SMARCA4-deficient undifferentiated thoracic tumor: A case report.

BACKGROUND: SMARCA4-deficient undifferentiated tumors (SMARCA4-DUTs) present with diverse clinical manifestations and progress to metastasis and even cause death within a few months. This novel subset of undifferentiated tumors occurs in the middle-aged population and is strongly associated with a smoking history. Distinguishing it from other malignancies is challenging. CASE SUMMARY: A 62-year-old man presented with chest pain for 7 d. The patient had no respiratory symptoms and normal pulmonary function test results. The patient had been a smoker for 8 years and quit smoking 2 years ago. Chest computed tomography revealed a huge mass involving the left upper and lower lung lobes with pericardial invasion and multiple metastases. Tumor samples were obtained using open frozen biopsy, after several unsuccessful attempts. The tumor was composed of sheets of undifferentiated disclosive cells with vesicular nuclei and prominent nucleoli. The differential diagnosis included high-grade lymphoma, germ cell tumor, NUT carcinoma, undifferentiated carcinoma, and sarcoma. The tumor cells were large, arranged in sheets, and did not exhibit glandular or squamous differentiation. Frequent foci of necrosis were noted. There was no evidence of epithelial differentiation on immunohistochemical staining. The SMARCA4 stain showed complete loss of expression of SMARCA4, which is diagnostic. CONCLUSION: In the present case, thoracic SMARCA4-DUT was diagnosed based on clinical features, absence of epithelial differentiation, and negative SMARCA4 expression.

Endobronchial ultrasound-guided re-biopsy of non-small cell lung cancer with acquired resistance after EGFR tyrosine kinase inhibitor treatment.

BACKGROUND: Few studies assessed the use of endobronchial ultrasound (EBUS)-guided re-biopsy for detecting the T790M mutation after epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure. METHODS: A total of 2996 EBUS procedures were performed during the study period (January 2019-June 2022). In total, 44 consecutive patients who underwent EBUS-guided re-biopsy (56 procedures) for detecting the T790M mutation were analyzed. The success rates and T790M mutation frequencies were analyzed according to the re-biopsy site and EBUS method. Multivariate logistic regression analyses were used to identify factors affecting the likelihood of the T790M mutation. RESULTS: The success rates for the mutation analyses using EBUS with a guide-sheath (EBUS-GS), EBUS guided transbronchial needle aspiration (EBUS-TBNA), and EBUS-GS with EBUS-TBNA for re-biopsy were 80.6% (29/36), 93.3% (14/15), and 100% (5/5), respectively. Patients who underwent lymph node biopsy using EBUS-TBNA had an increased rates of the T790M mutation compared with those undergoing lung biopsy using EBUS-GS (EBUS-TBNA, 60.0%; EBUS-GS with EBUS-TBNA, 40.0%; EBUS-GS, 11.1%; p < 0.001). In multivariate analysis, the use of a first-generation EGFR-TKI (odds ratio [OR], 4.29; 95% confidence interval [CI], 1.05-17.58; p = 0.043) was associated with occurrence of the T790M mutation. Re-biopsy of the metastatic site tended to be associated with a higher T790M mutation rate. Mild hemoptysis occurred in 3.6% (2/56) of the patients. CONCLUSIONS: EBUS-guided re-biopsy can be used for detecting the T790M mutation in patients who failed EGFR-TKI therapy. The T790M mutation frequency differed according to the re-biopsy site. The use of a first-generation EGFR-TKI was an independent predictor of the T790M mutation.

Chromophobe renal cell carcinoma-like thyroid carcinoma: possible misdiagnosis as metastatic renal cell carcinoma.

To date, multiple thyroid cancer variants have been reported. Herein, we report a rare case of chromophobe renal cell carcinoma-like thyroid carcinoma (CRETHCA) in a 60-year-old woman, for which the morphologic findings resembled those of chromophobe renal cell carcinoma (ChRCC). ChRCC of the kidney is characterized by large polygonal tumor cells with distinct cell borders, perinuclear clearing, multiple binucleate cells, and strongly positive immunostaining for paired box gene 8 (PAX8) and carbonic anhydrase IX (CA IX). In our case, the thyroid gland tumor was incidentally detected by routine medical screening without sufficient medical information; it showed similar histology and immunohistochemical features to ChRCC and was initially misdiagnosed as metastatic ChRCC. Additional tests, including kidney computed tomography and positron emission tomography, revealed no abnormalities in the patient's kidney; therefore, we diagnosed the tumor as CRETHCA. Focal weak staining for thyroid transcription factor 1 (TTF-1) was the only supporting evidence that it was a primary thyroid neoplasm. To the best of our knowledge, this is the second report of CRETHCA in literature. This novel variant is very difficult to distinguish from metastatic ChRCC and can be a diagnostic challenge for pathologists. Further studies of similar cases should be done to define this new entity.

Radial Probe Endobronchial Ultrasound Using Guide Sheath-Guided Transbronchial Lung Biopsy in Peripheral Pulmonary Lesions without Fluoroscopy.

BACKGROUND: Radial probe endobronchial ultrasound-guided transbronchial lung biopsy (RP-EBUS-TBLB) has improved the diagnostic yield of bronchoscopic biopsy of peripheral pulmonary lesions (PPLs). The diagnostic yield and complications of RP-EBUS-TBLB for PPLs vary depending on the technique, such as using a guide sheath (GS) or fluoroscopy. In this study, we investigated the utility of RP-EBUS-TBLB using a GS without fluoroscopy for diagnosing PPLs. METHODS: We retrospectively reviewed data from 607 patients who underwent RP-EBUS of PPLs from January 2019 to July 2020. TBLB was performed using RP-EBUS with a GS without fluoroscopy. The diagnostic yield and complications were assessed. Multivariable logistic regression analyses were used to identify factors affecting the diagnostic yields. RESULTS: The overall diagnostic accuracy was 76.1% (462/607). In multivariable analyses, the size of the lesion (≥20 mm; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.27-3.33; p=0.003), positive bronchus sign in chest computed tomography (OR, 2.30; 95% CI, 1.40-3.78; p=0.001), a solid lesion (OR, 2.40; 95% CI, 1.31-4.41; p=0.005), and an EBUS image with the probe within the lesion (OR, 6.98; 95% CI, 4.38-11.12; p<0.001) were associated with diagnostic success. Pneumothorax occurred in 2.0% (12/607) of cases and chest tube insertion was required in 0.5% (3/607) of patients. CONCLUSION: RP-EBUS-TBLB using a GS without fluoroscopy is a highly accurate diagnostic method in diagnosing PPLs that does not involve radiation exposure and has acceptable complication rates.

Delayed sarcoidosis onset mimicking mediastinal lymphoma recurrence after complete remission of diffuse large B cell lymphoma: A case report.

Sarcoidosis-lymphoma syndrome describes a pathological state wherein both sarcoidosis and lymphoma are present. Sarcoidosis and lymphoma may occur concurrently, or sarcoidosis may precede lymphoma. There are few reports which have previously described the temporal progression from lymphoma to sarcoidosis. Here, we present a patient with stage II diffuse large B-cell lymphoma in the right breast. The patient achieved complete remission after chemotherapy. Five years after remission, the patient visited our clinic with newly developed enlarged mediastinal lymph nodes; lymphoma recurrence was suspected. However, mediastinal lymph node biopsy showed numerous noncaseating granulomas with no evidence of malignancy in the mediastinal lymph nodes. Consequently, a diagnosis of sarcoidosis was made. This case report highlights the need for pathological confirmation following biopsy when recurrence of lymphoma is suspected.

Metastatic large cell carcinoma of the lung: A rare cause of acute small bowel obstruction.

Here, we report a case of acute intestinal obstruction as the initial presentation of primary lung cancer in a male patient. Abdominal computed tomography (CT) showed multiple polypoid masses and regional lymphadenopathy with small bowel obstruction. The patient underwent emergency surgery for multiple luminal malignancy with mesenteric masses. According to the various clinicopathological features, the tumor was confirmed to be metastatic large cell carcinoma originating from the lung. Large masses in the left lower lobe of the lung were identified on the chest CT after emergency surgery, and non-small cell lung cancer (NSCLC), not otherwise specified (NOS), was finally diagnosed on biopsy through bronchoscopy.

Role of Remote Ischemic Preconditioning in Hepatic Ischemic Reperfusion Injury.

The effect of remote ischemic preconditioning (RIPC) has been proposed that mediates the protective response in ischemia reperfusion injury (IRI) of various organs. In this study, we investigated the effect of RIPC in hepatic IRI, by assessing biomarker of oxidative stress and inflammatory cytokines. Moreover, we intended to demonstrate any such protective effect through nitric oxide (NO). Twenty-five rats were divided into the 5 groups: (1) Sham; (2) RIPC; (3) hepatic IRI; (4) RIPC + hepatic IRI; (5) C-PTIO, 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide, + RIPC + hepatic IRI. RIPC downregulated the level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), histologic damage, and activity of Malondialdehyde (MDA). However, there was no significant reduction in the level of tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). AST and ALT levels, and hepatic tissue morphology in the C-PTIO group showed a significant improvement compared to those of the RIPC + hepatic IRI group. The application of RIPC before hepatic ischemia downregulated the oxidative stress, not the inflammatory cytokines. Moreover, these protective effect of RIPC would be mediated through the activation of NO as well as anti-oxidant effect.

Undifferentiated carcinoma arising in ovarian mature cystic teratoma: a case report and literature review.

Malignant transformation is a rare complication of the mature cystic teratoma of the ovary. Most of these histologic types are squamous cell carcinoma, and other types are exceptionally rare. Here, we present an extremely rare histology of malignant transformation, an undifferentiated carcinoma, arising in mature cystic teratoma of the ovary. A 48-year-old woman was referred due to abdominal distension and palpable pelvic mass. Computed tomography showed 16- and 12-cm-diameter mixed solid and cystic tumors in bilateral ovaries. Surgical exploration revealed bilateral ovarian tumors with multiple nodules on the whole peritoneum, liver capsule, and diaphragm. Cytoreductive surgery was performed, leaving <1 cm tumors. On pathologic review, the tumor was confirmed as undifferentiated with an adenosquamous carcinoma component arising in mature cystic teratoma. The patient died 7 days postoperatively due to uncontrolled malignant ascites and pleural effusion. We report a case of undifferentiated carcinoma arising from mature cystic teratoma, and we review the clinicopathologic features of this rare case.

The updated 2018 American Society of Clinical Oncology/College of American Pathologists guideline on human epidermal growth factor receptor 2 interpretation in breast cancer: comparison with previous guidelines and clinical significance of the proposed in situ hybridization groups.

The aim of the study was to evaluate the impact of the updated 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline on human epidermal growth factor receptor 2 (HER2) interpretation in breast cancer compared with that of the previous guidelines and also the significance of in situ hybridization (ISH) groups proposed by the updated guideline. HER2 ISH reports and immunohistochemistry (IHC) data from 1,348 invasive breast cancers diagnosed at a single institution were included in this study. HER2 IHC was reassessed using the 2018 guideline, and HER2 ISH status was determined by the 2007, 2013, and 2018 guidelines. When applying the updated guideline, most of the HER2 ISH-equivocal cases as per the previous guidelines were reclassified as ISH negative, and 0.8% of HER2 ISH-positive tumors as per the 2007 guideline and 2.5% of those as per the 2013 guideline were changed to ISH negative. Accordingly, the negative HER2 ISH results significantly increased in the 2018 guideline compared with the 2013 guideline. HER2 ISH-positive tumors in ISH group 3 (HER2/chromosome enumeration probe 17 [CEP17] ratio <2.0 and average HER2 copy number ≥6.0 per cell) were characterized by equivocal HER2 protein expression, CEP17 copy number gain, and low HER2 copy numbers compared with classic HER2 ISH-positive tumors in ISH group 1 (HER2/CEP17 ratio ≥2.0 and average HER2 copy number ≥4.0 per cell). HER2 ISH-negative tumors in ISH group 4 (HER2/CEP17 ratio <2.0 with average HER2 copy number ≥4.0 and < 6.0 per cell) revealed more aggressive clinicopathologic features and poorer clinical outcomes than those in ISH group 5 (HER2/CEP17 ratio <2.0 and average HER2 copy number <4.0 per cell), especially in the hormone receptor-positive subgroup. In conclusion, implementation of the updated 2018 ASCO/CAP guideline leads to a significant increase in HER2 ISH-negative results compared with the 2013 guideline, mainly via reclassification of the ISH-equivocal cases to ISH-negative ones. ISH groups proposed by the updated guideline provide additional information on the clinicopathologic characteristics of the tumors.

Abdominopelvic Actinomycosis Mimicking Peritoneal Carcinomatosis: A Case Report.

Actinomycosis is a rare chronic bacterial infection primarily caused by Actinomyces israelii. A 47-year-old woman presented to our clinic with a 1-week history of lower abdominal pain. Preoperative imaging studies revealed multiple peritoneal and pelvic masses suggestive of malignancy. The primary tumor could not be identified despite further endoscopic and gynecological evaluation. On exploration for tissue confirmation, excisional biopsies from multiple masses were performed because complete excision was not possible. Histopathological examination confirmed actinomycosis with multiple abscesses, and the patient was treated with antibiotics. We present a case of disseminated peritoneal actinomycosis that mimicked malignant peritoneal carcinomatosis on imaging studies.

Centromere 17 copy number gain reflects chromosomal instability in breast cancer.

Chromosomal instability (CIN) is known to be associated with prognosis and treatment response in breast cancer. This study was conducted to determine whether copy number gain of centromere 17 (CEP17) reflects CIN, and to evaluate the prognostic and predictive value of CIN in breast cancer. CIN status was determined by summing copy number gains of four centromeric probes (CEP1, CEP8, CEP11, and CEP16) based on fluorescence in situ hybridization and CIN scores were calculated using next generation sequencing data. High CIN was associated with adverse clinicopatholgical parameters of breast cancer. Among them, positive HER2 status, high Ki-67 index and CEP17 copy number gain were found to be independent predictors of high CIN. High CIN was associated with poor clinical outcome of the patients in the whole group, as well as in luminal/HER2-negative and HER2-positive subtypes. CEP17 copy number was significantly higher in the high-CIN-score group than in the low-CIN-score group. A positive linear correlation between the mean CEP17 copy number and the CIN score was found. In conclusion, CEP17 copy number was confirmed as a useful predictor for CIN in breast cancer, and high CIN was revealed as an indicator of poor prognosis in breast cancer.

Pleural small cell carcinoma with massive pleural effusion: A case report.

RATIONALE: Small cell carcinoma (SCC) occurs mostly in the lung, and small cell lung cancer accounts for 13% of newly diagnosed lung cancers. Only 2.5% of SCC occurs in extrapulmonary sites, and SCC of pleural origin is especially very uncommon. PATIENT CONCERNS: An 85-year-old man presenting with progressive dyspnea for more than 7 days. DIAGNOSES: Computed tomography scan of the chest showed massive pleural effusion and diffuse nodular thickening of the pleura on the right chest. Sonography-guided needle biopsy of the pleural mass was performed and histologic and immunohistochemical findings revealed SCC. Since no parenchymal lung lesion was observed, the patient was finally diagnosed with SCC of the pleura (SCCP). INTERVENTIONS: Due to the patient's old age and poor performance status, chemotherapy was not performed and only drainage of pleural effusion was conducted for symptom relief. OUTCOMES: Dyspnea improved after pleural effusion drainage. The patient was discharged and transferred to a local medical center for hospice care. LESSONS: Although primary SCCP is extremely rare, SCCP should also be considered as well as mesothelioma in case of presence of a pleural-based mass with massive pleural effusion.

Mediastinal Epithelioid Hemangioendothelioma Invading Superior Vena Cava: A Case Report and Review of Literature.

INTRODUCTION: Epithelioid Hemangioendothelioma (EHE) is a rare vascular neoplasm. Common locations of EHE are the bone, soft tissue, liver, and lung, but the mediastinal location is extremely rare. Few cases of mediastinal EHE, invading the Superior Vena Cava (SVC) have been reported. CASE PRESENTATION: We report a case of a 21-year-old man with EHE invading the SVC, which was incidentally detected on performing chest radiography. A contrast-enhanced chest Computed Tomography (CT) scan demonstrated a well-defined, oval mass located on the right side of the anterior mediastinum. The mass showed homogeneous enhancement with punctate calcifications, and it invaded the SVC at the confluence area of the right and left brachiocephalic veins. CONCLUSION: Mediastinal EHE invading the SVC may present as a homogeneously enhancing mass with punctate calcifications. It should be added to the differential diagnosis of tumors of the mediastinum. Accurate preoperative diagnosis of EHE is critical for surgical planning; therefore, knowledge of the radiologic features of EHE is important.

Ovarian Gynandroblastoma with a Juvenile Granulosa Cell Tumor Component in a Postmenopausal Woman: A Case Report and Literature Review.

Gynandroblastoma is an extremely rare sex cord-stromal tumor with both female (granulosa cell tumor) and male (Sertoli-Leydig cell tumor) elements. Juvenile granulosa cell tumors are also very rare and are so named because they usually occur in children and adolescents. A 71-year-old woman with right upper quadrant abdominal pain visited our hospital. Pelvic computed tomography showed a large multilocular cystic mass, suspected to be of ovarian origin. We performed a total abdominal hysterectomy (total abdominal hysterectomy was performed) with bilateral salpingooophorectomy. A 13-cm multilocular cystic mass with serous fluid was observed in her right ovary. Upon microscopic examination, the solid component of the mass showed both Sertoli-Leydig cell and juvenile granulosa cell differentiation, which we diagnosed as gynandroblastoma. Gynandroblastoma with a juvenile granulosa cell tumor component is extremely rare and, until now, only six cases have been reported in the English literature. We report the first gynandroblastoma with a juvenile granulosa cell tumor component diagnosed in an elderly patient, along with a literature review.

Prognostic value of microRNA-9 and microRNA-155 expression in triple-negative breast cancer.

MicroRNAs (miRNAs) are involved in regulation of epithelial-mesenchymal transition (EMT) during breast cancer progression. The purpose of this study was to analyze the clinicopathologic significance of expression of EMT-related miRNAs, miR-9 and miR-155, in triple-negative breast cancers (TNBCs). We analyzed relative expression levels of miR-9 and miR-155 in 190 surgically resected TNBC specimens using quantitative real-time polymerase chain reaction. Then we analyzed the relationship between these miRNA expression levels and EMT marker expression (vimentin, smooth muscle actin [SMA], osteonectin, N-cadherin, E-cadherin, CD146, and ZEB1) assessed by immunohistochemistry. We also evaluated the prognostic significance of these miRNA expression levels. While miR-9 expression level showed a positive correlation with pT category, miR-155 expression level did not correlate with any clinicopathologic features of TNBCs. In relation to EMT phenotype, miR-9 expression was not associated with EMT marker expression except for SMA. However, miR-155 expression level correlated inversely with the expression of several EMT markers including SMA, osteonectin, and CD146. We observed that both miR-9 and miR-155 could be prognostic markers in TNBC in opposite ways; high level of miR-9 expression showed significant association with poor disease-free survival and distant metastasis-free survival (DMFS) in TNBC, while high level of miR-155 expression was associated with better DMFS. Our study suggests that expression levels of both miR-9 and miR-155 can serve as candidates for prognostic biomarkers in TNBCs.

Mutations of the Epidermal Growth Factor Receptor Gene in Triple-Negative Breast Cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). However, the frequency of EGFR gene mutation in TNBC is low and varies with ethnicity. This study aimed to investigate the incidence of EGFR gene mutation in TNBC. METHODS: EGFR protein expression was evaluated by immunohistochemistry in tissue microarrays of 493 TNBC cases using four different primary antibodies, which included mutation-specific antibodies. For cases with an immunoreactivity level ≥1+, we performed pyrosequencing analysis for EGFR gene mutation. A case was considered mutation-positive when its mutation frequency minus its limit of detection (LOD) was >10%. Cases with mutation frequency higher than LOD were assessed for EGFR gene mutation status using the Cobas assay and by peptide nucleic acid-mediated polymerase chain reaction (PNA-clamping). RESULTS: Among 493 TNBCs, 148 (30.0%) exhibited staining ≥1+ for EGFR, including 78 with 1+, 49 with 2+, and 21 with 3+. Positive EGFR expression (≥2+) was significantly associated with lymphovascular invasion (p=0.010), but not with overall survival (p=0.444) or disease-free survival (p=0.388). None of the 493 TNBCs harbored an EGFR gene mutation. Among 148 cases with an EGFR staining result ≥1+, five (3.4%) showed mutation frequencies (4.4%-10.9%) higher than LOD (2.6%-4.3%) in exons 19 (L747_P753>Q) or 21 (L858R and L861Q) as determined by pyrosequencing. However, Cobas and PNA-clamping failed to detect the presence of EGFR gene mutation in these five cases. CONCLUSION: No activating mutation of EGFR gene of clinical significance was observed in 148 TNBC cases using three commercially available methods. Thus, EGFR gene mutation appears to be an extremely rare event in patients with TNBC.

Expression of embryonal stem cell transcription factors in breast cancer: Oct4 as an indicator for poor clinical outcome and tamoxifen resistance.

The transcription factors of embryonic stem cells, such as Oct4, Sox2, Nanog, Bmi1, and Klf4, are known to be associated with stemness, epithelial-mesenchymal transition and aggressive tumor behavior. This study was designed to evaluate the clinicopathological significance of their expression in breast cancer. Immunohistochemistry for Oct4, Sox2, Nanog, Bmi1, and Klf4 was performed in 319 cases of invasive breast cancer. The relationship between the expression of these markers and clinicopathologic features of the tumors, including breast cancer stem cell phenotype and epithelial-mesenchymal transition marker expression, and their prognostic value in breast cancer, were analyzed. Expression of Oct4 and Sox2 was commonly associated with high histologic grade and high Ki-67 index in the whole group and in the hormone receptor-positive subgroup. On the other hand, expression of Nanog, Bmi1, and Klf4 was inversely correlated with aggressive features of the breast cancer. Oct4 expression was associated with ALDH1 expression but not with epithelial-mesenchymal transition marker expression. In survival analysis, Oct4 expression was independently associated with poor prognosis in the whole group and in the hormone receptor-positive subgroup, but not in hormone receptor-negative subgroup. Particularly, Oct4 expression was associated with poor clinical outcome in patients with hormone receptor-positive breast cancer treated with tamoxifen. Our results indicate that Oct4 expression is associated with aggressive features, ALDH1 expression, tamoxifen resistance and poor clinical outcomes in hormone receptor-positive breast cancer, and thus may be useful as a predictive and prognostic marker in this subgroup of breast cancer.

A comparison of Ki-67 counting methods in luminal Breast Cancer: The Average Method vs. the Hot Spot Method.

In spite of the usefulness of the Ki-67 labeling index (LI) as a prognostic and predictive marker in breast cancer, its clinical application remains limited due to variability in its measurement and the absence of a standard method of interpretation. This study was designed to compare the two methods of assessing Ki-67 LI: the average method vs. the hot spot method and thus to determine which method is more appropriate in predicting prognosis of luminal/HER2-negative breast cancers. Ki-67 LIs were calculated by direct counting of three representative areas of 493 luminal/HER2-negative breast cancers using the two methods. We calculated the differences in the Ki-67 LIs (ΔKi-67) between the two methods and the ratio of the Ki-67 LIs (H/A ratio) of the two methods. In addition, we compared the performance of the Ki-67 LIs obtained by the two methods as prognostic markers. ΔKi-67 ranged from 0.01% to 33.3% and the H/A ratio ranged from 1.0 to 2.6. Based on the receiver operating characteristic curve method, the predictive powers of the KI-67 LI measured by the two methods were similar (Area under curve: hot spot method, 0.711; average method, 0.700). In multivariate analysis, high Ki-67 LI based on either method was an independent poor prognostic factor, along with high T stage and node metastasis. However, in repeated counts, the hot spot method did not consistently classify tumors into high vs. low Ki-67 LI groups. In conclusion, both the average and hot spot method of evaluating Ki-67 LI have good predictive performances for tumor recurrence in luminal/HER2-negative breast cancers. However, we recommend using the average method for the present because of its greater reproducibility.

Prognostic value of tumor infiltrating lymphocyte subsets in breast cancer depends on hormone receptor status.

PURPOSE: Interaction between immune-regulatory proteins and tumor infiltrating lymphocytes (TILs) is complex, and their associations may have significant clinical implications. This study was designed to evaluate the relationships between immunomodulatory proteins and TIL subsets and their impact on prognosis in breast cancer. METHODS: 377 invasive breast cancer cases were selected, and immunohistochemistry was performed for HLA-A, HLA-ABC, and indoleamine 2,3-dioxygenase (IDO); CD4+, CD8+, and FOXP3+ T cells were counted in intratumoral and stromal areas for both absolute numbers as well as their ratios. RESULTS: While HLA-ABC and HLA-A expressions showed a positive correlation with CD8+ and FOXP3+ TIL infiltration, IDO expression showed a negative correlation with FOXP3+/CD4+ and FOXP3+/CD8+ T cell ratios. Expressions of HLA-ABC, HLA-A, and IDO shared an association with negative estrogen receptor status. Infiltration of CD4+, CD8+, and FOXP3+ TILs was significantly higher in tumors with high histologic grade, negative hormone receptor status, HER2 amplification, high Ki-67 index, and p53 overexpression. In survival analyses, increased CD4+ TIL infiltration was associated with better prognosis of the patients while other TIL subset infiltration and expression of immunomodulatory proteins had no prognostic significance. In subgroup analyses, high CD4+ TIL infiltration was revealed as an independent good prognostic factor in hormone receptor-negative subgroup while high FOXP3+/CD8+ T cell ratio was found to be an independent adverse prognostic factor in hormone receptor-positive subgroup, especially in luminal A subtype. CONCLUSION: CD4+ TIL subset and FOXP3+/CD8+ T cell ratio have different prognostic significance in breast cancer according to hormone receptor status.