An interpretable machine learning system for colorectal cancer diagnosis from pathology slides.

Considering the profound transformation affecting pathology practice, we aimed to develop a scalable artificial intelligence (AI) system to diagnose colorectal cancer from whole-slide images (WSI). For this, we propose a deep learning (DL) system that learns from weak labels, a sampling strategy that reduces the number of training samples by a factor of six without compromising performance, an approach to leverage a small subset of fully annotated samples, and a prototype with explainable predictions, active learning features and parallelisation. Noting some problems in the literature, this study is conducted with one of the largest WSI colorectal samples dataset with approximately 10,500 WSIs. Of these samples, 900 are testing samples. Furthermore, the robustness of the proposed method is assessed with two additional external datasets (TCGA and PAIP) and a dataset of samples collected directly from the proposed prototype. Our proposed method predicts, for the patch-based tiles, a class based on the severity of the dysplasia and uses that information to classify the whole slide. It is trained with an interpretable mixed-supervision scheme to leverage the domain knowledge introduced by pathologists through spatial annotations. The mixed-supervision scheme allowed for an intelligent sampling strategy effectively evaluated in several different scenarios without compromising the performance. On the internal dataset, the method shows an accuracy of 93.44% and a sensitivity between positive (low-grade and high-grade dysplasia) and non-neoplastic samples of 0.996. On the external test samples varied with TCGA being the most challenging dataset with an overall accuracy of 84.91% and a sensitivity of 0.996.

Gal-3 Protein Expression and Localization in Prostate Tumours.

Gal-3 plays an important role in cell survival, mRNA splicing, and cell-cell and cell-matrix interactions. Depending on its cellular localization and cancer type, Gal-3 may have tumour-suppressive or tumour-promoting activities. Given the promising diagnostic role of Gal-3 in the urine of PCa patients found in our previous study, its concordant gene and protein expression levels, and its involvement in PCa-related biological processes (e.g., morphogenesis of the prostate gland epithelium), we aimed to investigate this protein immunohistochemically in tumour and normal prostate tissues. Gal-3 protein expression was evaluated in 48 tumour prostate tissues, eight normal prostate tissues and 14 adjacent-normal prostate tissues. Decreased Gal-3 staining was detected in tumour tissues compared with normal tissues. Although Gal-3 staining was decreased in tumour tissues with GS 5-8 and pT2 and pT3 stages compared with normal prostate tissue, no correlation was found between Gal-3 expression and PCa progression. In the present study, the pattern of cellular localization differed between groups, as Gal-3 was predominantly excluded from the nucleus in tumour tissues. Furthermore, Gal-3 had no significant effect on survival and relapse in these PCa patients. This work confirms Gal-3 as a promising marker for PCa diagnosis.

iMIL4PATH: A Semi-Supervised Interpretable Approach for Colorectal Whole-Slide Images.

Colorectal cancer (CRC) diagnosis is based on samples obtained from biopsies, assessed in pathology laboratories. Due to population growth and ageing, as well as better screening programs, the CRC incidence rate has been increasing, leading to a higher workload for pathologists. In this sense, the application of AI for automatic CRC diagnosis, particularly on whole-slide images (WSI), is of utmost relevance, in order to assist professionals in case triage and case review. In this work, we propose an interpretable semi-supervised approach to detect lesions in colorectal biopsies with high sensitivity, based on multiple-instance learning and feature aggregation methods. The model was developed on an extended version of the recent, publicly available CRC dataset (the CRC+ dataset with 4433 WSI), using 3424 slides for training and 1009 slides for evaluation. The proposed method attained 90.19% classification ACC, 98.8% sensitivity, 85.7% specificity, and a quadratic weighted kappa of 0.888 at slide-based evaluation. Its generalisation capabilities are also studied on two publicly available external datasets.

Digital Pathology Implementation in Private Practice: Specific Challenges and Opportunities.

Digital pathology (DP) is being deployed in many pathology laboratories, but most reported experiences refer to public health facilities. In this paper, we report our experience in DP transition at a high-volume private laboratory, addressing the main challenges in DP implementation in a private practice setting and how to overcome these issues. We started our implementation in 2020 and we are currently scanning 100% of our histology cases. Pre-existing sample tracking infrastructure facilitated this process. We are currently using two high-capacity scanners (Aperio GT450DX) to digitize all histology slides at 40×. Aperio eSlide Manager WebViewer viewing software is bidirectionally linked with the laboratory information system. Scanning error rate, during the test phase, was 2.1% (errors detected by the scanners) and 3.5% (manual quality control). Pre-scanning phase optimizations and vendor feedback and collaboration were crucial to improve WSI quality and are ongoing processes. Regarding pathologists' validation, we followed the Royal College of Pathologists recommendations for DP implementation (adapted to our practice). Although private sector implementation of DP is not without its challenges, it will ultimately benefit from DP safety and quality-associated features. Furthermore, DP deployment lays the foundation for artificial intelligence tools integration, which will ultimately contribute to improving patient care.

Serous Borderline Tumor in Transgender Female-to-Male Individuals: A Case Report of Androgen Receptor-Positive Ovarian Cancer.

Ovarian cancer is the most fatal gynecologic malignancy. The incidence of ovarian cancer among female-to-male transsexuals receiving treatment with testosterone is unknown, and few cases have been reported in the literature. We report a recent case in our institution, a 23-year-old female-to-male transsexual patient who received testosterone supplementation. The patient underwent a pelvic magnetic resonance imaging to study an ovarian complex cyst that revealed the presence of a bilateral ovarian tumor with imaging features of borderline serous tumor. These masses were surgically removed and the pathology report confirmed the diagnosis associated with noninvasive peritoneal implants and the presence of numerous androgen receptors in the tumor cells. Although there is still insufficient data to validate a direct correlation between hormonotherapy and ovarian cancer in these patients, this case may reinforce previous reports on this association and highlights the relevance of radiological follow-up and bilateral salpingo-oophorectomy as part of gender reassignment surgery.

CAD systems for colorectal cancer from WSI are still not ready for clinical acceptance.

Most oncological cases can be detected by imaging techniques, but diagnosis is based on pathological assessment of tissue samples. In recent years, the pathology field has evolved to a digital era where tissue samples are digitised and evaluated on screen. As a result, digital pathology opened up many research opportunities, allowing the development of more advanced image processing techniques, as well as artificial intelligence (AI) methodologies. Nevertheless, despite colorectal cancer (CRC) being the second deadliest cancer type worldwide, with increasing incidence rates, the application of AI for CRC diagnosis, particularly on whole-slide images (WSI), is still a young field. In this review, we analyse some relevant works published on this particular task and highlight the limitations that hinder the application of these works in clinical practice. We also empirically investigate the feasibility of using weakly annotated datasets to support the development of computer-aided diagnosis systems for CRC from WSI. Our study underscores the need for large datasets in this field and the use of an appropriate learning methodology to gain the most benefit from partially annotated datasets. The CRC WSI dataset used in this study, containing 1,133 colorectal biopsy and polypectomy samples, is available upon reasonable request.

Hepatic Myxoid Leiomyoma: A Very Rare Tumor.

INTRODUCTION: Mesenchymal tumors of the liver are rare, and in this group, myxoid leiomyomas are even rarer. So far, only 2 cases have been reported in the literature. CASE PRESENTATION: We aim to report the case of a 16-year-old female with a large lesion on the right hepatic lobe, grossly composed of gelatinous and heterogeneous tissue. DISCUSSION: Histological evaluation revealed a benign mesenchymal neoplasm with expansive growth, paucicellular, with monotonous and dispersed spindle and ovoid cells, positive for α-smooth actin and h-caldesmon, without atypia or mitoses, consistent with the diagnosis of primary myxoid leiomyoma.

INTRODUÇÃO: Tumores mesenquimatosos do fígado são raros, e deste grupo os leiomiomas mixoides são ainda mais incomuns. Até ao momento foram apenas descritos dois casos na literatura. CASO CLÍNICO: Pretendemos efetuar a descrição de uma caso de uma menina de 16 anos com uma volumosa lesão no lobo hepático direito, que macroscopicamente era composta por um tecido gelatinoso e heterogéneo. CONCLUSÃO: Estudo histológico revelou uma lesão mesenquimatosa benigna de crescimento expansive, pouco celular, com células fusiformes e ovaladas, monótonas, com expressão de actina do músculo liso e h-caldesmon, sem atipia nem mitoses, consistente com o diagnóstico de leiomioma mixoide.

Central venous catheter insertion in adult patients: a best practice implementation project.

INTRODUCTION AND AIMS: The central venous catheter (CVC) is an indispensable device in the daily practice of modern medicine. Thus, the implementation of CVC interferes with the care of a large number of patients. This project aimed to implement the best practices in the insertion of CVC in adult hospitals in Brazil. METHODS: The project had three phases, including forming a team and conducting the baseline audit; identifying problems and developing strategies; and conducting a follow-up audit to assess the impact on compliance with best practices. A baseline audit was conducted at a public Hospital in Minas Gerais, Brazil, in June and July 2019. For data collection, direct observation of the procedure was performed and through the PACES (Practical Application of Clinical Evidence System) audit and feedback tool to check the compliance criteria established in the literature. After implementation, a second audit was conducted in August 2019. RESULTS: During the baseline audit, the absence of adequate compliance with the criteria for using an ultrasound to insert the catheter and correct hand hygiene before the procedure was identified. Theoretical-practical training was carried out, including the use of ultrasound to perform the procedure, using an adapted mannequin. The follow-up audit showed an improvement in the compliance rate for the following audit criteria: physical assessment before the procedure (92-100%); evaluation of the most suitable vein for insertion of the catheter, avoiding the femoral vein (92-100%); correct hand hygiene before the procedure (58-100%); maintenance of asepsis throughout the procedure (83-91%) and use of ultrasound to guide venous catheterization (17-100%). CONCLUSION: The current project proved that training the team can be effective in optimizing the implementation of evidence.

Neuroendocrine Carcinoma and Intracystic Papillary Neoplasm: A Rare Association in the Gallbladder.

Neuroendocrine carcinoma of the gallbladder is a very rare neoplasia comprising only 0.2% of all the gastrointestinal neuroendocrine tumors. We present the case of an 85-year-old male with nonspecific gastrointestinal symptoms, progressive weight loss, and deterioration in the preceding 15 days. Imaging study showed a 5-cm polypoid mass localized at the gallbladder fundus, leading to a radical cholecystectomy. Pathology revealed the known lobulated polypoid lesion, on cut section, constituted by friable tissue without evident infiltration of the gallbladder wall and a contiguous friable, brown, flat lesion. Histological evaluation displayed a small cell neuroendocrine carcinoma, consisting of intermediate and small cells, rounded or spindle, with extensive areas of necrosis, with positivity for neuroendocrine immunomarkers, associated with intracystic papillary neoplasm with high and low dysplasia. This is an uncommon association with few cases presented in the literature.

Carcinoma neuroendócrino da vesícula biliar é uma neoplasia muito rara, compreendendo cerca de 0.2% de todas as neoplasias neuroendócrinas do trato gastrointestinal. Apresentamos um caso de um homem de 85 anos, com sintomas gastrointestinais inespecíficos, perda de peso progressiva e deterioração do estado geral com 15 dias de evolução. Estudos de imagem demonstraram lesão polipóide com 5 cm localizada no fundo da vesícula biliar, motivando colecistectomia. Macroscopicamente observou-se lesão polipoide composta por tecido acastanhado e friável. Estudo histológico demonstrou lesão constituída por pequenas células, com extensas áreas de necrose e positivas para marcadores neuroendócrinos, associada a neoplasia papilar intraquística com displasia de baixo e alto grau. Esta associação é incomum, com apenas raros casos descritos na literatura.

Carvedilol-Induced Liver Injury, a Rare Cause of Mixed Hepatitis: A Clinical Case.

INTRODUCTION: Drug-induced liver injury is an increasingly prevalent consequence of the diversification of available therapeutic weapons, mostly idiosyncratic and with several possible mechanisms and patterns of specific damage for each drug. Carvedilol, a widely used non-selective alpha and beta blocker leads, in very rare cases, to injury of the bile ducts by toxic metabolites, resulting in a mixed-pattern hepatitis with possible progression to chronic cholestatic syndrome and cirrhosis. The authors report the second known case of this important toxicity. CLINICAL CASE: An 83-year-old woman was admitted to the Internal Medicine ward for etiological clarification of a mixed-pattern hepatitis. Clinical history was unremarkable and structural, infectious, and autoimmune causes were excluded by blood tests and imaging exams, ultimately leading to the diagnosis of toxic hepatitis that was further confirmed by liver biopsy with morphologic findings of mixed-pattern liver injury. Carvedilol, started 6 months before, was deemed the causal agent since it was the only drug with a clinically, temporally, analytically, and histologically compatible pattern. The withdrawal of the drug resulted in slow reversal of the referred abnormalities. CONCLUSION: In very rare cases, carvedilol can cause important liver toxicity as a chronic cholestatic syndrome which can evolve to cirrhosis. It should be taken in consideration as causal agent in similar cases and stopped immediately upon suspicion, as the timely withdrawal results in reversion of the pathological findings.

INTRODUÇÃO: A lesão hepática induzida por drogas é uma consequáncia cada vez mais prevalente da diversificação de armas terapáuticas disponíveis. São principalmente reacções idiossincráticas, com vários mecanismos possíveis e padrões de danos específicos de cada droga. O carvedilol, bloqueador alfa e beta não seletivo amplamente utilizado, leva, em casos muito raros, a lesão dos canalículos biliares por metabólitos tóxicos, resultando numa hepatite padrão misto com possível progressão a síndrome colestática crónica e potencialmente cirrose. Os autores relatam o segundo caso conhecido desta importante toxicidade. CASO CLÍNICO: Uma mulher idosa foi admitida na enfermaria de Medicina Interna para esclarecimento etiológico de uma hepatite de padrão misto. Esta investigação que incluiu uma extensa pesquisa de antecedentes, exclusão de causas estruturais, infecciosas e auto-imunes por análises sanguíneas e exames de imagem, levou ao diagnóstico de uma hepatite tóxica, confirmada por biópsia hepática com achados morfológicos de um padrão misto de lesão hepática. O carvedilol, introduzido 6 meses antes, foi considerado o agente causal dado ser a única substância com padrão clínico, temporal, analítico e histológico compatível. A retirada do medicamento resultou na reversão lenta das referidas anormalidades. DISCUSSÃO: Em casos muito raros, o carvedilol pode causar toxicidade hepática importante sob a forma de síndrome colestástica crónica que pode evoluir até uma cirrose hepática. Deve ser tomado em consideração como potencial agente causal em casos semelhantes e retirado imediatamente após suspeita, sendo que a suspensão atempada resulta na reversão completa dos achados patológicos.

Uncertainties in the Management of a Lynch Syndrome Patient: A Case Report.

INTRODUCTION: Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is characterized by mutations in mismatch repair (MMR) genes leading to an increased cancer risk, namely colorectal cancer. CASE: In the context of surveillance colonoscopy, a 40-mm flat lesion (0-IIa+b, Paris classification) was identified and submitted to piecemeal mucosal endoscopic resection in a 64-year-old LS patient with an MLH1 germline mutation (262delATC) and two previous segmental resections due to metachronous colorectal cancer. Pathology raised the suspicion of superficial submucosal invasive carcinoma with poor differentiation. Immunochemistry showed heterogeneous MLH1 expression and PMS2 loss. In a short-term follow-up colonoscopy, another 30-mm advanced carcinoma was identified. The patient was referred to surgery. CONCLUSION: This case raises several issues: (1) the potentially fast tumorigenesis and progression to carcinoma in LS and implications for endoscopic screening and surveillance; (2) pitfalls in the interpretation of MMR proteins immunochemistry; (3) the role of endoscopic resection in LS.

INTRODUÇÃO: O síndrome de Lynch (SL), a causa mais frequente de cancro colorectal hereditário, é caracterizado por mutações nos genes de reparação do ADN e risco aumentado de cancro, nomeadamente colorectal. CASO: No contexto de vigilância endoscópica, uma lesão plana com 40mm (0-IIa+b, classificação de Paris) foi identificada e submetida a resseção endoscópica fragmentada num doente de 64 anos com SL com mutação germinativa do gene MLH1 (262delATC) e duas resseções segmentares prévias por cancro colorectal metacrónico. A histologia era suspeita de invasão submucosa superficial por carcinoma pouco diferenciado. A imunohistoquímica mostrou expressão heterogénea de MLH1 e perda de PMS2. O diagnóstico de um segundo carcinoma avançado com 30 mm em reavaliação endoscópica determinou a referenciação para cirurgia. CONCLUSÕES: Este caso levanta várias questões: (1) tumorigénese e progressão para carcinoma aceleradas no SL e implicações no rastreio e vigilância endoscópica; (2) problemas na interpretação da imunohistoquímica das proteínas MMR; (3) papel da resseção endoscópica no SL.

Challenging and uncommon diagnosis of long-evolution ascites.

This is a case report of a 45-year-old Caucasian man with chronic alcoholism. No history of liver disease or asbestos exposure. He complained of ascites during the last 3 years with worsening in the last year with severe ascites development. Diagnostic paracentesis showed SAAG 1.1 and high cellularity with neutrophil count >250 cells/µL. Ascitic fluid cytology revealed reactive mesothelial hyperplasia. Thoracoabdominopelvic ultrasonography/CT/MRI and fludeoxyglucose positron emission tomography/CT showed 'omental cake' pattern suggesting peritoneal carcinomatosis. An exploratory laparoscopy revealed moderate interloop adhesions and necrosis with whitish exudate in the right pelvic excavation. Biochemical/cytological/histological/microbiological study only revealed reactive mesothelial cells, necrosis and lymphohistiocytic inflammatory infiltrate. A second exploratory laparoscopy with liver and peritoneal biopsies and appendectomy/mesoappendix excision showed a well-differentiated tubulopapillary mesothelioma. The patient was referred for intraperitoneal chemotherapy and is undergoing monthly therapeutic paracentesis.

[Retroperitoneal Cellular Angiofibroma: A Rare Gynecological Entity]. / Angiofibroma Celular Retroperitoneal: Uma Entidade Rara na Ginecologia.

Cellular angiofibroma is a mesenchymal tumor, described in 1997, without gender preference, that usually appears at age 40. The vulvovaginal area is the most common site in women, mimicking vulvar benign tumors, like Bartholin gland cyst. However, there are a few described cases of a deep or extra-pelvic angiofibroma. Excision is the treatment of choice and the recurrence rate appears to be low. We present the case of a woman with a heterogeneous tumor in the right adnexial region. At the surgery, a retroperitoneal tumor was excised and the histopathological tissue analysis revealed a cellular angiofibroma.

O angiofibroma celular é uma entidade tumoral mesenquimatosa rara, descrita pela primeira vez em 1997, sem predomínio de género e que surge tendencialmente na quarta década de vida. A localização mais habitual na mulher é superficial a nível da região vulvovaginal, confundindo-se muitas vezes a nível vulvar com quisto/tumor da glândula de Bartholin. No entanto, estão descritos alguns casos de tumor em localização profunda e extra-pélvica. O tratamento é excisional e a recorrência é baixa. É apresentado um caso de uma paciente com uma formação heterogénea a nível da região anexial direita, cuja cirurgia mostrou tratar-se de uma formação nodular alongada, retroperitoneal, localizada a nível dos espaços paracervical e paravesical direitos, que se excisou. O estudo histológico revelou tumor mesenquimatoso compatível com angiofibroma celular.

Intracystic Primary Squamous Cell Carcinoma of the Breast: A Challenging Diagnosis.

We report a case of a 36-year-old woman that presented with a painful mass in the outer quadrants of the left breast that had grown rapidly. Physical examination revealed a well circumscribed elastic mass and breast ultrasound showed a cyst measuring 26 mm with vegetation growing on the inner wall. Microscopic evaluation, after fine needle aspiration cytology (FNAC), suggested benign lesion. Tumorectomy was performed and the final diagnosis was a pure squamous cell carcinoma (SCC) of the breast. A simple mastectomy with sentinel node biopsy was performed. The histological study of the specimen revealed residual SCC and the sentinel lymph node was negative. The patient received 6 cycles of adjuvant chemotherapy and adjuvant radiotherapy. Four years later, the patient is free of disease.

Angiosarcoma of small intestine: case report and literature review / Angiossarcoma de intestino delgado: relato de caso e revisão da literatura

ABSTRACT Introduction: Angiosarcomas are rare pathologies, and their appearance in the small intestine is extremely unusual. Case report: Female patient presenting vomiting, colic, abdominal distension and peritoneal irritation. An exploratory laparotomy and an enterectomy were performed. Histopathology revealed vascular neoplasm; immunohistochemistry, markers CD31, p53 and cell proliferation antigen Ki-67. The patient developed diffuse sarcomatosis and died two months after the onset of symptoms. Conclusion: This case demonstrates the difficulty in early diagnosing this pathology, due to its nonspecific clinical presentation. The disease aggressiveness, its unestablished predisposing factors and the controversy around the adequate treatment engender the poor prognosis.

RESUMO Introdução: Angiossarcomas são patologias raras, e o aparecimento deles no intestino delgado é extremamente incomum. Relato de caso: Paciente do sexo feminino apresentando vômitos, cólica, distensão abdominal e irritação peritoneal. Foram realizadas laparotomia exploratória e enterectomia, evidenciando-se neoplasia vascular ao anatomopatológico e marcadores CD31, p53 e antígeno de proliferação celular Ki-67 à imuno-histoquímica. A paciente evoluiu com sarcomatose difusa e faleceu dois meses após o início dos sintomas. Conclusão: Demonstra-se a dificuldade em diagnosticar precocemente essa patologia devido à sua clínica inespecífica. A agressividade da doença, seus fatores predisponentes indeterminados e a controvérsia referente ao tratamento adequado suscitam seu péssimo prognóstico.