Micropapillary Pattern Research Articles

The Diagnosis, Treatment, Prognosis and Molecular Pathology of Borderline Ovarian Tumors: Current Status and Perspectives.

Borderline ovarian tumors (BOTs) are a type of low malignant potential tumor that is typically associated with better outcomes than ovarian cancer. Indeed, its 10-year survival rate is as high as 95%. However, there is a small subset of patients who experience relapse and eventually die. It has been shown that the prognosis of BOTs was based on pathological diagnosis, the age at diagnosis, pre-operative carbohydrate antigen 125 level, invasive implants, and micropapillary patterns. Now the molecular-targeted therapy and molecular-genetic diagnosis have developed into a form of precision medicine. Recent studies on extensive molecular characterizations and molecular pathological mechanisms of BOTs have helped us understand the genomic landscapes of BOTs, and therefore BOTs could be reclassified into biologically and clinically more accurate and effective subtypes. The purpose of this review is to summarize current status for the diagnosis and treatment of BOTs and to describe the research progress on molecular pathologies, with a goal of providing a theoretical perspective for the diagnosis and treatment of BOTs.

Establishment and characterization of a cell line and patient-derived xenograft (PDX) from peritoneal metastasis of low-grade serous ovarian carcinoma

Peritoneal spread indicates poor prognosis in patients with serous ovarian carcinoma (SOC) and is generally treated by surgical cytoreduction and chemotherapy. Novel treatment options are urgently needed to improve patient outcome. Clinically relevant cell lines and patient-derived xenograft (PDX) models are of critical importance to therapeutic regimen evaluation. Here, a PDX model was established, by orthotopic engraftment after subperitoneal tumor slurry injection of low-grade SOC, resulting in an early-stage transplantable peritoneal metastasis (PM)-PDX model. Histology confirmed the micropapillary and cribriform growth pattern with intraluminal tumor budding and positivity for PAX8 and WT1. PM-PDX dissociated cells show an epithelial morphotype with a 42 h doubling time and 40% colony forming efficiency, they are low sensitive to platinum derivatives and highly sensitive to paclitaxel (IC50: 6.3 ± 2.2 nM, mean ± SEM). The patient primary tumor, PM, PM-PDX and derived cell line all show a KRAS c.35 G > T (p.(Gly12Val)) mutation and show sensitivity to the MEK inhibitor trametinib in vitro (IC50: 7.2 ± 0.5 nM, mean ± SEM) and in the PM mouse model. These preclinical models closely reflecting patient tumors are useful to further elucidate LGSOC disease progression, therapy response and resistance mechanisms.

Discohesive growth pattern (Disco-p) as an unfavorable prognostic factor in lung adenocarcinoma: an analysis of 1062 Japanese patients with resected lung adenocarcinoma.

Discohesive growth pattern (Disco-p) is often observed in lung adenocarcinoma (ADC) and mimics tumor budding (TB), stromal invasive-type micropapillary pattern (SMPP), and complex glandular pattern. However, the clinical impact of Disco-p in lung ADC has not been well studied. To investigate the prognostic significance of Disco-p, we analyzed 1062 Japanese patients with resected lung ADC. Disco-p was defined as an invasive growth pattern composed of single tumor cells, or trabeculae or small nests of tumor cells associated with desmoplastic fibrous stroma. We recorded the percentage of Disco-p in 5% increments independent of the major histologic pattern and investigated its correlation with different clinicopathological factors. We also analyzed the overall survival (OS) and disease-free survival (DFS). Disco-p was observed in 203 tumors (19.1%). Disco-p was significantly associated with male sex, smoking, lymph node metastasis, large tumor size, high TNM stage, lymphovascular and pleural invasion, spread through air spaces, and TB (all, p < 0.001). Of the total cases, only eight cases exhibited a dubious pattern between SMPP and Disco-p. Disco-p was also associated with wild-type EGFR (p < 0.001) and ALK fusion (p = 0.008). Patients harboring tumors with Disco-p had significantly worse prognoses (OS and DFS (both, p < 0.001)) compared with those without Disco-p. On multivariate analysis, Disco-p was an independent prognostic factor of worse OS (hazard ratio (HR), 2.572; 95% confidence interval (CI), 1.789-3.680; p < 0.001), and DFS (HR, 3.413; 95% CI, 2.482-4.683; p < 0.001), whereas TB was not an independent unfavorable prognostic factor. Disco-p was an independent unfavorable prognostic factor in patients with resected lung ADC, although a careful evaluation is necessary to distinguish it from similar patterns. We proposed that Disco-p should be recognized as a new invasive pattern and accurately recorded for the better management of patients with lung ADCs.

Prognostic value of [18F]FDG PET/CT parameters in surgically resected primary lung adenocarcinoma: a single-center experience.

To evaluate the prognostic role of maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) measured by FDG-positron emission tomography (PET)/computed tomography (CT) in patients with primary lung adenocarcinoma undergoing surgical resection. All consecutive patients undergoing curative surgery for primary lung adenocarcinoma at the Thoracic Surgery Unit of the University Hospital of Parma between January 2009 and December 2014 were retrospectively analyzed. The cutoff point of each continuous PET parameter was determined through receiver operating characteristic curve and Youden index, using overall survival (OS) as the classification status. Univariate and multivariate Cox proportional hazards models were applied to evaluate the association between OS and potential prognostic variables, including SUVmax, MTV, and TLG. A total of 193 patients were considered eligible for this study. The mean 5-year OS rate was 70.5 ± 3.5%. Acinar and lepidic patterns were more frequently associated with absent or low (<2.5) SUVmax values [18F]FDG uptake. At univariate analysis, male sex, advanced stage, micropapillary and solid pattern, lymphatic, blood vessels and pleural invasion, high SUVmax, MTV, and TLG were significantly associated with poorer OS. Multivariate analyses revealed that only sex, stage, and TLG were independent factors for OS, with male sex, stage 3+4, and high TLG value (p = 0.041) significantly associated with poorer OS. In this study, [18F]FDG PET/CT parameters SUVmax, MTV, and TLG were prognostic factors in patients with surgically resected lung adenocarcinoma, able to predict OS and helping to further stratify these patients into prognostic subsets. Elevated TLG was also an independent predictor for shorter OS.

Oncofertility outcomes after fertility-sparing treatment of bilateral serous borderline ovarian tumors: results of a large retrospective study.

What are the oncofertility outcomes of young women (≤40years old) with bilateral serous borderline ovarian tumors (SBOTs) after fertility-sparing surgery? Fertility preservation with the bilateral ovarian cystectomy procedure is feasible for bilateral SBOTs, with an acceptable oncological outcome and worthwhile pregnancy rates. Fertility-sparing approaches are becoming the standard management of young patients with unilateral SBOTs and other borderline histological subtypes. However, there is a paucity of evidence to dictate the best management in bilateral SBOTs. This was a retrospective observational study performed at the Peking Union Medical College Hospital in Beijing, China, between January 1999 and January 2019. Ninety-four women (≤40 years old) with pathologically confirmed bilateral SBOTs were included. Following preoperative counseling, patients self-selected into one of three treatment modalities: bilateral ovarian cystectomy (n = 48), unilateral adnexectomy plus contralateral cystectomy (UAC; n= 31), and radical surgery (n= 15). Univariate and multivariate analyses were used to determine the clinical and pathological features associated with disease-free survival and reproductive outcomes. During the median follow-up of 64 months (range, 4-243 months), 61 patients (65%) developed relapse, including 3 (20%) in the radical group, 26 (84%) in the UAC group and 32 (67%) in the bilateral cystectomy group. In the multivariate analyses, preoperative CA-125>300U/mL, fertility preservation and micropapillary pattern were independently associated with adverse disease-free survival (P= 0.001, 0.03 and 0.026, respectively). Fourteen patients (15%) experienced invasive recurrence, and three (3%) died of progressive disease. The micropapillary pattern was significantly associated with invasive evolution risk (P = 0.006). Of the 49 patients who attempted to conceive, 23 (47%) achieved 27 pregnancies (24 spontaneous and three after IVF-ET), resulting in 19 live births. There was no significant difference in disease-free survival (P = 0.13) or pregnancy rate (41 vs. 50%, P = 0.56) between the UAC and bilateral procedures. As a retrospective study conducted in a referral center, inherent biases exist. The nonrandom allocation to treatment groups and relatively small number of patients attempt to conceive might limit the statistical power of our findings. Only 41 patients (43.6%) received complete staging during their initial surgeries, so an underestimation bias in terms of the FIGO stage and extraovarian implants might have occurred. The ultraconservative bilateral ovarian cystectomy procedure should be proposed in bilateral SBOTs when technically feasible. Invasive evolution occurs frequently in these women, and intense follow-up and oncofertility counseling are warranted, especially for those with micropapillary patterns. No external funding was used for this study. There are no conflicts of interest to declare. N/A.

2020 challenges in diagnosis and staging of lung cancer

Pathology plays an important role in diagnosis and management of patients with non-small cell lung carcinoma (NSCLC). The current (2015) WHO classification of lung tumours includes histologic and immunophenotypic (IHC) criteria. Adenocarcinomas are the primary focus of shifting nomenclature, emphasising histologic patterns with clinical and biological relevance. Minimally invasive and lepidic-predominant non-mucinous adenocarcinomas represent well-differentiated tumours, while solid and/or micropapillary growth patterns signify poorly-differentiated adenocarcinomas. Poorly-differentiated carcinomas that cannot be classified on the basis of histology alone can instead be subclassified using a limited IHC panel targeting TTF-1 and p63/p40. For adenocarcinomas with non-invasive (lepidic) components, pT staging hinges on the size and extent of only the invasive component. Multifocal tumours are staged based on a combination of gross growth characteristics and histologic findings. Pathology’s role extends beyond diagnosis and staging in response to expectations that cells and tissues will be available for expanded biomarker testing in patients with advanced stage disease. Testing strategies for predictive biomarkers frequently include a combination of immunohistochemistry and increasingly comprehensive molecular profiling as single gene assays become less common. Panels are constructed to balance the number of actionable targets over and against our ability to test extremely small amounts of viable tumour.

Micropapillary pattern is associated with the development of brain metastases and the reduction of survival time in EGFR-mutation lung adenocarcinoma patients with surgery

ObjectiveThe role of micropapillary pattern (MIP) in EGFR-mutated NSCLC patients with brain metastases (BM) after complete surgical resection still remains unclear. Therefore, a retrospective study was conducted to evaluate the role of MIP in those patients. MethodsThis study included 332 stage I-III patients with EGFR-mutant lung adenocarcinoma and complete resection. Patients were classified in four groups: the MIP-positive patients without BM development, the MIP-negative patients without BM development, the MIP-positive patients with BM development and the MIP-negative patients with BM development. Intracranial disease-free survival (iDFS), systemic disease-free survival (DFS) and overall survival (OS) were evaluated. ResultsThe median OS in the whole group was 70 months. The patients with MIP show inferior DFS (13 months vs. 22 months; P < 0.001) and OS (56 months vs. 74 months; P < 0.001). Furthermore, BM development was more likely to be found in patients with MIP (P = 0.001). In addition, the MIP-positive patients showed a significantly shorter iDFS compared with MIP-negative patients (14.5 months vs. 26 months; P < 0.001). Furthermore, the MIP-positive patients had significantly inferior iDFS in both BM as first line development groups (13 months vs. 19 months; P < 0.001) and BM as non-first line development groups (18 months vs. 33 months; P = 0.007). ConclusionsMIP was related to the earlier recurrence and shortened survival time. In addition, MIP was an independent poor prognostic factor for the increase of BM rate and the shortened time of BM development after surgery.

Clinicopathologic characteristics of HER2-positive pure mucinous carcinoma of the breast.

BackgroundPure mucinous carcinoma (PMC) is a rare type of breast cancer, estimated to represent 2% of invasive breast cancer. PMC is typically positive for estrogen receptors (ER) and progesterone receptors (PR) and negative for human epidermal growth factor receptor 2 (HER2). The clinicopathologic characteristics of HER2-positive PMC have not been investigated.MethodsPathology archives were searched for PMC diagnosed from January 1999 to April 2018. Clinicopathologic data and microscopic findings were reviewed and compared between HER2-positive PMC and HER2-negative PMC. We also analyzed the differences in disease-free survival (DFS) and overall survival according to clinicopathologic parameters including HER2 status in overall PMC cases.ResultsThere were 21 HER2-positive cases (4.8%) in 438 PMCs. The average tumor size of HER2-positive PMC was 32.21 mm (± 26.55). Lymph node metastasis was present in seven cases. Compared to HER2-negative PMC, HER2-positive PMC presented with a more advanced T category (p < .001), more frequent lymph node metastasis (p = .009), and a higher nuclear and histologic grade (p < .001). Microscopically, signet ring cells were frequently observed in HER2-positive PMC (p < .001), whereas a micropapillary pattern was more frequent in HER2-negative PMC (p = .012). HER2-positive PMC was more frequently negative for ER (33.3% vs. 1.2%) and PR (28.6% vs. 7.2%) than HER2-negative PMC and showed a high Ki-67 labeling index. During follow-up, distant metastasis and recurrence developed in three HER2-positive PMC patients. Multivariate analysis revealed that only HER2-positivity and lymph node status were significantly associated with DFS.ConclusionsOur results suggest that HER2-positive PMC is a more aggressive subgroup of PMC. HER2 positivity should be considered for adequate management of PMC.

P1.03 Case Series of Double Mutations in Patients with Lung Adenocarcinoma

The introduction of targeted therapies has increased the survival time in a subset of patients with NSCLC. The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology recommend measuring the local EGFR gene mutations of NSCLC patients before treatment. Sensitivity to EGFR TKIs in patients with double or multiple mutations is not well described. In the literature there are few reported cases of double mutations. We present a series of six cases of Lung Adenocarcinoma with double mutations found between 2006 and 2017 in a hospital in Northern MX. 450 patients with Lung cancer were evaluated from 2006 to 2017. DNA extraction is performed using a commercial extraction kit, the process is performed by real-time PCR on an automated platform in a closed circuit with a commercial panel. The DNA quantification quality control process is analyzed, validating with positive and negative controls, then analysis of the 29 known mutations of EGFR gene exons 18, 19, 20, 21. This study includes 450 patients, 141 (31.33%) patients had EGFR mutations, of which six (4.25%) had double exons EGFR mutations. Of the six cases with double mutations, male to female ratio was 1:1. The histological patterns reported in the double mutations were: 3 (50%) cases with acinar pattern, 2 (33.33%) with micropapillary pattern, and 1 (16.66%) solid pattern. The median age of the six patients is 54 years (range 38-78).Tabled 1First MutationSecond MutationHistological patternAge of patientCase #1L858RL861QAcinar52Case #2L858RExon 19 deletionMicropapillary55Case #3Exon 19 deletionL861QMicropapillary38Case #4Exon 19 deletionT790MSolid53Case #5Exon 19 deletionL861QAcinar78Case #6Exon 19 deletionL858RAcinar55 Open table in a new tab EGFR co-mutation had a significantly lower mean progression-free survival than those with a single mutation (5.7 months vs. 12.3 months). The response rate to TKI was significantly worse in those with co-mutation compared to those without co-mutation (38% vs 89%). There are few studies evaluating all the characteristics of cases with double mutations, such as histological pattern and the mutations of EGFR gene exons. Further research on double mutations is suggested because of the impact on treatment and prognosis of the patient.

Heterogeneity of PD-L1 Expression in Lung Mixed Adenocarcinomas and Adenosquamous Carcinomas

Immune checkpoint inhibitors against programmed cell death protein 1/programmed death-ligand 1 (PD-L1) have proven to be remarkably effective in non-small cell lung cancer. PD-L1 represents a predictive biomarker in lung cancer, although its heterogenous expression represents an emerging challenge for accurate biomarker-based patient selection. Lung adenocarcinomas (ADCs) show a high rate of intratumor morphologic heterogeneity that may reflect a heterogenous molecular and immunophenotypic profile. The aim of our study was to analyze the expression of PD-L1 in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas (mADCs) and adenosquamous lung carcinomas (AdSqLCs). As many as 73 mADCs and 6 AdSqLCs were selected. Comprehensive histologic subtyping was performed, and PD-L1 expression was assessed by immunohistochemistry assay using different primary antibodies and automated immunostainers. Overall, PD-L1 expression was observed in 37 of 79 cases (39.2%) (31 mADCs and all AdSqLCs). PD-L1 expression was heterogenous in 22 of 37 PD-L1-positive cases (23.2% mADC and 83% AdSqLC). PD-L1 expression was observed more frequently in ADC with solid pattern. Heterogeneity of PD-L1 expression was significantly related to the presence of micropapillary (P=0.028) and solid (P=0.017) patterns. All PD-L1-positive cases were epidermal growth factor receptor wild-type, 2 cases harbored concomitantly PD-L1 expression and ALK rearrangement. Our data suggest that PD-L1 expression is quite heterogenous in mADCs and AdSqLCs, partly contributing to explaining the discrepant results between biopsy and surgical resections and discordant clinical effectiveness in regard to PD-L1-positive or negative ADC diagnosed on cytology/small biopsy.

Frequent appearance of club cell (Clara cell)-like cells as a histological marker for ALK-positive lung adenocarcinoma.

Anaplastic lymphoma kinase-rearranged (ALK+ ) lung cancers show characteristic histological features, such as solid signet ring cell patterns and mucinous cribriform patterns; however, these features are not always observed in ALK+ lung cancers. We noticed that club cell (Clara cell)-like cells (CLCs) were frequently present in the papillary portion of ALK+ lung adenocarcinomas. In this study, we investigated the importance of CLCs in papillary patterns of ALK+ lung cancers. We compared the histological features of 18 ALK+ cases with 62 control cases (22 epidermal growth factor receptor-positive (EGFR+ ) and 40 ALK- and EGFR-negative (ALK- /EGFR- ) cases). The present study analyzed presence of papillary pattern, proportion of papillary pattern area, presence of micropapillary pattern, frequency of CLCs and lengths of snout. The frequency of CLCs in ALK+ cases was significantly higher than that in EGFR+ cases and ALK- /EGFR- cases. Micropapillary pattern was more frequently observed in ALK+ cases than that in ALK- /EGFR- cases (P < 0.001). The present study indicated that the high frequency of CLCs in papillary patterns was significantly associated with ALK+ cases. When solid signet ring cell patterns and mucinous cribriform patterns are absent, the high frequency of CLCs in papillary adenocarcinoma could be a useful histological marker for ALK+ lung cancers.

Clinical and pathological factors in pathologic stage IA lung adenocarcinoma: relevance of the micropapillary pattern and tumor necrosis

Introduction: The objective was to investigate and correlate clinical and morphological lung adenocarcinoma factors with clinical results in patients treated with surgery in pathological stage IA. Methodology: An observational, analytical and retrospective study of patients diagnosed with pathological stage IA pulmonary adenocarcinoma was performed and the clinical and pathological variables were analyzed using disease-free survival (DFS) and cancer-specific survival (CSS), in a univariate and multivariate study. Results: 77.3% of men were found, with an average age of 61.6 (SD 8.5) and 83.2% of smokers and ex-smokers. 93.3% of the patients underwent lobectomy with lymphadenectomy. The mean total tumor size was 21.9mm (SD 6.4) and the size of the invasion was 16.9mm (SD 9.4). The most frequent histological pattern was acinar and the least frequent was micropapillary. A total of 28.6% of patients with tumor recurrence were found, which were distant metastases in 70.6%. The DFS and CSS at 5 years was 74.9% and 82.7% respectively. Clinical-pathological variables were analyzed as prognostic factors in a multivariable model for DFS and CSS. The micropapillary component obtained an HR of 3.9 for DFS and 3.4 for CSS, while the tumor necrosis obtained an HR of 3.4 and 3, respectively. Conclusions: Presence of the micropapillary component and tumor necrosis were independent factors with poor prognosis in clinical outcome.

P2.09-04 The Clinicopathological Characteristics and Prognosis of Lung Cancer with Tumor Spread Through Air Spaces: A Meta-Analysis

The clinicopathological characteristics of lung cancer with tumor spread through air spaces (STAS) has not been clearly characterized yet. Also, it is still not clear whether the presence of STAS correlated with worse prognosis in patients with lung cancer. Thus, we aim to systematically evaluate the clinicopathological characteristics and prognosis of the patients with or without STAS undergoing surgical resection for lung cancer. A comprehensive search of online databases was performed. Clinicopathological characteristics, 5-year RFS and OS rate were compared between 2 groups. Cumulative meta-analysis was performed to evaluate the temporal trend of pooled outcomes. Specific subgroups according to different types of lung cancer are examined. A total of 25 eligible studies including 8494 patients were recruited. STAS occurred in 2881 patients (34%) while non-STAS occurred in 5613 patients (66%). Overall, patients with STAS manifested significantly more aggressive characteristics, including lymphatic invasion (SMD=2.935; P=0.000), pleural invasion (SMD=2.329; P=0.000), vascular invasion (SMD=2.306; P=0.000) as well as lymph node metastasis (OR=3.510; P=0.000). Patients with STAS also correlated with significantly higher pathological stage (OR=2.216; P=0.003), T stage (OR=1.756; P=0.000), N stage (OR=2.395; P=0.000) and larger tumor size (OR=0.275; P=0.001). Meanwhile, the incidence of STAS was significantly associated with the micropapillary (OR=9.792; P=0.000) and solid patterns (OR=2.451; P=0.000). Moreover, the presence of STAS was related to male sex (OR=1.493; P=0.000), smoking history (OR=1.637; P=0.000) and necrosis (OR=2.300; P=0.000). As for the outcomes of the prognosis, patients with STAS linked with significant worse prognosis than those without STAS, including both 5-year RFS (HR=0.585; 95% CI: 0.486–0.684; P=0.000) and 5-year OS rate (HR=0.788; 95% CI: 0.596–0.980; P=0.000). The presence of STAS was associated with several invasive pathological characteristics, which might explain the worse prognosis in patients with STAS compared with those without STAS.

OA06.07 Discrimination of Lung Invasive Adenocarcinoma with Micropapillary Pattern Based on CT Radiomics

OA06.07 Discrimination of Lung Invasive Adenocarcinoma with Micropapillary Pattern Based on CT Radiomics

GR03.02 Adenocarcinoma

GR03.02 Adenocarcinoma

Prognostic factors of acinar- or papillary-predominant adenocarcinoma of the lung

ObjectiveHistologic types are correlated with prognosis in lung adenocarcinoma. The acinar/papillary type is most common, although this group comprises heterogeneous tumor types. However, the prognostic factors in this group have not been well studied. Therefore, we investigated the prognostic factors of acinar/papillary lung adenocarcinomas and attempted to define the so-called “intermediate grade” group of lung adenocarcinoma. Materials and methodsWe classified surgically resected invasive non-mucinous adenocarcinomas of the lung and analyzed their clinicopathological features and prognostic factors, focusing on the acinar/papillary type. ResultsA total of 301 cases with stage I-III lung adenocarcinoma were enrolled, of which 193 were acinar/papillary type (64.1%). In survival analysis of the entire cohort, acinar/papillary types showed intermediate survival compared with lepidic and micropapillary/solid types. In the univariate survival analysis for acinar/papillary types, stage, age, lymphovascular invasion, spread through air spaces, presence of micropapillary or solid pattern, and programmed death-ligand 1 (PD-L1) positivity were associated with poor recurrence-free survival and overall survival. In multivariate analysis, spread through air spaces and PD-L1 expression were independent poor prognostic factors of recurrence-free survival and overall survival in the acinar/papillary cohort, respectively. ConclusionsEvaluation of spread through air spaces and PD-L1 expression may be useful to stratify patients with acinar/papillary lung adenocarcinomas in terms of prognosis.

Expanded study on the risk of lymphovascular space invasion and lymph node metastasis of endocervical adenocarcinoma using Pattern Classification: a single-centre analysis of 213 cases

A new three-tiered Pattern Classification system for usual-type endocervical adenocarcinomas (U-EACs) recommends using tumour invasive patterns rather than depth of invasion (DOI) and horizontal spread to categorise tumours. Tumours categorised by Pattern Classification are associated with lymph node (LN) metastasis and adverse outcomes. The aim of this study is to further explore the potential of Pattern Classification in surgical pathology practice. A total of 213 consecutive cases [201 U-EACs and 12 gastric-type adenocarcinomas (GACs)] diagnosed between 2006 and 2017 was retrospectively analysed. Clinicopathological data included age at diagnosis, DOI measurement, the status of lymphovascular space invasion (LVSI) and LN metastasis, and the number of LVSI foci, dissected and metastatic LNs. Immunostaining for CD34 and D2-40 was performed to identify LVSI in 14 challenging cases. Overall, mean age at diagnosis was 51 years (range 23-75). LVSI and LN metastasis occurred in 128 (60.1%, 128/213) and 42 (20.5%, 42/205) cases, respectively. Also, 28 (13.1%), 21 (9.9%), and 164 (77.0%) patients had pattern A, B, and C tumours, respectively. Patients with pattern C tumours had the oldest age at diagnosis (p=0.007), the highest incidence of LVSI and LN metastasis, and the highest DOI (p<0.001). Due to a highly heterogeneous growth pattern, pattern C U-EACs were stratified into four subgroups: C1, C2 and C3 corresponded to solid, extensive linear destructive, and band-like lymphocytic infiltrate growth patterns, respectively, and C4 included diffuse destructive, confluent, micropapillary and mixed growth pattern. C2 and C3 subgroup tumours had lower incidence of LVSI (20% and 40%, respectively) than the other two subgroups (p<0.001). None of the patients with C2 and C3 subgroup had LN metastasis and ≥3 LVSI foci. All GACs belonged to pattern C and had deeper stromal invasion (p=0.008), higher incidence of LN metastasis (p=0.001), and larger quantity of LVSI foci (p=0.008) and metastatic LNs (p=0.004) than those of pattern C U-ECAs. Number of LVSI foci were moderately positively correlated with LN metastasis status (p<0.001, γ=0.489) or number of metastatic LNs (p<0.001, γ=0.409). Our study further supports that Pattern Classification is a system easy to follow, which has a strong correlation to LVSI and an effective predictability for LN metastasis. Extensive linear destructive and band-like lymphocytic infiltrate growth patterns in pattern C U-EACs need to be recognised, as they behave less aggressively than that for the other growth pattern subgroups. Our study supports that Pattern Classification can be routinely applied to guide therapies for patients with U-EACs.

Expansion of the Concept of Micropapillary Adenocarcinoma to Include a Newly Recognized Filigree Pattern as Well as the Classical Pattern Based on 1468 Stage I Lung Adenocarcinomas

IntroductionThe classical micropapillary (MIP) pattern is defined in the 2015 WHO classification as tumor cells growing in papillary tufts forming florets that lack fibrovascular cores, and it is associated with poor prognosis. We observed a novel pattern that we termed a filigree MIP pattern and investigated its relationship with the classical MIP pattern. MethodsFiligree pattern was defined as tumor cells growing in delicate, lace-like, narrow stacks of cells without fibrovascular cores. We required at least three piled-up nuclei from the alveolar wall basal layer, with a breadth of up to three cells across. To assess the relationship of the filigree pattern with the classical MIP pattern, we documented their frequencies in the context of the clinical and pathologic characteristics of 1468 stage I invasive adenocarcinomas, including survival analysis using cumulative incidence of recurrence by competing risks. ResultsWe observed the filigree MIP pattern in 35% of cases. By including the filigree pattern as an MIP pattern, we identified 57 more MIP predominant cases in addition to the previously diagnosed 87 MIP predominant adenocarcinomas. These 57 cases were reclassified from papillary (n = 37), acinar (n = 16), and solid (n = 4) predominant adenocarcinoma, respectively. Of the 144 MIP predominant adenocarcinomas, the filigree predominant MIP pattern (n = 78) showed a poor prognosis like the classical predominant MIP pattern (n = 66) (p = 0.464). In addition, like the classical MIP pattern (p = 0.010), even a small amount (≥5%) of filigree MIP pattern was significantly associated with worse cumulative incidence of recurrence (p = 0.001) in multivariable analysis. ConclusionThe frequent association with the classical MIP pattern and the similar poor prognosis supports inclusion of the filigree pattern in the MIP pattern subtype.

Diagnostic upgrade of atypical ductal hyperplasia of the breast based on evaluation of histopathological features and calcification on core needle biopsy.

Atypical ductal hyperplasia (ADH) of breast is increasingly diagnosed in core needle biopsy (CNB). As higher-grade lesions were found in the excision in a substantial proportion of ADH on CNB, factors predicting risk of subsequent upgrade are clinically significant. This study aims to investigate relevant histopathological factors in CNB that could predict diagnostic upgrade at excision. One hundred and forty-three cases of CNB with paired subsequent excision were evaluated for multiple clinicopathological parameters related to CNB sampling, ADH morphology, calcification and other co-existing histological features, and which of these parameters were associated with diagnostic upgrade at subsequent excisions were determined. Forty-eight cases (34.3%) were upgraded to malignancy, including 15 invasive cancers and 33 ductal carcinomas in situ (DCIS). An increased tissue area occupied by ADH (P=0.026), a higher number of ADH foci (P=0.004), the presence of solid pattern (P=0.037) and older age (P=0.012) were positively associated with upgrade, while negative associations were found with the presence of micropapillary pattern (P=0.025), co-existing columnar cell lesions (CCL) (P=0.001) and the presence of calcifications (P=0.009). Multivariate logistic regression analysis showed that the number of ADH foci (HR=2.810, P=0.013) was an independent positive predictor, while co-existing CCL (HR=0.391, P=0.013) was an independent negative predictor for upgrade. Patients with ADH in CNB showing the presence of co-existing CCL and a lower number of ADH foci have a lower risk of disease upgrade at excision, and are potential candidates for observation-only management.

Impacts of thoracoscopic surgery and high grade histologic subtypes on spread through air spaces in small stage I lung adenocarcinomas.

Spread through air spaces (STAS) as a pattern of invasion in lung adenocarcinomas had been recognized by WHO in 2015. Moreover, STAS was associated significantly with aggressive micropapillary or solid components when presented predominant pattern in lung adenocarcinomas, which had a poor prognostic significance. Small amounts of micropapillary or solid with components could also reduce overall survival and recurrence-free survival but its impact on STAS is unknown now. Some studies have demonstrated manipulations of surgeons and pathologists could affect STAS but the degree of these impacts is not clear. We reviewed resected small (≤ 2cm) stage I invasive lung adenocarcinomas by thoracoscopic surgery at our institution from January 2017 to October 2018 (n = 277). Micropapillary or solid pattern was considered to be present when the subtype occupied at least 1% of the entire tumor. Lobectomy and segmentectomy were performed using three portals thoracoscopic surgery. Statistical analysis was performed to analyze the correlations of STAS and clinicopathological characteristics. Moreover, we also analyzed the correlated factors of STAS in solid nodules. STAS was found in 59 of 163 (36.2%) lobectomy cases and 27 of 114 (23.7%) limited resection cases. Lobectomy group showed a higher incidence of STAS compared with limited resection group (p = 0.027), but the difference was disappeared in multivariate analysis, which showed that STAS was significantly correlated to solid nodules and presence of high grade histologic subtype (mircopapillary or solid). However, both lobectomy and presence of high grade histologic subtype were significantly correlated with STAS in solid nodules. The small amounts of high grade histologic subtypes were also associated with STAS. Thoracoscopic surgery could affect STAS to some degree.