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Gynecologic Serous Carcinoma: An Immunohistochemical Analysis of Malignant Body Fluid Specimens.

About 225 000 new ovarian carcinomas are diagnosed annually, with 140 000 related deaths worldwide. (1) Of all patients with ovarian carcinoma, 69% will succumb to their disease, as compared with 19% for those with breast cancer. Ovarian carcinomas grow rapidly, metastasize early, and have an aggressive disease course. Diagnosis is often delayed because symptoms are nonspecific. The high mortality of this tumor is largely explained by most patients (75%--80%) presenting at an advanced stage and with widely metastatic disease within the peritoneal cavity. (2) Extensive seeding of the peritoneal cavity by tumor cells is often associated with ascites. Current treatment strategies for advanced ovarian carcinoma consist of aggressive surgery (tumor debulking) often involving en bloc resection of the ovarian tumor, reproductive organs, and, sometimes, the sigmoid colon. (3,4) Omental/peritoneal nodules and ascites are often the presenting symptoms identified by imaging studies. Accurate assessment of pelvic washing/ ascites and pleural fluid specimens is critical for diagnosis and for assigning the pathologic stage in these tumors. Pathologists often employ immunohistochemical stains, such as PAX8, p53, p16, WT1, and estrogen receptor antibodies, in the evaluation of body fluid involvement by gynecologic serous carcinoma. To exclude other potential primary tumors, it is sometimes necessary for the pathologist to employ additional immunohistochemical markers, such as GATA3 and uroplakin II for urothelial carcinoma and SALL4 and SOX2 for germ cell tumors.

GATA3 is a transcription factor important in the differentiation of breast epithelia, urothelia, and subsets of T lymphocytes. A recent study showed that GATA3 is a useful marker in the characterization of not only mammary and urothelial tumors but also renal and germ cell neoplasms, mesotheliomas, and paragangliomas. (5) The recently developed antibody against uroplakin II shows utility in diagnosing primary urothelial carcinoma. (6,7) SOX2 has been shown to be amplified and functionally relevant in various cancer types, where it functions through multiple mechanisms that vary depending on the cancer type. However, in most cases, SOX2 has been shown to increase cell proliferation, invasion, migration, metastasis, and self-renewal of cancer stem cells. (8) Overexpression of SOX2 has been described in germ cell tumors,9 all types of lung cancer tissues (including small cell carcinoma, squamous cell carcinoma, and adenocarcinoma), uterine and ovarian tumors, carcinoma of the breast, (10) prostate carcinoma, (11) hepatocellular carcinoma, (12) and osteosarcoma. (13) A recent study (14) found mutation and protein overexpression of SOX2 in fallopian tube epithelial cells of patients with highgrade, serous ovarian cancer, which was not found in patients without cancer. The finding of SOX2 overexpression in fallopian tube epithelial cells could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease. (14) Transcription factor SALL4 (sal-like protein 4) has been recognized as a sensitive marker for both primary and metastatic, malignant germ cell tumors. (15) A recent article reported that SALL4 expression was an independent predictor of poor overall survival in human hepatocellular carcinoma. (16)

To our knowledge, no comprehensive studies analyzing these relatively new immunohistochemical markers have been performed on cytology fluid specimens in patients with high-grade serous carcinoma. In this study, we investigated expression of the immunohistochemical markers PAX8, GATA3, uroplakin II, SOX2, and SALL4 on tumor cells within fluid specimens of patients with high-grade serous carcinoma of gynecologic/Mullerian origin.

DESIGN

Patient Case Selection

Records for patients diagnosed with positive peritoneal fluid or pleural fluid of gynecologic/peritoneal origin (n = 113) and treated at the Cooper University Hospital (Camden, New Jersey) were retrospectively obtained for the years 2011 to 2015. All slides were reviewed by 2 board-certified, blinded cytopathologists (the authors). For each patient, the histologic subtype was recorded. Adequate paraffin cell blocks for immunohistochemical studies were available for all 113 patients (94 serous carcinomas, 83.2% [93 high grade and 1 low grade]; 5 endometrioid adenocarcinomas [4.4%], 2 mucinous carcinomas [1.8%], 1 undifferentiated carcinoma [0.9%], 1 high grade neuroendocrine carcinoma [0.9%], and 10 carcinomas of unknown type [8.8%]). The 10 carcinomas of unknown type were considered to be of gynecologic origin based on immunohistochemical studies performed on fluid specimens and on clinical information. The study was conducted with approval of the Cooper Health System's institutional review board (reference 00000211).

Immunohistochemistry

Immunohistochemistry was performed on a Discovery automated immunostaining system (Ventana Medical Systems, Tucson, Arizona) with Ventana reagents. The sections on Superfrost slides were deparaffinized with inorganic buffer. Pretreatment was conducted with an EDTA-based buffer at pH 8.4, and heat-induced epitope retrieval was performed before the primary antibodies were applied. Immunohistochemical markers included GATA3 (clone L50-823, dilution 1:10, Cell Marque, Rocklin, California), SOX2 (clone SP76, prediluted, Cell Marque), PAX8 (clone MrQ-50, dilution 1:15, Roche, Indianapolis, Indiana), uroplakin II (clone BC21, dilution 1:50, Biocare Medical, Concord, California), and SALL4 (clone 6E3, dilution 1:20, Cell Marque). UltraView Universal DAB Detection Kit was from Ventana Medical Systems. Slides were counterstained with hematoxylin and bluing reagent, washed, and dehydrated with an ascending alcohol series (40%, 70%, and 96%). Finally, the slides were covered with Symphony Clear (Ventana Medical Systems).

Evaluation of Immunohistochemistry

All immunohistochemical staining was performed with adequate positive and negative controls. Cases were included in the analysis if at least 10 malignant cells were present. Only nuclear staining was considered positive in evaluation of PAX8, GATA3, SOX2, and SALL4. Faint cytoplasmic staining was observed occasionally but did not interfere with interpretation of the nuclear stain. The analysis was independently performed by 2 board-certified pathologists (the authors). A 3-tier scale was used to assess the relative number of positive cells (absence of staining, negative; >0%-10%, focal positive; >10%, positive).

RESULTS

PAX8, GATA3, SOX2, Uroplakin II, and SALL4 Expression in Fluid Specimens Involved by Carcinoma (All Types)

The 113 cytologic fluid specimens involved by gynecologic/primary peritoneal carcinoma supported by resection specimens and/or immunohistochemical studies were evaluated (Figure; Table 1). PAX8 reactivity was present in 99 of 113 fluids (87.6%) and demonstrated diffuse staining in most cases (92 of 99; 92.9%). GATA3 reactivity was present in 19 of 113 fluids (16.8%), and most cases showed focal staining (14 of 19; 73.7%). SOX2 reactivity was present in 19 of 113 fluids (16.8%), and approximately half of those cases demonstrated strong, diffuse staining. Uroplakin II reactivity was present in 23 of 113 fluids (20.4%), and most showed focal positivity (16 of 23; 69.6%). SALL4 reactivity was present in only 8 of the 113 fluids (7.1%), and most showed focal positivity (5 of 8; 62.5%).

PAX8, GATA3, SOX2, Uroplakin II, and SALL4 Expression in Fluid Specimens Involved by Gynecologic High-Grade Serous Carcinoma

PAX8 reactivity was present in 84 of 94 fluids (89.4%) with serous carcinoma, predominantly strong and diffuse (77 of 84; 91.7%) (Table 2). GATA3 reactivity was present in 18 of 94 fluids (19.1%) with serous carcinoma, predominantly exhibiting focal positivity (14 of 18; 77.8%). SOX2 reactivity was present in 17 of 94 fluids (18.1%) with serous carcinoma, exhibiting both focal and diffuse pattern types. Uroplakin II reactivity was present in 22 of 94 fluids (23.4%) with serous carcinoma, predominantly showing focal reactivity (16 of 22; 72.7%). SALL4 reactivity was present in 8 of 94 fluids (8.5%) with serous carcinoma, predominantly exhibiting focal reactivity (5 of 8; 62.5%).

PAX8, GATA3, SOX2, Uroplakin II, and SALL4 Expression in Fluid Specimens Involved by Nonserous Carcinoma and Low-Grade Serous Carcinoma

Endometrioid adenocarcinoma with either uterine or ovarian origin demonstrated PAX8 expression in 4 of 5 total cases (80%; Table 3). The case without PAX8 expression showed mucinous morphology. None of the cases of endometrioid carcinoma showed reactivity for GATA3, SOX2, uroplakin II, or SALL4. One case of mucinous carcinoma showed reactivity for PAX8 but had negative results for the remaining immunohistochemical markers. An interesting case of poorly differentiated neuroendocrine carcinoma (positive for neuroendocrine markers TTF-1, synaptophysin, and CD56 at diagnosis) showed positive staining results for SOX2 but was negative for other tested markers. One case of low-grade serous carcinoma was negative for all evaluated markers, including PAX8. Ten cases of carcinoma of unknown type showed reactivity to PAX8, lending support to their gynecologic origin. Those specimens were negative for the other markers, with the exception of one case showing reactivity for SOX2.

Because there were few cases in this data set, results are included anecdotally to preface future studies examining the investigated antibodies in non-high-grade serous carcinoma.

DISCUSSION

In postmenopausal women, a gynecologic (especially ovarian) primary should be considered as a major differential diagnostic consideration in the setting of malignant ascites and/or pleural effusion. Ovarian carcinoma frequently spreads by direct extension from the primary site to neighboring organs and/or disseminates within the abdominal cavity. Extensive seeding of the peritoneal cavity by tumor cells is often associated with ascites, particularly in advanced, high-grade serous carcinomas. (17) Patients with ovarian carcinoma often have peritoneal deposits with contiguous extension to, or encasement of, internal organs (uterus, fallopian tube, ovaries) and the rectosigmoid colon. Pelvic and/or para-aortic lymph nodes may be involved. The greater omentum has considerable phagocytic capacity for carcinoma cells, so that organ is almost always infiltrated by the tumor. (2) The symptoms of peritoneal progression from ovarian carcinoma are often nonspecific and frequently caused by advanced disease. Therefore, ascites and/or peritoneal washings are used as the standard of care for tumor staging to guide patient management. Cytologic fluid specimens may require immunohistochemical analysis to document tumor involvement and/or to define tumor type.

Immunohistochemical stains, such as PAX8, p53, p16, WT1, and estrogen receptor antibodies, are commonly used in tumors of gynecologic serous carcinoma, but there are few reports evaluating the markers with body fluid involvement. PAX8 is expressed in most gynecologic tumors. One comprehensive study showed that 164 of 165 ovarian high-grade serous carcinomas (99%) and 152 of 155 (98%) of endometrioid adenocarcinomas were positive for PAX8 expression. (18) Two separate studies performed on fluids in patients with ovarian serous carcinoma demonstrated that 94% (32 of 34) (19) and 69.6% (16 of 23) had positive stains for PAX8, (20) respectively. In the current study examining cytologic fluid specimens, 99 of 113 fluid specimens (87.6%) involved by gynecologic malignancy and 84 of 94 fluids (89.4%) specifically involved by highgrade serous carcinoma exhibited reactivity for PAX8, and most cases showed diffuse, strong staining. These results confirm the utility of PAX8 in assessing fluid specimens involved by gynecologic malignancy.

GATA3 is important in the differentiation of breast epithelia and urothelia, and this immunohistochemical stain is well recognized as a marker for breast and urothelial carcinoma. The few studies have shown varying results for GATA3 expression in Mullerian neoplasms. One study (21) showed that all 15 cases of primary, ovarian, high-grade serous carcinoma were negative for GATA3 expression. However, another study (5) demonstrated that 4 of 73 ovarian serous carcinomas (6%) were positive for GATA3 expression, and none of the 25 other ovarian carcinomas showed GATA3 expression. One study (22) performed on fluid specimens for GATA3 showed only 1 of 22 patients (4.5%) with ovarian serous carcinoma had a weakly positive result. In the current study, 18 of 94 fluid specimens (19.1%) involved by high-grade serous carcinoma showed GATA3 expression with 14 (77.8%) exhibiting focal expression within the study criteria. Additionally, 1 undifferentiated carcinoma was positive, and 5 endometrioid adenocarcinomas were negative for GATA3.

Uroplakin II, also an important marker for diagnosing urothelial carcinoma, was analyzed in this study. Interestingly, 22 of 94 (23.4%) of the fluids positive for high-grade serous carcinoma exhibited uroplakin II expression, with most (16 of 22; 72.7%) showing focal expression, according to study criteria. In addition, 1 undifferentiated carcinoma had positive staining for uroplakin II. These results illustrate the necessity of using clinical information and a battery of immunohistochemical stains to avoid misdiagnosis of gynecologic malignancy (as urothelial or breast primary, for example).

Previous genome-wide analysis of ovarian serous carcinomas has shown frequent gains and amplifications on chromosome arm 3q26, and SOX2 has been implicated as a target gene of that region. Nuclear expression of SOX2 has been confirmed in such diverse entities as various germ cell tumors, (23,24) adenocarcinomas of the lung, (25,26) squamous carcinomas of the lung and other organs, (26,27) pancreatic and biliary cancers, (28,29) glioblastomas,30 and breast cancer. In vitro, SOX2 has profound effects on genes involved in cell proliferation, such as Ki67 and cyclin D1. The divergent effect of SOX2 on survival in different tumor types may also be due to tissue-specific cofactors: SOX2+ adenocarcinomas of the lung show a worse outcome,25,26 whereas SOX2+ squamous cell lung cancers are associated with a better prognosis. (26,31) In primary breast cancer, SOX2 expression correlates with poorly differentiated tumors and with the basal-like phenotype. (32)

Regarding ovarian carcinoma, 1 study (33) found SOX2 nuclear staining (monoclonal anti-SOX2 antibody) in fewer tumors (15%), and that finding was associated with decreased duration for disease-free survival. However, another study (34) found that SOX2 nuclear expression (polyclonal anti-SOX2 antibody) was a common feature in ovarian carcinomas (60.5%) irrespective of the histopathologic type and correlated with increased tumor grade (64.6% in high-grade serous carcinoma). Interestingly, in patients with high-grade serous ovarian carcinoma at an advanced stage, SOX2 protein expression was associated with improved clinical outcome. (34) In the current investigation, monoclonal anti-SOX2 antibody was used, and overall, 19 of 113 specimens (16.8%) that were positive for gynecologic malignancy and 17 of 94 specimens (18.1%) specifically involved by high-grade serous carcinoma showed SOX2 nuclear staining. Further investigation and patient follow-up would be relevant regarding the relationship of SOX2 expression and prognosis/patient survival in that patient population. The authors plan to investigate that in a forthcoming study.

Another transcription factor, SALL4, is also associated with embryonic cell pluripotency and has been shown as a useful immunohistochemical marker for germ cell tumors. In 1 study, (35) SALL4 was detected in 29% cases of serous carcinoma of the ovary, 22% cases of urothelial high-grade carcinoma, 24% cases of gastric adenocarcinoma (especially the intestinal type), and 31% of metastatic carcinoma. SALL4 was only rarely ([less than or equal to] 5%) expressed in mammary, colorectal, prostatic, and squamous cell carcinomas. Many SALL4+ carcinomas showed poorly differentiated patterns. (35) Another small study, (36) however, found that all ovarian serous carcinomas were SALL4~ (0 of 23; 0%). In the current study, 8 of 113 positive fluid specimens (7.1%) and 8 of 94 fluids (8.5%) specifically involved by high-grade serous carcinoma showed SALL4 nuclear staining. The SOX2 and SALL4 genes, associated with embryonic cell pluripotency, appear to be expressed in some serous carcinomas. Whether they represent primitive/undifferentiated features of the tumor and the clinical significance of their tumor expression are still uncertain, and further research is needed.

In summary, immunohistochemical studies employed in evaluating fluid specimens for identifying tumor origin should be interpreted with caution. Most gynecologic serous carcinomas involving fluid specimens expressed PAX8, although at a lower percentage rate than did those of the primary tumor, as reported in other studies. GATA3 and uroplakin II can be expressed in serous carcinoma of the gynecologic system, although predominantly showing focal reactivity. Two transcription factors associated with pluripotency, SOX2 and SALL4, were found to be expressed in some cases. There are controversial reports regarding gene expression, such as SOX2, and prognosis. Further studies and follow-up with those patients would provide useful information for prognosis and patient survival data. In conclusion, to avoid misdiagnosis of cytologic fluid specimens, multiple combined immunohistochemical markers should be employed for identifying primary tumor origin, and the potential cross-reactivity of the marker with other tumor types must be considered when assessing body fluids involved by serous carcinoma.

We acknowledge the administrative support from Roland Schwarting, MD, and Dale Morrone, BS Ed; the essential technical assistance from Danielle Zaccagni, Associate in Science histotechnician; Nova Smith, Associate in Science and histotechnician; Jennifer McErlane, BS and cytotechnologist (American Society for Clinical Pathology); and Tara Coombs, Associate in Science and histotechnician, of Cooper University Hospital. Research support was provided by COOPER Foundation.

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Shuyue Ren, MD, PhD; William Klump, MD

Accepted for publication December 1, 2017.

Published online April 24, 2018.

From the Department of Pathology and Laboratory Medicine, Cooper Medical School of Rowan University, Camden, New Jersey.

The authors have no relevant financial interest in the products or companies described in this article.

Corresponding author: Shuyue Ren, MD, PhD, Department of Pathology and Laboratory Medicine, Cooper Medical School of Rowan University, 1 Cooper Plaza, Pavilion Basement, Room P065, Camden, NJ 08103 (email: Ren-Shuyue@Cooperhealth.edu).

Caption: Cytology fluid specimens positive for gynecologic carcinoma in cell blocks with hematoxylin-eosin (A) and immunohistochemical stains for PAX8 (B), GATA3 (C), SOX2 (D), uroplakin II (E), and SALL4 (F) (original magnification X200 [A through F]).
Table 1. Immunohistochemical Staining Results
of 113 Fluid Specimens With Positive Results

               Negative,       Focal       Positive,   Positive,
Markers           No.      Positive, No.      No.          %

PAX8              14             7            92         87.6
GATA3             94            14             5         16.8
SOX2              94             9            10         16.8
Uroplakin II      90            16             7         20.4
SALL4             105            5             3          7.1

Table 2. Immunohistochemical Staining Results
of Serous Carcinoma in 94 Fluid Specimens

               Negative,       Focal       Positive,   Positive,
Markers           No.      Positive, No.      No.          %

PAX8              10             7            77         89.4
GATA3             76            14             4         19.2
SOX2              77             9             8         18.1
Uroplakin II      72            16             6         23.4
SALL4             86             5             3          8.5

Table 3. Immunohistochemical Staining Results
of Non-High-Grade Serous Carcinoma in 19 Fluid
Specimens

Cancer Types       PAX8,   GATA3,   SOX2,   Uroplakin   SALL4,
(No. of Cases)      No.     No.      No.     II, No.     No.

Endometrioid         4       0        0         0         0
  carcinoma (5)
Low-grade serous     0       0        0         0         0
  carcinoma (1)
Mucinous             1       0        0         0         0
  carcinoma (2)
Undifferentiated     0       1        0         1         0
  carcinoma (1)
Neuroendocrine       0       0        1         0         0
  carcinoma (1)
Unknown cancer      10       0        1         0         0
  types (10)
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Author:Ren, Shuyue; Klump, William
Publication:Archives of Pathology & Laboratory Medicine
Date:Jun 1, 2019
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