Micropapillary Adenocarcinoma Research Articles

Computed tomography imaging and clinical characteristics of pulmonary ground-glass nodules ≤2 cm with micropapillary pattern.

The aim of this study was to investigate the imaging features, lymph node metastasis, and genetic mutations in micropapillary lung adenocarcinoma (imaging with mixed ground-glass nodules) ≤2 cm, to provide a more precise and refined basis for the selection of lung segment resection. A retrospective analysis of 162 patients with surgically resected pathologically confirmed cancers ≤2.0 cm in diameter (50 cases of micropapillary mixed ground-glass nodules [mGGNs], 50 cases of nonmicropapillary mGGNs, and 62 cases of micropapillary SNs [solid nodules]) was performed. mGGNs were classified into five categories according to imaging features. The distribution of these five morphologies in micropapillary with mGGN and nonmicropapillary with mGGN was analyzed. The postoperative pathology and prognosis of lymph node metastasis were also compared between micropapillary mGGNs and micropapillary with SNs. After searching the TCGA database, we demonstrated heterogeneity, high malignancy and high risk of microcapillary lung cancer cancers. Different pathological subtypes of mGGN differed in morphological features (p < 0.05). The rate of lymph node metastasis was significantly higher in micropapillary mGGNs than in nonmicropapillary mGGNs. In the TCGA database samples, lactate transmembrane protein activity, collagen transcription score, and fibroblast EMT score were remarkably higher in micropapillary adenocarcinoma. Other pathological subtypes had a better survival prognosis and longer disease-free survival compared with micropapillary adenocarcinoma. mGGNs ≤2 cm with a micropapillary pattern have a higher risk of lymph node metastasis compared with SNs, and computed tomography (CT) imaging features can assist in their diagnosis.

Tumor immune microenvironment (TIME) analysis of stage I lung adenocarcinoma with micropapillary pattern.

e20510 Background: Micropapillary is one of the most aggressive histologic subtypes of lung adenocarcinoma, which is considered a poor prognostic marker. Comprehensive analysis of tumor immune microenvironment (TIME) features of micropapillary of early invasive lung adenocarcinoma may provide better insight and facilitate the development of novel strategies for early detection and intervention. Methods: A total of 15 patients who underwent anatomical resection and were pathologically diagnosed with stage I micropapillary adenocarcinomas were included in this study. Gene expression profiles (GEPs) of tumor immune-related 289 genes were analyzed using NanoString nCounter. Differentially expressed genes(DEGs), estimation of TIME cell infiltration, and TIME signatures between micropapillary and non-micropapillary were assessed. Results: The number of micropapillary and non-micropapillary patients was 5 and 10. The comparison revealed CD69, IL6, CXCL8, CXCL2, POLR2A and so on were significantly upregulated in the micropapillary group compared with the non-micropapillary group, while HLA-DPA1, IFIT2, and other seven genes were down-regulated in the micropapillary group. These DEGs were mostly enriched in “positive regulation of cytokine production”， “T cell activation”， “receptor ligand activity，” and “signaling receptor activator activity” pathways according to GO enrichment analysis. The results of the KEGG analysis revealed that genes were significantly enriched in “IL-17 signaling pathway”, “TNF signaling pathway”, “cytokine-cytokine receptor interaction”, and so on. Meanwhile, different immune infiltration of the two groups was analyzed. Totally, there was a better TIME cell infiltration in the micropapillary group compared with the non-micropapillary group. Especially, the score of DCs and mast cells was significantly higher in micropapillary group. However, TIME signature scores were similar in both groups. Conclusions: Our study demonstrated that the TIME between micropapillary and non-micropapillary of stage I lung adenocarcinoma was different. Increased mast cells explained poor prognosis in lung adenocarcinoma with micropapillary pattern. A high level of DCs infiltration indicated that micropapillary adenocarcinoma might benefit from immunotherapy.

The anticarcinogenic effect of eugenol on lung cancer induced by diethylnitrosamine/2-acetylaminofluorene in Wistar rats: insight on the mechanisms of action

This study was designed to assess the ameliorative effects of eugenol and to propose the possible mechanisms of action of eugenol in diethylnitrosamine (DENA)/acetylaminofluorene (AAF)-caused lung cancer in Wistar rats. To induce lung cancer, DENA at a dose of 150 mg/kg body weight (b.wt) for 2 weeks were intraperitoneally injected once each week and AAF was administered orally at a dose of 20 mg/kg b.wt. four times each week for the next 3 weeks. DENA/AAF-administered rats were orally supplemented with eugenol at a dose of 20 mg/kg b.wt administered once a day until 17 weeks starting from the 1st week of DENA administration. Lung histological lesions, including sheets of tumor cells, micropapillary adenocarcinoma, and apoptotic cells, resulting from the DENA/AAF dosage, were ameliorated by eugenol treatment. However, a significant drop in the levels of LPO in the lungs and a remarkable rise in GSH content and GPx and SOD activities were observed in DENA/AAF-administered rats treated with eugenol compared with those in DENA/AAF-administered controls. Moreover, in DENA/AAF-administered rats, eugenol supplementation significantly reduced TNF-α and IL-1β levels and mRNA expression levels of NF-κB, NF-κB p65, and MCP-1 but significantly elevated the level of Nrf2. Furthermore, the DENA/AAF-administered rats treated with eugenol exhibited a significant downregulation of Bcl-2 expression levels in addition to a significant upregulation in P53 and Bax expression levels. Otherwise, the administration of DENA/AAF elevated the protein expression level of Ki-67, and this elevation was reversed by eugenol treatment. In conclusion, eugenol has effective antioxidant, anti-inflammatory, proapoptotic, and antiproliferative properties against lung cancer.Graphical abstract

99. Histopathologic Correlation Somatic Variants in Non Small Cell Lung Cancer with High Tumor Mutation Burden

<h3>Introduction</h3> High tumor mutation burden (TMB), having at least 10 mutations/megabase (mut/Mb), is reported to be as high as 42% of non small cell lung adenocarcinoma (LADC). Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC) and is often associated with a poor prognosis. <h3>Methods</h3> We performed next-generation sequencing (NGS) with and explored histologic and molecular features in 33 consecutive TMB High LADC utilizing the Ion Oncomine Comprehensive Panel Plus (OCAPlus). <h3>Results</h3> LADC with high tumor mutation burdens (TMBs) were more likely to display necrosis, as well as papillary and aggressive micropapillary features. Interestingly, RBM10 truncations were enriched in aggressive TMB LACD, seen in 2/2 cases of pleomorphic carcinoma and 4/7 cases with papillary or micropapillary features. BRAF class 2 mutations (non V600E) were also more likely to be seen in these aggressive tumors, identified in 5/33 cases of TMB high LADC, while no class 1 BRAF V600E mutations were observed. <h3>Conclusions</h3> A subset of high TMB LADC is especially aggressive, with histology including necrosis, micropapillary, and pleomorphic features. A subset of these tumors, with an especially poor overall survival rate contain either class 2 BRAF variants or truncated RBM10 mutations in 7/10 cases identified with these aggressive histologic features.

Feline pulmonary carcinoma: Gross, histological, metastatic, and immunohistochemical aspects.

Feline pulmonary carcinoma (FPC) is an uncommon neoplasm with unique morphological features. We describe the gross, histological, metastatic, and immunohistochemical aspects of FPC, based on postmortem examinations from an 11-year retrospective study. Thirty-nine cases were selected. Predispositions were observed in senior (P < .001) and Persian (P = .039) cats. There were three gross patterns of the pulmonary tumors: (a) a large nodule and additional smaller nodules, (b) a solitary nodule, and (c) small, multifocal to coalescent nodules. Extrapulmonary metastases were present in 22/39 cases (56.4%), mainly in the regional lymph nodes (17/39, 43.5%), skeletal muscles (9/39, 23%), kidneys (6/39, 15.3%), and parietal pleura (4/39, 10.2%). The primary tumor size was correlated with the occurrence of extrapulmonary metastases (P = .002). Histologically, the tumors were classified as papillary adenocarcinoma (19/39, 48.7%), adenosquamous carcinoma (ADS) (8/39, 20.5%), acinar adenocarcinoma (6/39, 15.3%), solid adenocarcinoma (3/39, 7.6%), lepidic adenocarcinoma (2/39, 5.1%), and micropapillary adenocarcinoma (1/39, 2.5%). By immunohistochemistry, 39/39 cases (100%) were positive for pancytokeratin, 34/39 (87.1%) for thyroid transcription factor-1, and 8/39 (20.5%) for vimentin. Immunoreactivity for p40 was detected in the squamous component of all ADSs (8/8, 100%) and occasionally in the glandular component of adenocarcinomas (10/31, 32.2%). Napsin A expression was absent in all feline tissue tested. The results indicate that a modified and simplified histological classification based on current human and domestic animal systems is appropriate for cats. Additionally, this study highlights the utility of p40 as an immunohistochemical marker for the diagnosis of FPC with squamous differentiation.

Integrated analysis of genomic alterations of Chinese lung adenocarcinoma with micropapillary component.

e15130 Background: Lung adenocarcinoma (LADC) with micropapillary component (MPC) is a special pathological subtype of LADC, which poses higher invasive with poor prognosis, regardless of proportion of MPC. The effectiveness of molecular targeted therapy in MPC-LADC patients is still being explored without sufficient clinical evidence. Herein, we comprehensive analyzed the genetic alterations of MPC-LADC in order to find effective potential drug-target genes and guide new therapeutic strategies. Methods: We enrolled 31 MPC-LADC patients at Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University from January 2019 to December 2020, and also randomly selected 89 non-MPC-LADC patients as a reference cohort. FFPE or fresh tumors and matched blood samples were performed for NGS-based target panel detection of at least 420 genes (range 420-638 genes), and we analyzed the genomic alterations of the genes with intersection in the above panels sequencing. Results: In our MPC-LADC cohort, the proportion of micropapillary component in 31 tumors were: 5 cases with MPC &lt; 5%, 13 cases with MPC 5% - 20%, 10 cases with MPC ≥20% and other 3 cases unclear. The most frequently mutant genes were EGFR (61.3%, 19/31), TP53 (41.9%, 13/31), ALK (19.4%, 6/31), CTNNB1 (16.1%, 5/31), KRAS (12.9%, 4/31) and SMAD4 (12.9%, 4/31). Moreover, 90.3% (28/31) patients harbored genomic alterations in RTK/RAS/MAPK pathway, 54.8% (17/31) in cell-cycle pathway, 38.7% (12/31) in Wnt pathway, and 19.4% (6/31) in PI3K/AKT/mTOR pathway. Notably, the median age of patients with ALK fusions were younger than wild-type patients (53 vs 60 years, p &lt; 0.05). Patients with KRAS mutations had larger tumor sizes than wild-type patients (Median: 3.4 vs 2.2 cm, p &lt; 0.05), and their lesions are more prone to vascular invasion (p &lt; 0.05). Compared with the reference group of non-MPC-LADC patients, three mutant genes were significantly enriched in MPC-LADC group, namely, CTNNB1 (16.1% vs 1.1%, p &lt; 0.01), ALK (16.1% vs 2.2%, p &lt; 0.05) and SMAD4 (12.9% vs 2.2%, p &lt; 0.05). Finally, we obtained the date of micropapillary lung adenocarcinoma in Memorial Sloan-Kettering Cancer Center (MSK) from cBioPortal database, and survival outcome analysis displayed that EGFR mutations were significantly associated with poor overall survival (OS) (p &lt; 0.05). Conclusions: In this study, we comprehensive revealed the genomic alterations of Chinese MPC-LADC patients and their association with clinicopathological characteristic. Several MPC-enriched genes including EGFR, ALK, KRAS, CTNNB1 and SMAD4 were identified which may be potential genetic drivers of micropapillary lung tumors and could help us to reveal distinct therapeutic avenues of MPC-LADC.

A semi-supervised learning framework for micropapillary adenocarcinoma detection.

Micropapillary adenocarcinoma is a distinctive histological subtype of lung adenocarcinoma with poor prognosis. Computer-aided diagnosis method has the potential to provide help for its early diagnosis. But the implementation of the existing methods largely relies on massive manually labeled data and consumes a lot of time and energy. To tackle these problems, we propose a framework that applies semi-supervised learning method to detect micropapillary adenocarcinoma, which aims to utilize labeled and unlabeled data better. The framework consists of a teacher model and a student model. The teacher model is first obtained by using the labeled data. Then, it makes predictions on unlabeled data as pseudo-labels for students. Finally, high-quality pseudo-labels are selected and associated with the labeled data to train the student model. During the learning process of the student model, augmentation is added so that the student model generalizes better than the teacher model. Experiments are conducted on our own whole slide micropapillary lung adenocarcinoma histopathology image dataset and we selected 3527 patches for the experiment. In the supervised learning, our detector achieves a precision of 0.762 and recall of 0.884. In the semi-supervised learning, our method achieves a precision of 0.775 and recall of 0.896; it is superior to other methods. We proposed a semi-supervised learning framework for micropapillary adenocarcinoma detection, which has better performance in utilizing both labeled and unlabeled data. In addition, the detector we designed improves the detection accuracy and speed and achieves promising results in detecting micropapillary adenocarcinoma.

The Role of Histogram-Based Textural Analysis of 18F-FDG PET/CT in Evaluating Tumor Heterogeneity and Predicting the Prognosis of Invasive Lung Adenocarcinoma.

Objectives:This study aimed to investigate the contributory role of histogram-based textural features (HBTFs) extracted from 18fluorinefluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in tumoral heterogeneity (TH) evaluation and invasive lung adenocarcinoma (ILA) prognosis prediction.Methods:This retrospective study analyzed the data of 72 patients with ILA who underwent 18F-FDG PET/CT followed by surgical resection. The maximum standardized uptake value (SUVmax), metabolic tumor volume, and total lesion glycolysis values were calculated for each tumor. Additionally, HBTFs were extracted from 18F-FDG PET/CT images using the software program. ILA was classified into the following five histopathological subtypes according to the predominant pattern: Lepidic adenocarcinoma (LA), acinar adenocarcinoma, papillary adenocarcinoma, solid adenocarcinoma (SA), and micropapillary adenocarcinoma (MA). Differences between 18F-FDG PET/CT parameters and histopathological subtypes were evaluated using non-parametric tests. The study endpoints include overall survival (OS) and progression-free survival (PFS). The prognostic values of clinicopathological factors and 18F-FDG PET/CT parameters were evaluated using the Cox regression analyses.Results:The median SUVmax and entropy values were significantly higher in SA-MA, whereas lower in LA. The median energy-uniformity value of the LA was significantly higher than the others. Among all parameters, only skewness and kurtosis were significantly associated with lymph node involvement status. The median values for follow-up time, PFS, and OS were 31.26, 16.07, and 20.87 months, respectively. The univariate Cox regression analysis showed that lymph node involvement was the only significant predictor for PFS. The multivariate Cox regression analysis revealed that higher SUVmax (≥11.69) and advanced stage (IIB-IIIA) were significantly associated with poorer OS [hazard ratio (HR): 3.580, p=0.024 and HR: 7.608, p=0.007, respectively].Conclusion:HBTFs were tightly associated with clinicopathological factors causing TH. Among the 18F-FDG PET/CT parameters, only skewness and kurtosis were associated with lymph node involvement, whereas SUVmax was the only independent predictor of OS. TH measurement with HBTFs may contribute to conventional metabolic parameters in guiding precision medicine for ILA.

Factors associated with lymph node metastasis upstage after resection for patients with micropapillary lung adenocarcinoma.

BackgroundMicropapillary adenocarcinoma has a poor prognostic histological pattern. Additionally, preoperative detection of lymph node metastases by preoperative examination is difficult in some patients with micropapillary adenocarcinoma, and postoperative upstage may occur. However, clinicopathological features of patients with micropapillary adenocarcinoma with nodal upstage have not been established, therefore this study aimed to identify the factors associated with potential lymph node metastases during preoperative examination to ensure effective surgical procedures.MethodsBetween January 2011 and December 2020, 1029 patients received complete resection for primary non‐small‐cell lung cancer by lobectomy or more extensive resection with systematic lymph node dissection at this institution. One hundred and thirty‐one patients diagnosed with adenocarcinoma with micropapillary component were included in this study. The clinicopathological features of patients with nodal upstage whose postoperative N stage was more advanced than the preoperative N stage were examined.ResultsForty patients had nodal upstage after resection. 18F‐fluorodeoxyglucose (FDG) positron emission tomography‐computed tomography (PET‐CT) revealed that a maximum standardized uptake value (SUVmax) ≥5 for the primary lesion was significantly associated with postoperative nodal upstage. There were no significant differences in terms of sex, age, smoking history, surgical procedure, and diabetes. Among 38 patients with nodal upstage, 23 patients had no significant preoperative lymphadenopathy and showed no abnormal FDG uptake in the lymph nodes on 18F‐FDG‐PET‐CT, respectively.ConclusionsLymph node metastases were suspected in patients preoperatively diagnosed with micropapillary adenocarcinoma with FDG SUVmax ≥5 for the primary tumor. Therefore, standard surgical resection and careful lymph node dissection should be performed for such patients.

Characterization of morphological alterations in micropapillary adenocarcinoma of the lung using an established cell line.

Micropapillary adenocarcinoma of the lung is a type of cancer associated with a poor prognosis and is characterized by the presence of tumor cells with a ring‑like glandular structure floating within alveolar spaces. In the present study, the association between its morphological, biochemical and immunohistochemical characteristics, and malignancy was investigated using the KU‑Lu‑MPPt3 cell line established from a patient with MIP adenocarcinoma. Two subpopulations of KU‑Lu‑MPPt3 cells, namely adhesive (AD) and clumpy and suspended (CS) cells, were prepared and subjected to DNA microarray, reverse transcription‑quantitative PCR, western blot and immunostaining analyses. Protein expression patterns were compared between the cell types and their derived tissues using immunostaining. The results revealed similar protein expression patterns between the tumor cells found in the alveolar spaces and CS cells, which exhibited morphological characteristic of MIP adenocarcinoma. Based on the results of DNA microarray analysis, the present study then focused on Akt and focal adhesion kinase (FAK), which were markedly activated in the KU‑Lu‑MPPt3 CS and AD cells, respectively. Following KU‑Lu‑MPPt3 CS cell plating onto collagen‑coated culture dishes, some cells exhibited a transformation of their morphology into KU‑Lu‑MPPt3 AD‑like cells within a few days, and their Akt and FAK activities were similar to those of the AD cells. Additionally, the inhibition of Akt and FAK activities with Akt and FAK inhibitors reduced KU‑Lu‑MPPt3 CS cell adhesion and proliferation. Thus, the aforementioned results indicated that the phosphorylation of FAK and Akt may play a crucial role in the regulation of KU‑Lu‑MPPt3 CS cell adhesion and proliferation, respectively. Furthermore, the malignant potential of MIP adenocarcinoma may be attributed to these morphological and biochemical alterations in the KU‑Lu‑MPPt3 cells.

Micropapillary Adenocarcinoma of the Sigmoid Colon Presenting as Intestinal Obstruction in an Elderly Woman

Colorectal carcinoma (CRC) is the second most common malignancy in Malaysia. Nonetheless, micropapillary adenocarcinoma (MPA) subtype has not been studied extensively since its initial description in 2005. This article is the first reported case of MPA of the sigmoid colon in Malaysia. An 84-year-old Chinese woman presented with a three-day history of obstipation and progressive abdominal distension. She was nauseated with poor oral intake and vomiting gastric content. Otherwise, she did not experience constitutional and gastrointestinal red flag symptoms. Systemic reviews were non-significance. Her elder brother had colon cancer, but she was never screened for CRC. Her abdomen was distended with no peritonism nor palpable mass. Erect abdominal radiograph showed dilated small and large bowels with multiple air fluids levels, no air under diaphragm seen in chest roentgenogram. Apart from elevated carcinoembryonic antigen and cancer antigen 125, her initial blood works were normal. Urgent surgical consult obtained for suspected malignant bowel obstruction. Contrasted computed tomography scan delineated a luminal narrowing at the sigmoid colon and confirmed the diagnosis. She underwent proctosigmoidectomy and discharged postoperatively. Histopathological examination came back as moderately differentiated MPA with nodal extension at stage pT4N2a. Despite 10% of CRC presented with intestinal obstruction, the cohort had a significantly lower survival rate with more advanced disease. Histologically, MPA behaves invasively and predicts nodal metastasis. Identification of micropapillary components is linked to poorer disease prognosis. Effective therapy remained unknown. This case describes the late presentation of MPA variant of CRC, which highlights its clinical and research implications.International Journal of Human and Health Sciences Supplementary Issue-2: 2021 Page: S11

SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy

The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive patients treated with platinum-based chemotherapy had poor outcome (all patients were dead and the mean survival time was 12 months), compared to 72 months for patients with ALK inhibitor therapy. Furthermore, Five ALK-positive cases were analyzed by whole exome sequencing (WES) and via direct transcript counting using a digital probe-base (NanoString) to explore the driver genes. Deregulation of PI3K/AKT signaling pathway in ALK-positive lung cancer was demonstrated by WES analysis, and significantly increased mRNA of ALK, ROS1, MET, SPP1 and PI3K signaling pathway was identified by NanoString assay. The concordance between NanoString, IHC and FISH methodologies for detecting ALK fusion was 100%. Significant overexpression of SPP1 protein in ALK-positive lung cancer was confirmed by IHC compared to paired adjacent normal tissues and ALK-negative cancers. Thus we concluded that SPP1 overexpression is associated with poor outcomes for patients with ALK fusion lung cancer without receiving targeted therapy and PI3K/AKT/SPP1 pathway may become the promising targets in patients with aggressive lung cancer.

Micropapillary Predominance Is a Risk Factor for Brain Metastasis in Resected Lung Adenocarcinoma

BackgroundHistologic subtyping offers some prognostic value in lung adenocarcinoma. We thus hypothesized that histologic subtypes may be useful for risk stratification of brain metastasis (BM). In this study, we aimed to investigate the impact of histologic subtypes on the risk for BM in patients with resected lung adenocarcinoma. Patients and MethodsOf 1099 consecutive patients who had undergone curative-intent surgery (2000-2014), 448 patients who had undergone complete resection for lung adenocarcinoma were included in this study. Correlated clinical variables and BM-free survival were analyzed. ResultsMicropapillary predominance was significantly associated with higher risk of BM after complete resection in univariate analyses (P < .001). In addition, multivariate analyses showed that micropapillary predominance was an independent risk factor for BM (hazard ratio = 2.727; 95% confidence interval, 1.260-5.900; P = .011), along with younger age and advanced pathologic stage. Unlike the other subtypes, an increase in the percentage of the micropapillary subtype was positively correlated with an increase in BM frequency. Patients with micropapillary adenocarcinoma showed significantly poorer brain metastasis-free survival compared with those with non-micropapillary adenocarcinoma (3 years, 78.2% vs. 95.6%; 5 years, 67.3% vs. 94.3%; P < .001). ConclusionThe current study demonstrated a significant correlation between micropapillary subtype and higher risk of BM in patients with resected lung adenocarcinoma. This routine histologic evaluation of resected adenocarcinoma may provide useful information for the clinician when considering postoperative management in patients with lung adenocarcinoma. Histologic subtyping offer some prognostic value in lung adenocarcinoma. Because brain metastasis is critical and often refractory to systemic chemotherapy, early detection is clinically important to achieve effective local treatment. We retrospectively analyzed the association between histologic subtypes and occurrence of brain metastasis and found a significant association between micropapillary predominance and higher risk for brain metastasis. Our findings may be relevant when considering postoperative management.

Comprehensive genetic profiling of six pulmonary nuclear protein in testis carcinomas with a novel micropapillary histological subtype in two cases

Nuclear protein in testis (NUT) carcinoma (NC) is a rare and aggressive neoplasm associated with a rearrangement of the NUT gene on chromosome 15q14. To date, genomic alterations of NCs, especially those in the lung, are poorly understood. In this study, immunohistochemistry staining, fluorescence in situ hybridization, and two next-generation sequencing (NGS) panels of 56 and 701 genes were used to explore the clinical, pathological, and genetic profiling of pulmonary NCs. Six pulmonary NC cases were confirmed, with a mean age of 41 years (range: 22-69 years) and a median survival time of 6.5 months (range: 2-19 months). Morphologically, typical abrupt keratinization was observed in four of six cases (67%), and two patients presented a mixed pattern of classical squamous component and micropapillary adenocarcinoma morphology. We also identified a case with NUT gene amplification instead of rearrangement. Furthermore, NGS analysis demonstrated the following fusions: BRD4-NUTM1 (2/4 cases) and NSD3-NUTM1 (2/4 cases), and the analysis highlighted 53 gene mutations, including 50 (94.3%, 50/53) single-nucleotide variations (SNVs) and three (5.7%, 3/53) long insertions/deletions. SNVs of MUC16 were the most common and occurred in three cases (75%). Moreover, SNVs of EPHA8, FANCA, TRIO, and USP6 were detected in two of four cases (50%). These 53 mutated genes were involved in 13 functional pathways based on enrichment analysis, especially in the PI3K-Akt signaling pathway. Finally, none of the cases showed obvious copy number variations and had low tumor mutational burden and stable microsatellite sites.

Correlation between spread through air spaces (STAS) and other clinicopathological parameters in lung cancer

Background“Spread through airspace” (STAS) is defined as micropapillary clusters, solid nests or single cells of tumor extending beyond the edge of the tumor into the air spaces of the surrounding lung parenchyma. It is associated with reduced overall survival and disease-free survival. Assessment of STAS in lung cancer appears to be necessary to guide clinical interventions. However, data on the correlation between the status of STAS and other lung cancer clinicopathological parameters are scarce. MethodsWe reviewed 240 resected lung cancers and investigated the clinical significance of STAS in relation to other relevant lung cancer clinicopathological variables. We performed univariate and multivariate logistic regression analyses with STAS as a dependent variable. ResultsOf the total 240 patients, STAS was observed in 67 (27.9 %) of them. STAS is highly prevalent in adenocarcinoma with a micropapillary growth pattern (70.0 %) than in other lung cancer growth patterns. STAS was frequently reported in wedge resections (31.0%) than in lobectomy specimens (26.7 %). STAS was significantly associated with advanced pN stage (p < 0.001) and lymphovascular invasion (p = 0.005). In multivariate models, we found that lung cancers in the right lower lobe (RLL) (OR, 2.674; 95 % CI = 1.313−5.448, p = 0.007), micropapillary lung cancer growth pattern (OR = 5.199, 95 % CI = 1.220−22.162, p = 0.026), and pN2 stage (OR = 3.683, 95 % CI = 1.324−10.245, p = 0.013) serve as independent predictors for STAS. ConclusionOur findings suggest that the presence of STAS is associated with right lower lobe tumors, micropapillary adenocarcinoma, and pN2 tumor stage. Hence, it could serve as one of the prognostically significant histologic findings in lung cancer. It is thus valid to mandate reporting STAS status in CAP surgical pathology lung cancer case summaries.

[Pathological and Molecular Features of Lung Micropapillary Adenocarcinoma].

肺微乳头腺癌作为高级别肺腺癌，具频发转移、淋巴结浸润、复发率高和总体生存率低的临床特征。该亚型肿瘤中存在特征致癌因子通路的激活和肿瘤免疫微环境的建立。本文拟对近年来微乳头腺癌的病理学表现及分子学特征研究进展作一综述，旨在加深对微乳头型病变的认识，进而为制定特异性治疗策略奠定基础。

Micropapillary Adenocarcinoma of the Lung that Metastasized to the Same Site in the Brain Twice: A Rare Case Report and Review of Literature

BACKGROUND: Adenocarcinoma (ADC) of the lung is the most common subtype of non-small cell lung cancer (NSCLC), occurring in ~40% of all patients with significantly higher incidence of brain metastasis compared with other subtypes of NSCLC. Among the five subtypes ADC of the lung, micropapillary predominant ADC may be more likely to metastasize. There are almost no reports of micropapillary ADC of the lung initially discovered to metastasis into the same site in the brain that has been previously operated.&#x0D; CASE REPORT: We reported a 54-year-old woman who was referred to ICU of Dr. Hasan Sadikin Hospital, Bandung, due to a decreased of consciousness. Head computed tomography scan revealed multiple isohypodense lesions in the right frontal with brain edema. She had craniotomy total tumor removal 8 months earlier and diagnosed as brain metastasis due to micropapillary ADC of the lung. She refused to receive chemoradiotherapy. At the operation site, multilobulated lesions were found, and hence, she was operated for the 2nd time at the same site with the first one, exhibited the same histology. Immunohistological shown positive results for thyroid transcription factor (TTF)-1 and cytokeratin (CK)-7; negative for CK-20, led to a diagnosis of micropapillary ADC of the lung.&#x0D; CONCLUSION: Herein, we reported our experience regarding a case of micropapillary ADC of the lung, considered as poorly differentiated ADC and associated with a high-grade lesion that metastasized to the same site that had been previously operated, twice. A definitive diagnosis was possible only through a histopathological examination along with a good communication between the surgeon and the pathologist.

Characterizing the molecular and immunological features of lung micropapillary adenocarcinoma.

e21036 Background: Micropapillary adenocarcinoma (MPC) is one of the most aggressive histologic subtypes of lung adenocarcinoma (ADC). Although the incidence of MPC predominant ADC is low, nearly half of ADCs contain a minor proportion of MPC, which could contribute to poor prognosis in these patients. Comprehensive analysis of genetic and immunological features of ADC with different MPC contents would help better understand cancer biology of this ADC subtype and direct future treatments. Methods: We performed panel next-generation sequencing (NGS) of 425 cancer-related genes for a discovery cohort of 43 ADC patients whose tumors were microdissected to separate MPC and non-MPC regions and a reference cohort of 113 ADC patients with unknown ADC histologic subtypes. MPC-enriched mutations were identified by comparing tumors with different original MPC contents within these cohorts, which was then confirmed using a validation cohort of 183 ADC patients. Staining of immunological markers was also conducted for MPC samples from the discovery cohort to investigate their tumor microenvironment. Results: We found that ADC tumors with higher MPC contents/similarities tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). In addition, genetic alterations in transcription termination factor 1 ( TTF1), brain-specific angiogenesis inhibitor 3 ( BAI3), mammalian target of rapamycin ( MTOR), cyclin-dependent kinase inhibitor 2A ( CDKN2A), and CDKN2A were found to be enriched in MPC using the discovery and reference cohorts, which could then be cross-validated using the validation cohort. Tumors with higher MPC content were associated with elevated infiltration of CD4+, CD8+ and FOXP3+ T cells, especially at the peritumor regions. Higher percentage of PD-L1+ tumor cells were also found to be correlated with higher MPC content, suggesting of more immunosuppression in MPC predominant tumors than low MPC tumors. Conclusions: We identified multiple novel MPC-enriched genetic changes that could help understand the nature of MPC. MPC predominant tumors tended to have higher levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, making it a potential candidate for immunotherapy, especially the combination therapy of anti-PD-1/PD-L1 drugs and anti-CTLA-4 drugs, which could inhibit PD-1/PD-L1 pathway and FOXP3+ Treg cells simultaneously.

Clinicopathological features and prognosis of rare carcinomas of the breast: A comparative analysis from the NCDB.

e19256 Background: A comparative analysis of the clinicopathological features, immunohistochemistry, and overall (OS) for rare ( &lt; 10%) of all breast cancers (BCs) has not been widely explored. Methods: The National Cancer Database (NCDB) was reviewed for patients with a confirmed diagnoses of the following rare BC tumors: Mucinous adenocarcinoma (MuC), tubular adenocarcinoma (TuC), intraductal micropapillary (IMP), papillary carcinoma (PaC), and intraductal papillary adenocarcinoma (IPA) between 2010 and 2016. Patients with an unknown stage were excluded. Univariate analyses &amp; multivariable Cox-regression models were performed in SAS v. 9.4. Results: Analysis included 70,341 patients. MuC was the most common histologic type seen among the rare tumors in our cohort n = 30,087 (43%), compared with 9,681 (13.8%) TuC, 12,735 (18.1%) IMP, 435 ( &lt; 1%) PaC, &amp; 17,403 (24.7%) IPA. TuC &amp; IMP both presented earlier in life, with a median age of 60 versus 69 years for MuC patients and 67 years for both PaC &amp; IPA. The majority of carcinomas were ER+/PR+/HER2- (MuC 88.6%, TuC 89.9%, IMP 67.3%, PaC 76.8%, &amp; IPA 79.6%); ER+/PR+/HER2+ were noted in 3.5% of Muc and 13.2 % of IMP, and ER-/PR-/HER2- were seen in PaC 8.7% and IPA 7.3%. Two highly significant factors for inferior outcome were stage (III &amp; IV) and metastasis to the brain. Stage ≥3 at diagnosis conferred a worse prognosis for MuC patients (HR 3.1, p &lt; 0.0001), IPA patients (HR 3.5, p &lt; 0.0001), &amp; IMP patients (HR 4.8; p &lt; .0001) when compared to patients with stage 0 &amp; 1. Brain metastasis was an adverse mortality indicator for MuC patients (HR 2.4, p &lt; .0003), IPA patients (HR 6.8, p &lt; 0.0001), &amp; IMP patients (HR 10.4, p &lt; .0001). For MuC, age ≥60 was also prognostic (HR 2.7; p &lt; .0001). The 5-year OS was 92.2% for patients with MuC, 94.7% for TuC patients, 93.1% for IMP patients, 81% for PaC &amp; 90% for IPA overall (p-values &lt; 0.0001). Conclusions: The rare BC tumors analyzed in this large database confirm that these tumors are typically seen at an older age, are commonly ER+/PR+/HER2 -, and rarely HER2 + or Triple negative. Mucinous adenocarcinoma being the most common type. They have an overall good prognosis, with papillary carcinoma having inferior OS. Other poor prognostic factors include older age, brain metastasis and advanced stages at diagnosis.

Unusual synchronous double primary treatment-na\xefve lung adenocarcinoma harboring T790M and L858R mutations in early-stage lung cancer

BackgroundConcurrent mutations of synchronous multiple primary non-small cell lung cancer (SMPNSCLC) is rare, and only a few cases have been reported. Herein, we present a case of early-stage SMPNSCLC with T790M and L858R mutations.Case presentationA 68-year-old male patient presented to the Thoracic Surgery Department due to a tumor in the right lower lung. The tumor was detected more than 5 years previously during a health examination; however, the patient ignored the problem because the clinician at that time stated that the lesion was highly likely to be benign. Chest computed topography (CT) was ordered and the images showed a well-defined tumor in the right lower lung and a faint nodular lesion over the left lower lung field. A CT-guided biopsy results showed the presence of atypical cells and positive staining of TTF-1 and CK7. Surgical intervention was performed. The right- and left-sided tumors disclosed micropapillary predominant adenocarcinoma and acinar-predominant adenocarcinoma, respectively. Both tumors were positive for TTF-1 but negative for ALK and p40. Real-time PCR analysis showed that the right-sided tumor had an epidermal growth factor receptor (EGFR) mutation presenting as point mutation T790M in exon 20, while the left-sided tumor had a point mutation L858R in exon 21 of EGFR.ConclusionsOur patient’s case suggests that tumors resembling a benign pattern with central calcification may be misdiagnosed. Thus, early screening for lung cancer is important, and intensive efforts to make a diagnosis through surgical resection or biopsies to allow for tailored optimal treatment may be preferential for the best patient outcomes.