Tumor Growth Pattern Research Articles

Longitudinal characteristics of T2-FLAIR mismatch in IDH-mutant astrocytomas: Relation to grade, histopathology, and overall survival in the GLASS-NL cohort.

The T2-FLAIR mismatch sign is defined by signal loss of the T2-weighted hyperintense area with Fluid-Attenuated Inversion Recovery (FLAIR) on magnetic resonance imaging, causing a hypointense region on FLAIR. It is a highly specific diagnostic marker for IDH-mutant astrocytoma and is postulated to be caused by intercellular microcystic change in the tumor tissue. However, not all IDH-mutant astrocytomas show this mismatch sign and some show the phenomenon in only part of the lesion. The aim of the study is to determine whether the T2-FLAIR mismatch phenomenon has any prognostic value beyond initial noninvasive molecular diagnosis. Patients initially diagnosed with histologically lower-grade (2 or 3) IDH-mutant astrocytoma and with at least 2 surgical resections were included in the GLASS-NL cohort. T2-FLAIR mismatch was determined, and the growth pattern of the recurrent tumor immediately before the second resection was annotated as invasive or expansive. The relation between the T2-FLAIR mismatch sign and tumor grade, microcystic change, overall survival (OS), and other clinical parameters was investigated both at first and second resection. The T2-FLAIR mismatch sign was significantly related to Grade 2 (80% vs 51%), longer post-resection median OS (8.3 vs 5.2 years), expansive growth, and lower age at second resection. At first resection, no relation was found between the mismatch sign and OS. Microcystic change was associated with areas of T2-FLAIR mismatch. T2-FLAIR mismatch in IDH-mutant astrocytomas is correlated with microcystic change in the tumor tissue, favorable prognosis, and Grade 2 tumors at the time of second resection.

Nadir and Finical-Minimally Invasive Adenocarcinoma Lung

Minimally invasive adenocarcinoma emerges as a miniature, solitary, localized, primary pulmonary adenocarcinoma ≤ 3.0 centimetre magnitude and ≤ 0.5 centimetre zone of stromal invasion or non-invasive (lepidic) pattern of neoplastic evolution. Minimally invasive adenocarcinoma lung is predominantly comprised of non-mucinous component and is confined within peripheral pulmonary parenchyma. Preponderantly asymptomatic, poorly defined areas appear concurrent with lepidic pattern of tumour growth whereas solid foci are concordant with focal tumour invasion. Cogent histopathological subtypes appear as non-mucinous variant, mucinous variant and mixed variant. Stromal invasion configures acinar, papillary, micropapillary, solid, colloid, foetal or invasive mucinous lesions. Neoplastic cells appear immune reactive to CK7, thyroid transcription factor1(TTF-1) or Napsin A and immune non-reactive to p40. Minimally invasive adenocarcinoma lung requires segregation from neoplasms such as invasive pulmonary adenocarcinoma, lepidic predominant pattern, adenocarcinoma in situ or atypical adenomatous hyperplasia lung. The gradually progressive neoplasm demonstrates ‘ground glass’ opacities. Appropriate neoplastic discernment necessitates comprehensive histological assessment of entire surgical resection specimens. Minimally invasive adenocarcinoma lung can be appropriately treated with surgical extermination of the neoplasm followed by extensive monitoring. Neoplasm is devoid of lymphatic invasion, vascular invasion, tumour necrosis or pleural invasion.

Liver metastasis of breast carcinoma: An unusual presentation and growth pattern

Breast carcinoma is one of the tumors that frequently metastasize to the liver. Extramedullary hematopoiesis (EMH) usually occurs due to insufficient medullary hematopoiesis. In this case report, we present a female patient with sinusoidal breast carcinoma metastasis and extramedullary hematopoiesis in liver biopsy. A 63-year-old female patient with history of breast carcinoma was admitted to our center with respiratory distress. Pleural effusion was detected and thoracentesis was planned. Treatment was given after detection of non-mycobacterial tuberculosis bacillus in the thoracentesis fluid. Antibiotherapy was terminated due to elevation of liver enzymes and bilirubin. The patient's clinical status was evaluated and treatment was re-initiated. The patient did not have any mass lesion in the liver. Tru-cut biopsy was performed to evaluate a possible tuberculosis involvement in the liver. The diagnosis of metastatic breast carcinoma located in the sinusoidal area and cholestatic liver with extramedullary hematopoiesis foci was given using the histomorphological, immunohistochemical and histochemical findings. Radiological evaluation has an important role in staging of malignancies. However, it should be kept in mind that hepatic metastases may present without formation of a mass lesion, and unexpected laboratory results of cases without abnormal radiological features should raise the suspicion of a metastasis. Such materials should be evaluated in detail by making multiple serial sections in the pathology laboratory. Rare metastatic tumor growth patterns not causing a mass lesion such as sinusoidal or portal pattern, should also be kept in mind.

Histopathological investigation of colon liver metastases – which factors affect survival after surgery?

Introduction Novel therapeutic options have improved prognosis for patients with colonic liver metastases (CLM) over the last decades. Despite this, the challenge to select and stratify patients for optimal treatment regimen persists. This study aimed to evaluate established and novel histopathological features and investigate the impact on overall survival (OS) and recurrence in patients undergoing surgery for CLM. Methods Two hundred and sixty patients who underwent resection of CLM with curative intent 2006–2017 were included in the study. Clinicopathological characteristics were retrieved from patient medical records. The following histopathological parameters were investigated: vascular/lymphatic invasion, perineural invasion, tumor regression grade (TRG), tumor growth pattern, pseudocapsule and acellular mucin. Histopathological traits were correlated to OS. Results Vascular and lymphatic invasion, as well as perineural invasion, significantly correlated with an adverse prognosis hazard ratio (HR) = 1.7, 95% confidence interval (CI) 1.23–2.40 and HR = 1.7, 95% CI 1.20–2.51, respectively. Results retrieved from the study could not propose any novel explorative histopathological features (TRG, tumor growth pattern, pseudocapsule and acellular mucin) to be of significant value as comes correlation with patient OS. Discussion Classical histopathological characteristics of previously reported influence on survival were confirmed, while more novel factors that has been proposed, like tumor growth pattern, tumor regression and grade and presence of a pseudocapsule, were not. Further studies are thus needed to identify better ways of understanding the impact of tumor microenvironment and tumor biology on patient outcome and not at least for stratification and improved treatment response.

Selective inhibition of integrin αvβ6 leads to rapid induction of urinary bladder tumors in cynomolgus macaques.

Administration of a novel and selective small molecule integrin αvβ6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction of epithelial proliferative changes in the urinary bladder of 2 animals, in the absence of test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae of epithelial cells, variable cytologic atypia, and high mitotic rate, without invasion into the tunica muscularis. Morphologic features and patterns of tumor growth were consistent with a diagnosis of early-stage invasive urothelial carcinoma. Ki67 immunohistochemistry demonstrated diffusely increased epithelial proliferation in the urinary bladder of several monkeys, including those with tumors, and αvβ6 was expressed in some epithelial tissues, including urinary bladder, in monkeys and humans. Spontaneous urothelial carcinomas are extremely unusual in young healthy monkeys, suggesting a direct link of the finding to the test agent. Inhibition of integrin αvβ6 is intended to locally and selectively block transforming growth factor beta (TGF-β) signaling, which is implicated in epithelial proliferative disorders. Subsequent in vitro studies using a panel of integrin αvβ6 inhibitors in human bladder epithelial cells replicated the increased urothelial proliferation observed in monkeys and was reversed through exogenous application of TGF-β. Moreover, analysis of in vivo models of liver and lung fibrosis revealed evidence of epithelial hyperplasia and cell cycle dysregulation in mice treated with integrin αvβ6 or TGF-β receptor I inhibitors. The cumulative evidence suggests a direct link between integrin αvβ6 inhibition and decreased TGF-β signaling in the local bladder environment, with implications for epithelial proliferation and carcinogenesis.

Histopathological prognosticators and their clinicopathological correlation in oral squamous cell carcinomas of the tongue.

Tongue carcinomas account for 25%-40% of intraoral squamous cell carcinomas (OSCCs). Although TNM staging systems is an international standard for cancer reporting, prognosis evaluation, and treatment planning, multiple histopathological risk assessment predictors such as tumor thickness (TT), tumor shape, tumor growth pattern, and invasive malignancy grading scoring systems have been studied and should form a basis for prediction and prognostication of such aggressive carcinomas. To evaluate and characterize the histomorphological prognostic indicators in OSCCs of tongue and compare it with OSCCs of other anatomic sites within the oral cavity. Furthermore, to elucidate the significance of histopathological indicators in predicting prognosis of tongue squamous cell carcinomas (SCCs). Forty SCC cases with 20 each of tongue and 20 from other intraoral sites were retrieved from department archives. Clinical data and staging were obtained for each case. Histomorphological parameters including pattern of invasion (POI), tumor budding (TB), depth of invasion (DOI), TT, lymphocytic host response, tumor-associated tissue eosinophilia (TATE), vascular invasion, perineural invasion (PNI), and muscular invasion were assessed. The results were statistically evaluated. TB, DOI, and sarcolemmal spread were significant histologic predictors in tongue SCC. Upon correlation of histomorphological parameters with clinical staging, TT, POI, and TATE were observed to be significantly correlated (P ≤ 0.05). The histomorphological risk assessment model may serve as important addition to the existing prognosticators and may be used as a prognostic index to help plan and individualize treatment protocol in cases with aggressive high-risk disease for whom the use of multimodality treatment seems beneficial.

Cricotracheal Adenoid Cystic Carcinoma: Insights Into the Diagnosis and Management of an Uncommon Anatomic Variant

Adenoid cystic carcinoma (ACC) is the second most common malignant salivary gland tumor and accounts for 30% of minor salivary gland tumors. Its location in the larynx and trachea are rare.We present the case of a 45-year-old healthy male whoseMRI revealed a posterior endoluminal tumor that invaded the posteroinferior perichondrium of the cricoid lamina and displaced the hypopharynx and esophagus. A left-limited cervical surgical exploration and an intraluminal incisional biopsy through the tracheostomy space were performed by another surgical team. The pathological study reported an ACC, T4aN0M0, stage IVA tumor. Then, a circular tracheal resection and an excision of the inferior part of the posterior cricoid lamina were carried out. The macroscopic study showed a lesion, 3cm long, 2.2cm wide, and 1cm thick, located at the posterior wall of the cricoid cartilage and proximal trachea. Only the upper margin was compromised. Microscopically, the tumor showed tubular, solid, cribriform, and trabecular patterns. One and a half years after surgery, the patient still has bilateral vocal cord mobility and normal speech. It is clear that a contrast-enhanced CT scan is useful to assess tumor extent and growth pattern in these rare variants. Among treatment alternatives, surgery sometimes complemented with radiotherapy is essential; constant follow-up is mandatory.

Primary intracranial extraosseous Ewing's sarcoma of the skull base in an elderly adult: illustrative case.

BACKGROUNDPrimary extraosseous intracranial Ewing’s sarcoma, also known as a peripheral primitive neuroectodermal tumor or “small round blue cell tumor,” is an extremely rare entity with limited representation in the literature beyond the pediatric population.OBSERVATIONSA 67-year-old male suffering occipital headache, nausea, and gait disturbance was found to have a large, avidly contrast-enhancing cerebellopontine angle mass extending into the cervical spinal canal with associated mass effect on medulla, cerebellum, fourth ventricle, and cervical spinal cord. This mass was not present on the imaging from 8 years prior. He underwent surgical debulking and pathology results demonstrated a malignant small round cell tumor showing diffuse immunopositivity for cytokeratins, CD99 and NKX2.2 with EWRS1-FLI1 rearrangement in 84% of the nuclei confirmatory of Ewing’s sarcoma. After 14 cycles of chemotherapy and 6 weeks of radiotherapy, 22 months after discovery, the patient remains in clinical and radiographic remission with complete return to his baseline functioning.LESSONSPrimary skull base extraosseous Ewing’s sarcoma should be considered in the differential diagnosis even in the elderly population when imaging studies demonstrate aggressive tumor growth patterns. Tumor debulking to establish a diagnosis followed by adjuvant chemoradiation therapy can result in clinical improvement with remission.

PHENOTYPIC CHARACTERISTICS OF ANDROGEN RECEPTOR-POSITIVE CANCER IN THE TRIPLE-NEGATIVE BREAST CANCER GROUP

The aim of the paper is to reveal the phenotypic characteristics of androgen-receptor-positive breast cancer in triple-negative breast cancer.
 Materials and Methods. The authors analyzed clinical and morphological tumour data in 253 patients with morphologically verified invasive triple-negative breast cancer (TNBC). The patients were treated at the Regional Clinical Oncologic Dispensary (Ulyanovsk) and the Breast Pathology Department of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov (Moscow) from 2014 to 2021.
 Results. Statistical analysis of 45 patients (18 % of the total sample) showed that androgen receptor (AR) expression in TNBC was observed in patients older than 61 years (p=0.054). It was associated with a more common stage of the disease (starting with IIB) (p=0.004), multifocal growth pattern (p=0.025), invasive lobular cancer (p=0.04), higher tumor differentiation (p<0.0001), low Ki67 level (p=0.000001), and more frequent involvement of regional lymph nodes (p=0.005). At the same time, there were no statistically significant correlations between the AR expression and menstrual function, breast lesion quadrant, and pathomorphological response after neoadjuvant polychemotherapy.
 Conclusion. AR expression in TNBC occurs in patients over 61 years of age, with a locally advanced disease stage, a multifocal tumor growth pattern, an invasive lobular cancer, and well-differentiated tumors with low proliferative activity.

Posterior fossa ependymoma H3 K27-mutant: an integrated radiological and histomolecular tumor analysis

Posterior fossa group A ependymomas (EPN_PFA) are characterized by a loss of H3 K27 trimethylation due to either EZHIP overexpression or H3 p.K27M mutation, similar to H3 K27-altered diffuse midline gliomas (DMG), but in reverse proportions. Very little data is available in the literature concerning H3 K27M-mutant EPN_PFA. Here, we retrospectively studied a series of nine pediatric tumors initially diagnosed as H3 K27M-mutant EPN_PFA to compare them to EZHIP-overexpressing EPN_PFA in terms of radiology, follow-up, histopathology, and molecular biology (including DNA-methylation profiling). Seven tumors clustered within EPN_PFA by DNA-methylation analysis and t-distributed stochastic neighbor embedding. Among the two remaining cases, one was reclassified as a DMG and the last was unclassified. H3 K27M-mutant EPN_PFA cases were significantly older than their counterparts with an EZHIP overexpression. Radiological and histopathological central review of our seven H3 K27M-mutant EPN_PFA cases found them to be similar to their counterparts with an EZHIP overexpression. Sequencing analyses revealed HIST1H3B (n = 2), HIST1H3C (n = 2), H3F3A (n = 1), and HIST1H3D (n = 1) K27M mutations (no sequencing analysis available for the last case which was immunopositive for H3K27M). Consequently, HIST1H3C/D mutations are more frequently observed in EPN_PFA than in classic pontine DMG, H3K27-mutant. Overall survival and event-free survival of EZHIP-overexpressing and H3 K27M-mutant EPN_PFA were similar. After surgery and radiation therapy, 5/7 patients were alive at the end of the follow-up. In summary, the diagnosis of EPN_PFA must include tumor location, growth pattern, Olig2 expression, and DNA-methylation profiling before it can be differentiated from DMG, H3 K27-altered.

Depletion of Foxp3+ regulatory T cells but not the absence of CD19+IL-10+ regulatory B cells hinders tumor growth in a para-orthotopic neuroblastoma mouse model.

Adaptive immune cells with regulatory function reportedly mediate immune escape in a variety of tumors. Little is known regarding the relevance of the most prominent regulatory cell populations, namely Foxp3+ T regulatory cells (Tregs) and CD19+IL-10+ B regulatory cells (Bregs), for neuroblastoma (NB) survival. After establishing a novel immunocompetent syngeneic NB mouse model where orthotopic tumors can be generated after intrarenal injection of NB975A cells, we studied the importance of Tregs and Bregs in Foxp3-DTR mice whose Tregs can be depleted by diphtheria toxin (DT) application as well as in CD19-specific IL-10 deficient mice that lack IL-10+ Bregs (CD19cre+/- × IL-10fl/fl mice). We observed Foxp3 Treg cells in tumors from wild type mice. On the contrary, Bregs or B cells were scarce. Specific depletion of Tregs in Foxp3-DTR mice resulted in an 85% reduction of tumor volume and weight compared to DT-treated wild type mice and untreated Foxp3-DTR mice. In contrast, NB tumor growth was not affected in CD19-specific IL-10 deficient mice. Similarly, mice lacking mature B cells (μMT mice) and CD19 deficient mice (CD19cre mice) showed no change in growth pattern of NB tumors. In Treg-depleted mice, reduced tumor growth was associated with an increased concentration of IFN-gamma, TNF-alpha, IL-4, IL-6, and IL-10 in isolated splenocytes. In summary, transient ablation of Tregs but not absence of Bregs hindered the growth of NB, strongly suggesting the therapeutic potential of targeting Tregs for this aggressive childhood tumor.

Tumour budding and poorly differentiated clusters in colon cancer - different manifestations of partial epithelial-mesenchymal transition.

Morphological features including infiltrative growth, tumour budding (TB), and poorly differentiated clusters (PDCs) have a firmly established negative predictive value in colorectal cancer (CRC). Despite extensive research, the mechanisms underlying different tumour growth patterns remain poorly understood. The aim of this study was to investigate the involvement of epithelial-mesenchymal transition (EMT) in TB and PDCs in CRC. Using laser-capture microdissection, we obtained distinct parts of the primary CRC including TB, PDCs, expansive tumour front, and the central part of the tumour, and analysed the expression of EMT-related markers, i.e. the miR-200 family, ZEB1/2, RND3, and CDH1. In TB, the miR-200 family and CDH1 were significantly downregulated, while ZEB2 was significantly upregulated. In PDCs, miR-141, miR-200c, and CDH1 were significantly downregulated. No significant differences were observed in the expression of any EMT-related markers between the expansive tumour front and the central part of the tumour. Our results suggest that both TB and PDCs are related to partial EMT. Discrete differences in morphology and expression of EMT-related markers between TB and PDCs indicate that they represent different manifestations of partial EMT. TB seems to be closer to complete EMT than PDCs. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Prognostic Significance of Intramural and Extramural Lymphovascular Invasion in Colorectal Carcinoma

ABSTRACT Introduction: Evaluation of lymphovascular invasion (LVI) in Colorectal Carcinoma (CRC) may help to predict the metastatic potential and identify patients with aggressive tumor. Such patients may benefit from adjuvant therapy, hence improving their survival and disease-free outcome. Aims and Objectives: To identify LVI in cases of CRC and classify them as intramural and extramural and find its correlation with parameters such as tumor volume, location, growth pattern, histological type, grade, tumor budding, stage, and nodal metastasis. Materials and Methods: A prospective study was conducted from November 2018 to April 2020 at a tertiary care hospital, New Delhi, which included 27 cases of CRC. Demographic and perioperative data were collected. LVI identified on H and E, further differentiated into intramural and extramural and correlated with clinicopathological data. Observation and Results: About 70.3% of cases showed the presence of LVI. A statistically significant association between intramural and extramural LVI and nodal metastasis was identified. A statistically significant association was also noted between extramural LVI and staging. Conclusion: LVI is an independent predictor of recurrence and silent metastasis in many cancers, especially colorectal cancer. It is a cost-effective and simple method. The result of the present study adds on to the growing literature on the significance of LVI in CRC. However, more work needs to be done with a large sample size to fulfill the limitations.

Genetic Determination of Regressive Pattern of Walker 256 Carcinosarcoma in Rats with Hypothalamic Diabetes Insipidus.

We studied the growth dynamics of Walker 256 carcinosarcoma in recombinant progeny of dihybrid crosses of Brattleboro and WAG rats. A mutation in the vasopressin gene determining hypothalamic diabetes insipidus was detected in Brattleboro rats. WAG rats are carriers of normal vasopressin gene. Another interlinear difference was linked to tyrosinase gene controlling melanin synthesis. WAG rats express mutant allele determining albino phenotype. Brattleboro rats had normal working tyrosinase gene. F2 segregation yielded phenotypic classes with two patterns of tumor growth: linear growth or regression. Tumors regression was not linked to tyrosinase activity and was observed only in rats with diabetes insipidus. Analysis of mutants in next generations F3 and F4 confirmed this regularity in the Walker 256 carcinosarcoma growth pattern.

Transarterial Chemoembolization in Hepatocellular Carcinoma, Albanian Experience.

Liver cancer is the sixth most common cancer worldwide in terms of the number of cases (626,000 or 5.7% of new cancer cases) but due to the very poor prognosis, the number of deaths is nearly similar (598,000). The survival rate is 3% to 5% in cancer registries for the United States and developing countries. The modality of treatment in hepatocellular carcinoma (HCC) patients depends on the stage of the disease. The Barcelona Clinic Liver Cancer Classification (BCLC) is the favorite staging system. There are many patients who initially present with the intermediate-stage disease, and in this setting transarterial chemoembolization (TACE) is the treatment of choice.
 The purpose of this article is to highlight and discuss the role of chemoembolization in the treatment of hepatocellular carcinoma, including the results of recent large studies, and the concept of combined therapies, illustrating our case.
 The differences in individual factors that are not captured by the BCLC framework, such as the tumor growth pattern, degree of hypervascularity, and vascular supply, complicate the further evaluation of these patients. Because of these differences, not all patients benefit equally from TACE. Several tools have been devised to aid the decision-making process which have shown promising initial results but have failed external evaluation and have not been translated to the clinical aspects. Criteria for treatment decisions in daily clinical practice are needed in all stages of the disease.
 Conclusion: TACE is a safe method for prolonging patients' survival with unresectable HCC. The correct treatment of HCC is concentrated in cancer centers, and cooperation between multiple specialists is necessary.

Review of Mass-Forming Intrahepatic Cholangiocarcinoma

The incidence of intrahepatic cholangiocarcinoma (iCCA) is highest in Eastern countries, such as Thailand, South Korea, and China, but its incidence and mortality are increasing worldwide. Over recent decades, the worldwide age-standardized incidence for iCCA has been steadily increasing, whereas that for perihilar CCA and distal CCA has been decreasing. The macroscopic growth pattern of CCA is somewhat different according to the anatomic location of the tumor. iCCA can show three main patterns of growth: mass forming, periductal infiltrating, and intraductal growing. Morphologic classification is important to understand the mode of tumor spread, which is critical in predicting a tumor’s resectability and in planning the extent of surgery. Furthermore, different macroscopic growth types are resulting in different imaging findings and different list of differential diagnosis. This review provides a comprehensive and critical overview of current knowledge and what is envisaged on the horizon for iCCA, focusing on mas-forming type. 1. Tumor growth pattern 2. Histological subtype of iCCA 3. Imaging phenotype and differential diagnosis of iCCA 4. Staging of iCCA 5. Preoperative prognostic prediction of iCCA

Integrative Analysis of Intrahepatic Cholangiocarcinoma Subtypes for Improved Patient Stratification: Clinical, Pathological, and Radiological Considerations.

Simple SummaryLiver cancer subtypes differ in prognosis and genetic alterations. An accurate diagnosis made on time is the key aspect of clinical decision-making. Hence, a correct diagnosis is of pivotal importance for individual patients. In this study, we identified the most relevant clinical, radiological, and histological parameters for an improved subtype diagnosis of intrahepatic cholangiocarcinoma. As a result of our study, the radiologist should consider factors such as growth pattern, location, and contrast agent behavior. For the pathologist, precursor lesions, mucin secretion, and a periductal-infiltrating growth are of utmost importance, while immunohistochemical analyses are essential for exclusion of extrahepatic malignancies, but have so far only value for iCCA subtype analysis in the context with other parameters.Intrahepatic cholangiocarcinomas (iCCAs) may be subdivided into large and small duct types that differ in etiology, molecular alterations, therapy, and prognosis. Therefore, the optimal iCCA subtyping is crucial for the best possible patient outcome. In our study, we analyzed 148 small and 84 large duct iCCAs regarding their clinical, radiological, histological, and immunohistochemical features. Only 8% of small duct iCCAs, but 27% of large duct iCCAs, presented with initial jaundice. Ductal tumor growth pattern and biliary obstruction were significant radiological findings in 33% and 48% of large duct iCCAs, respectively. Biliary epithelial neoplasia and intraductal papillary neoplasms of the bile duct were detected exclusively in large duct type iCCAs. Other distinctive histological features were mucin formation and periductal-infiltrating growth pattern. Immunohistochemical staining against CK20, CA19-9, EMA, CD56, N-cadherin, and CRP could help distinguish between the subtypes. To summarize, correct subtyping of iCCA requires an interplay of several factors. While the diagnosis of a precursor lesion, evidence of mucin, or a periductal-infiltrating growth pattern indicates the diagnosis of a large duct type, in their absence, several other criteria of diagnosis need to be combined.

Abstract LB153: Clinical relevance of spatial intermixing of growth patterns and immune infiltration in lung adenocarcinoma-from TRACERx to LATTICe-A

Abstract Adenocarcinoma, the most common histologic variant of lung cancer, is morphologically diverse. The International Association for the Study of Lung Cancer (IASLC) grading system, based on the percentages of growth patterns within the tumour, is highly prognostic (Moreira et al. 2020). However, the clinicopathological significance of transitions between growth patterns, and the combinatorial effects of growth pattern and inflammatory cell infiltration are not yet known. We used a deep learning model to delineate six growth patterns (lepidic, acinar, papillary, micropapillary, solid, and cribriform) at pixel level on hematoxylin and eosin diagnostic whole slide images. The model was trained on 49 slides from the TRACERx cohort (AbdulJabbar et al. 2020), and subsequently applied to 4324 slides from 970 adenocarcinoma cases from the Leicester Archival Thoracic Tumor Investigatory Cohort (Moore et al. 2019). To examine how tumor growth patterns are spatially intermixed, we created a graph network of growth patterns. A linking criterion based on effective cell-cell communication distance was established, whereby adjacent compact tumor islands were linked together. Frequencies of 15 types of pairwise links were further evaluated. A higher intermixing score, measured as the Shannon diversity of link percentages, was associated with adverse relapse free survival (RFS) (p<0.001, Hazard Ratio (HR)=1.5, 95% Confidence Interval (CI)=1.3-1.8, n=966), independently of automated IASLC grading (p=0.001, HR=1.4, 95% CI=1.1-1.7). The clinical relevance of intermixing profiles was investigated by clustering patients into 3 groups, based on the similarity between link percentages. The group dominated by links involving high grade patterns (solid, micropapillary, cribriform), showed the highest risk of relapse (p<0.001, HR=1.7, 95% CI=1.4-2.2), followed by the group enriched with papillary-acinar links (p=0.006, HR=1.4, 95% CI=1.1-1.7). Although micropapillary subtype per se confers an unfavorable prognosis (Cao et al. 2016), its association with papillary morphology increased the risk of relapse (p=0.002, HR=4.2, 95% CI=1.6-11.0), independently of micropapillary burden. To investigate the immune microenvironment surrounding growth patterns, we quantified immune cells at the interface between growth patterns. We observed significantly reduced immune infiltration between micropapillary and papillary than between micropapillary and acinar, solid, and cribriform patterns (p<0.001). In conclusion, we showed that tumor growth pattern spatial intermixing is associated with adverse prognosis and immune infiltration. These findings offer novel insights into the spatial interplay of histological phenotypes and its clinical relevance, which may have an impact on immune escape. Citation Format: Anca-Ioana Grapa, Hanyun Zhang, Xiaoxi Pan, Khalid AbdulJabbar, Jose Coelho-Lima, Ho Kwan Alvin Cheung, Sarah J. Aitken, David A. Moore, Charles Swanton, John Le Quesne, Yinyin Yuan. Clinical relevance of spatial intermixing of growth patterns and immune infiltration in lung adenocarcinoma-from TRACERx to LATTICe-A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB153.

Abstract LB504: Automated grading of growth patterns in lung adenocarcinoma-from TRACERx to LATTICe-A

Abstract Lung adenocarcinoma exhibits distinct growth patterns (WHO, 2021) and the International Association for the Study of Lung Cancer (IASLC) grading system, based on the nature and proportion of histologic subtypes, is highly prognostic (Moreira et al. 2020). However, both recognition and quantification of growth patterns suffer from high interobserver variability among pathologists. Here, we present a large-scale application to automate the segmentation of histologic patterns and reproduce the IASLC grading system to stratify patients and predict prognosis. A deep learning model was trained to recognize and segment 6 histologic patterns (lepidic, acinar, papillary, micropapillary, solid, and cribriform) on 49 whole-slide images from TRACERx (AbdulJabbar et al. 2020). This model was directly applied to an independent cohort, consisting of 4324 hematoxylin and eosin-stained sections from 970 patients (the Leicester Archival Thoracic Tumor Investigatory Cohort, Moore et al. 2019). Growth pattern segmentation performance was first evaluated against 2433 hand annotations covering 6 patterns from 9 images at a pixel level using Dice coefficient. The average Dice was 0.502. Predicted predominant pattern per tumor was then compared to a subspecialty pathologist, achieving an overall agreement (51%), comparable to the interobserver rate among pathologists (52%, Boland et al. 2017). Discordant cases were more heterogeneous (p=4.5e-10, Shannon diversity based on pathological scores), underscoring the challenges posed by intratumor heterogeneity. Patients with a high proportion of micropapillary in the tumor, identified by deep learning, had significantly worse relapse-free survival (RFS) in multivariate analyses including clinical parameters (p=0.00127, Hazard Ratio (HR)=6.4, 95% confidence interval (CI)=2.07-19.8, n=827), consistent with previous publication (Cha et al. 2014). The Kaplan-Meier curve for RFS was significantly differentiated with both automated and pathological IASLC grading (p<0.0001). Moreover, patients with predominantly high-grade patterns (solid, micropapillary, cribriform) identified by deep learning had significantly reduced RFS (p=6.22e-4, HR=1.5, 95% CI=1.18-1.8, n=970). The prognostic effect was stronger using IASLC grading (cutoff: 20%, p=5.56e-6, HR=1.7, 95% CI=1.36-2.2), comparable to the pathological score at IASLC grade 3 (cutoff: 20%, p=2.41e-5, HR=1.8, 95% CI=1.35-2.3). A similar performance was observed for overall survival regarding above analyses. To the best of our knowledge, this study represents the largest application of deep learning to recognize tumor growth patterns in lung adenocarcinoma. Histologically heterogeneous growth patterns can be automatically identified using a method trained on an independent cohort. Automated tumor grading is significantly associated with patient outcomes, supporting its potential clinical utility. Citation Format: Xiaoxi Pan, Khalid AbdulJabbar, Jose Coelho-Lima, Anca-Ioana Grapa, Hanyun Zhang, Ho Kwan Alvin Cheung, Sarah J. Aitken, David A. Moore, Charles Swanton, John Le Quesne, Yinyin Yuan. Automated grading of growth patterns in lung adenocarcinoma-from TRACERx to LATTICe-A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB504.

Risk factors for urgent complications of colorectal cancer

Objective: to identify the main factors associated with an increased risk of urgent complications of colorectal cancer. Materials and methods. This retrospective cohort study included 214 patients with colorectal cancer who had undergone emergency surgery in Smolensk hospitals between January 2016 and January 2020. Their median age was 66 years. We analyzed patients’ sociodemographic characteristics (sex, age, settings (urban or rural), education, employment, profession, and family status), disease history, clinical characteristics (type of urgent complication, comorbidities), morphological tumor characteristics (histological type, pTNM stage, pattern of tumor growth (exo- or endophytic, mixed), tumor length along the intestine (<4 cm, 4–7 cm, >7 cm), presence of lymph node metastases and distant metastases). Multivariate logistic regression was used to analyze factors that were independently associated with an increased risk of decompensated intestinal obstruction and colon perforation. Results. The most significant risk factors for decompensated intestinal obstruction included T4 stage (odds ratio (OR) 3.19; 95 % confidence interval (CI) 1.66–7.12; p <0.001), high-grade tumor G3–G4 (OR 2.93; 95 % CI 0.89–3.97; p = 0.008), and presence of competing diseases (OR 2.03; 95 % CI 1.84–2.39; p <0.001). The risk of perforation was higher among patients with T4 tumors (OR 3.74; 95 % CI 2.61–5.48; p <0.001), lymph node involvement (N+) (OR 1.61; 95 % CI 1.33–2.01; p <0.001), high-grade tumors G3–G4 (OR 3.56; 95 % CI 2.08–4.93; p <0.001), and diabetes mellitus requiring insulin therapy (OR 2.11; 95 % CI 1.78–2.42; p <0.001). Conclusion. Elderly patients with stage III and IV colorectal cancer and high comorbidity are more likely do develop urgent complications, such as decompensated acute intestinal obstruction or tumor perforation.