nodal stage pN0 24 29.2 20.8 16.7 33.3 0.0345
pN+ 21 71.4 9.5 9.5 9.5
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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.

Acknowledgments

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

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.

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).

Click here for additional data file. (6.7MB, pdf)
Supplementary 2

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

Click here for additional data file. (35.4KB, pdf)
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.

Click here for additional data file. (437.4KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

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).

Click here for additional data file. (6.7MB, pdf)
Supplementary 2

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

Click here for additional data file. (35.4KB, pdf)
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.

Click here for additional data file. (437.4KB, pdf)

Data Availability Statement

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

Articles from Analytical Cellular Pathology (Amsterdam) are provided here courtesy of Wiley

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