Purpose
High-density tumor-infiltrating lymphocytes (TILs) are a prognostic marker for triple-negative breast cancer (TNBC). However, lymphocytic infiltration is heterogeneous in its pattern. We ...aimed to explore the utility of TIL distribution patterns against TIL density for predicting TNBC prognosis and chemotherapeutic effects.
Methods
Primary invasive TNBC cases were retrieved from a single institutional cohort, and archived samples were reviewed by two board-certificated pathologists. We used 154 consecutive surgical specimens from patients with standard adjuvant therapy, and 80 biopsies taken before primary systemic chemotherapy. The average density of stromal TILs was scored at 10% intervals, while the distribution pattern of TILs was evaluated as diffuse or non-diffuse. The association between TILs and prognosis or pathological complete response (pCR) was statistically analyzed.
Results
A diffuse pattern of TILs at primary surgery correlated with better prognosis (relapse-free survival RFS, hazard ratio HR 3.71, 95% confidence interval CI 1.60–8.57; overall survival OS, HR 3.87, 95% CI 1.46–10.27), as well as high TIL density (≥ 50%; RFS, HR 4.51, 95% CI 2.06–9.90; OS, HR 3.28, 95% CI 1.32–8.14). Diffuse TIL pattern and nodal status were independent prognostic factors in multivariate analysis. Diffuse TIL pattern upon biopsy was associated with higher pCR rate (diffuse, 46%; non-diffuse, 21%;
P
= 0.032). All high TIL cases had diffuse patterns and the best outcome. Interobserver concordance was moderate (
k
= 0.53–0.55; distribution pattern) to good (weighted
k
= 0.67–0.69; density), and it was faster to assess the distribution pattern than to assess the density of TIL.
Conclusions
Showing similar clinical impacts to the TIL density, diffuse TILs could be a predictive marker for better prognosis and higher pCR. The assessment of TIL distribution pattern is simple, faster, and practical. Heterogeneous tumor immunity may contribute to further stratification of TNBC treatment.
Purpose
The therapeutic effect of systemic treatment for breast cancer (BC) generally depends on its intrinsic subtypes. In addition, tumor infiltrating lymphocytes (TILs) are considered to be an ...independent factor for tumor shrinkage and disease prognosis. High TILs at baseline or after primary systemic chemotherapy are reported to be associated with better survival in triple-negative or human epithelial growth factor receptor 2 (HER2)-positive BCs. However, the prognostic value of TILs in estrogen receptor (ER)-positive and HER2-negative (ER+/HER2−) BC is still controversial.
Methods
We assessed TIL score (low, intermediate, and high) before and after primary systemic chemotherapy in every subtype of BC, and compared the clinical outcomes. Biopsy specimens of 47 triple-negative, 58 HER2+ and 91 ER+/HER2− BCs were used to assess TILs before treatment. To assess TILs after treatment, we examined residual invasive carcinoma in surgically resected samples of 28 triple-negative, 30 HER2+ and 80 ER+/HER2− BCs.
Results
A high TIL score in triple-negative BC before treatment resulted in a significantly higher proportion of pathological complete response (pCR). In contrast, ER+/HER2− BC exhibited fewer instances of pCR than other subtypes. Although not statistically significant, ER+/HER2− cases with a high TIL score also tended to achieve pCR (
p
= 0.088). Moreover, we revealed that low TIL BCs after chemotherapy, but not at baseline, had significantly better relapse-free survival in ER+/HER2− BC (
p
= 0.034).
Conclusion
Pathological examination of TILs after treatment may be a surrogate marker for prognosis in ER+/HER2− BC.
Aims
Precise evaluation of proliferative activity is essential for the stratified treatment of luminal‐type breast cancer (BC). Immunohistochemical staining of Ki‐67 has been widely used to determine ...proliferative activity and is recognised to be a useful prognostic marker. However, there remains discussion concerning the methodology. We aimed to develop an automated and reliable Ki‐67 assessment approach for invasive BC.
Materials and results
A retrospective study was designed to include two cohorts consisting of 152 and 261 consecutive patients with luminal‐type BC. Representative tissue blocks following surgery were collected, and three serial sections were stained automatically with Ki‐67, pan‐cytokeratin and p63. The whole slides were scanned digitally and aligned using VirtualTripleStaining – an extension to the VirtualDoubleStaining™ technique provided by Visiopharm software. The aligned files underwent automated invasive cancer detection, hot‐spot identification and Ki‐67 counting. The automated scores showed a significant positive correlation with the pathologists' scores (r = 0.82, P < 0.0001). Among selected patients with curative surgery and standard adjuvant therapies (n = 130), the digitally assessed low Ki‐67 group (<20%) demonstrated a significantly better prognosis (breast cancer‐specific survival, P = 0.030; hazard ratio = 0.038) than the high Ki‐67 group.
Conclusions
Digital image analysis yielded similar results to the scores determined by experienced pathologists. The prognostic utility was verified in our cohort, and an automated process is expected to have high reproducibility. Although some pitfalls were confirmed and thus need to be monitored by laboratory staff, the application could be utilised for the assessment of BC.
Background
The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been established in breast cancers with estrogen receptor (ER)-negative and human epithelial growth factor receptor ...2 (HER2)-negative or HER2-positive subtypes; however, its utility concerning the ER + /HER2 − subtype remains unclear.
Methods
We evaluated the prognostic value of TILs by analyzing 717 invasive breast cancer operation cases. TILs were classified into three groups based on the proportion of area within the tumor: low ( < 10%), intermediate (10–50%), and high ( > 50%). Disease-free survival (DFS) and overall survival (OS) were calculated according to TIL levels.
Results
Although there was no significant association between TIL levels and DFS or OS in all patients, high TILs were significantly associated with favorable DFS in Ki67-high (
n
= 238,
p
= 0.035) but not in Ki67-low (
n
= 470,
p
= 0.46) breast cancers. Multivariable analysis showed that high TILs were a significant and independent factor for DFS (HR 0.34; 95% CI 0.10–0.87;
p
= 0.023) among the Ki67-high group. In the ER + /HER2 − subtype, high-TILs showed favorable DFS in the Ki67-high group, although this was not statistically significant (
p
= 0.48); in contrast, unfavorable DFS was observed in the Ki67-low group (
p
= 0.027).
Conclusions
In Ki67-high breast cancers, high TILs were associated with favorable DFS, irrespective of subtype, but increasing TIL levels correlated with worse DFS in the Ki67-low group with the ER + /HER2 − subtype. These results highlight variation in TIL prognostic significance between Ki67-high and -low breast cancers, particularly for the ER + /HER2 − subtype.
IgG4-related disease is a recently recognized systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration, increase in the number of IgG4+ cells in affected tissues ...and elevation of serum IgG4 levels. In 2009, we were the first to report skin lesions in patients with IgG4-related disease, but no large case series has been reported and clinicopathological findings remain unclear. To clarify these features, we herein report 10 patients (9 men and 1 woman; median age, 64 years; age range, 46–81 years) with IgG4-related skin disease. All patients had erythematous and itchy plaques or subcutaneous nodules on the skin of the head and neck, particularly in the periauricular, cheek, and mandible regions, except for one patient, whose forearm and waist skin were affected. In addition, eight patients had extracutaneous lesions: these were found on the lymph nodes in six patients, the lacrimal glands in three patients, the parotid glands in three patients, and the kidney in one patient. Histologically examined extracutaneous lesions were consistent with IgG4-related disease; five of six lymph node lesions showed progressively transformed germinal centers-type IgG4-related lymphadenopathy. Cases of IgG4-related skin disease were classified into two histological patterns: those exhibiting a nodular dermatitis pattern and those with a subcutaneous nodule pattern. The infiltrate was rich in plasma cells, small lymphocytes, and eosinophils; the majority of the plasma cells were IgG4+. The IgG4+ cell count was 49–396 per high-power field (mean±s.d., 172±129), with an IgG4+/IgG+ cell ratio ranging from 62 to 92%. Serum IgG4 levels were elevated in all examined patients. In conclusion, patients with IgG4-related skin disease had uniform clinicopathology. Lesions were frequently present on the skin of the periauricular, cheek, and mandible regions, and were frequently accompanied by IgG4-related lymphadenopathy.
To investigate prospectively the prevalence of congenital cytomegalovirus (CMV) infection and the pathologic features of the placenta in cases of fetal growth restriction (FGR).
Forty-eight pregnant ...women who were diagnosed with FGR during pregnancy were enrolled for 15 months. Maternal CMV serologic tests, pathologic examinations of the placenta, and newborn urinary CMV-DNA polymerase chain reaction tests were performed in all the cases. The clinical characteristics and laboratory findings of the pregnant women and their newborns were collected. Biomarkers for inflammation, angiogenesis, and placental hormones were measured in the maternal serum at FGR diagnosis or in the neonatal urine at birth.
One of the 48 cases with FGR was a congenital CMV infection. CMV antigen was detected in the placenta of 7 cases with FGR. The change rate of the estimated fetal body weight was significantly lower in FGR cases with placental CMV detection. Placental villitis was observed more frequently in FGR cases with placental CMV detection. Human placental lactogen was significantly decreased in FGR cases with placental CMV detection. Increased C-reactive protein and serum amyloid A levels in the maternal serum were observed more frequently in FGR cases with placental CMV detection. Newborn urine β-2 microglobulin levels were significantly higher in FGR cases with placental CMV detection.
Serologic tests for maternal CMV, the change rate of the estimated fetal body weight, analysis of several biomarkers, and placental pathologic examinations might be helpful in comprehensively predicting the possibility of congenital CMV infection.
Various studies have demonstrated the causal relationship between gut microbiota and efficacy of chemotherapy; however, the impact of gut microbiota on breast cancer has not been fully elucidated. ...This study aimed to evaluate the associations between the gut microbiota before neoadjuvant chemotherapy and its consequent efficacy in breast cancer.PURPOSEVarious studies have demonstrated the causal relationship between gut microbiota and efficacy of chemotherapy; however, the impact of gut microbiota on breast cancer has not been fully elucidated. This study aimed to evaluate the associations between the gut microbiota before neoadjuvant chemotherapy and its consequent efficacy in breast cancer.This prospective observational study included patients who received neoadjuvant chemotherapy for primary early breast cancer at eight institutions between October 1, 2019, and March 31, 2022. We performed 16S rRNA analysis of fecal samples and α and β diversity analyses of the gut microbiota. The primary endpoint was the association between the gut microbiota and pathological complete response (pCR) to neoadjuvant chemotherapy.METHODSThis prospective observational study included patients who received neoadjuvant chemotherapy for primary early breast cancer at eight institutions between October 1, 2019, and March 31, 2022. We performed 16S rRNA analysis of fecal samples and α and β diversity analyses of the gut microbiota. The primary endpoint was the association between the gut microbiota and pathological complete response (pCR) to neoadjuvant chemotherapy.Among the 183 patients, the pCR rate after neoadjuvant chemotherapy was 36.1% in all patients and 12.9% (9/70), 69.5% (41/59), and 29.6% (16/54) in those with the luminal, human epidermal growth factor receptor 2, and triple-negative types, respectively. The α diversity of the gut microbiota did not significantly differ between patients with pCR and those without pCR. Among the gut microbiota, two species (Victivallales, P = 0.001 and Anaerolineales, P = 0.001) were associated with pCR, and one (Gemellales, P = 0.002) was associated with non-pCR.RESULTSAmong the 183 patients, the pCR rate after neoadjuvant chemotherapy was 36.1% in all patients and 12.9% (9/70), 69.5% (41/59), and 29.6% (16/54) in those with the luminal, human epidermal growth factor receptor 2, and triple-negative types, respectively. The α diversity of the gut microbiota did not significantly differ between patients with pCR and those without pCR. Among the gut microbiota, two species (Victivallales, P = 0.001 and Anaerolineales, P = 0.001) were associated with pCR, and one (Gemellales, P = 0.002) was associated with non-pCR.Three species in the gut microbiota had potential associations with neoadjuvant chemotherapy efficacy, but the diversity of the gut microbiota was not associated with response to chemotherapy. Further research is needed to validate our findings.CONCLUSIONThree species in the gut microbiota had potential associations with neoadjuvant chemotherapy efficacy, but the diversity of the gut microbiota was not associated with response to chemotherapy. Further research is needed to validate our findings.
Tumor-infiltrating lymphocytes (TILs) have potential value for stratifying the treatment of breast cancer (BC), though their precise use remains unclear. We aimed to investigate the utility of TILs ...using an alternative approach in different settings. We reviewed patients with triple-negative (TN) or human epithelial growth factor receptor 2 (HER2)-positive invasive ductal carcinomas from a single institutional cohort and classified archived hematoxylin–eosin-stained samples in terms of TIL score as low (<10 %), intermediate, and high (>50 %). The prognostic and predictive values of TILs were analyzed retrospectively in both adjuvant and neo-adjuvant settings. In the adjuvant setting, the presence of TILs at primary surgery was a significant favorable prognostic factor among 154 TNBCs relapse-free survival (RFS):
p
= 0.015, but not among 183 HER2+ BCs (RFS:
p
= 0.097). The TNBC low-TIL group tended to relapse earlier. In the neo-adjuvant setting, detection of TILs on biopsy before primary systemic therapy was associated with the ratio of patients achieving pathological complete response among 48 TNBCs (
p
= 0.024), but not among 58 HER2+ BCs (
p
= 0.30). The presence of TILs in surgical specimens after systemic therapy had prognostic value in HER2+ BC (RFS:
p
= 0.007). The impact of TILs differs between patients with TN and HER2+ BC treated with standard therapies. Our three-grade scale for TILs may contribute to our understanding of the importance of the tumor microenvironment in routine practice. TILs after primary systemic therapy may be useful for the further stratification of treatment of HER2+ BC.
Dedifferentiated liposarcoma is a rare cancer with a poor prognosis. A 52-year-old man presented with a chief complaint of a mass in his left scrotum. He came with suspected testicular tumor, but all ...the measured tumor markers were negative. Imaging test showed approximately 2 cm diameter mass accompanied by calcification with some substantial components between the testis and epididymis. Left high testicular resection was performed. The tumor had no continuity between the testis and epididymis, and the spermatic cord transection was negative. Pathological findings showed well differentiated fatty component and a dedifferentiated component around the trabecular bone-like tissue. We observed dedifferentiated dysmorphic cells mixed with fatty droplets of unequal size. Immunostaining led to the diagnosis of dedifferentiated liposarcoma. No additional postoperative therapy was performed. The possibility of dedifferentiated liposarcoma should be kept in mind even if mass is confined to the scrotum and consisted of calcification. In the case of an intrascrotal calcified mass with malignant perspective, radical surgery is highly recommended.
Background
The Ki67 labeling index (LI) reflects the proliferative activity of breast cancers and defines luminal A and B tumors; however, no detailed method to measure Ki67 has been standardized. ...Here, we propose a fast and easy way to evaluate Ki67.
Methods
Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki67 (MIB-1) was performed on 235 primary invasive ductal carcinomas. For each sample, a hot spot with many Ki67+ cells was identified using a low-power field (40×, 4× objective). Three independent areas in high-power field (400×) were selected at the hot spot, and all cancer cells in the 3 areas were manually counted to calculate LI (% Ki67+ cells). Alternatively, micrographs taken at 100× and 200× fields including the hot spot were shown to 2 pathologists, who visually assessed percentages of Ki67+ cells in 10 % intervals at a glance (Eye-10).
Results
Eye-10 and LI were strongly correlated (
r
= 0.9412,
P
< 0.0001). All cases of Eye-10 ≥ 30 % had LI > 14 %; most of those <10 % had LI < 14 %. Of 170 ER+/HER2− tumors, Eye-10-based subtypes matched 87 % of LI-driven subtypes, and interobserver agreement was good (
κ
= 0.705).
Conclusion
Eye-10 is far easier than counting many cancer cells and useful for classifying breast cancers. Eye-10 can exclude obviously high and low Ki67 cases, leaving a “gray zone” around a cutoff point. Combining Eye-10 and manual counting is a good candidate for a standard method to evaluate Ki67.
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