Adenocarcinoma e Carcinóide Gástricos

Os autores apresentam um caso clínico de adenocarcinoma e carcinóide gástricos síncronos. Discutem o diagnóstico de carcinóide gástrico e a sua associação a adenocarcinoma

Adenocarcinoma do Íleon. Uma Entidade Rara e de Diagnóstico Tardio

INTRODUÇÃO A neoplasia do intestino delgado é uma entidade rara, apresentando uma incidência anual de cerca de 2.1 casos por 100,000 pessoas, sendo o adenocarcinoma, o segundo tipo histológico mais frequente (em 33% dos casos). A localização distal deste tipo de tumor é menos habitual, o que torna o adenocarcinoma do íleon num evento invulgar. A raridade deste tipo de patologia, associada a uma apresentação clínica pouco específica, origina habitualmente um atraso no diagnóstico e tratamento. CASO CLÍNICO Doente de 66 anos admitida no S.U. com quadro de dor abdominal localizada na fossa ilíaca direita com cerca de 6 dias de evolução e agravamento progressivo. Anorexia, náuseas e vómitos no dia de admissão. Empastamento doloroso à palpação na fossa ilíaca direita. Exames complementares revelaram tumor inflamatório do apêndice ileocecal. Intraoperatoriamente constatou-se neoformação com envolvimento do apêndice ileocecal, cego e segmento de íleon distal. Adenopatias na raíz do mesentério. Optou-se pela realização de hemicolectomia direita com ressecção em bloco de íleon distal. O resultado histológico revelou adenocarcinoma do íleon, que se estendia ao apêndice ileocecal e condicionando apendicite aguda (pT4N0). DISCUSSÃO/CONCLUSÃO Este caso apresenta uma patologia pouco frequente, caracterizada por um diagnóstico tardio e de difícil realização. Sublinhamos neste trabalho, a importância de um diagnóstico mais precoce e um tratamento adequado, de forma a obter um aumento da taxa de sobrevivência destes doentes.

Gastric adenocarcinoma: contribute of computed tomography in preoperative T nad N staging

RESUMO:Os recentes progressos na imagiologia médica possibilitaram um papel de destaque para a Tomografia Axial Computorizada Multicorte no estadiamento do carcinoma do estômago (GA). Foi objetivo deste estudo avaliar a acuidade desta técnica no estadiamento T (invasão mural) e N (ganglionar) e avaliar fatores de prognóstico como fatores de representação/substituição para melhorar a referida acuidade. Sessenta e nove pacientes operados a carcinoma gástrico (GA) entre Janeiro de 2010 e Julho de 2012 e avaliados por Tomografia Computorizada, a maioria recorrendo a técnica de multicorte com distensão gástrica, foram estadiados retrospetivamente por três imagiologistas. Utilizaram-se critérios de avaliação referidos na literatura especializada e fatores de substituição/representação nos estadios menos eficazes. O estadiamento T revelou acuidade de 66,7% e sensibilidade de 92% e a acuidade, sensibilidade e especificidade obtidas para o estadiamento N foram respetivamente 49%, 40,9% e 64%. Usando um fator de substituição de estadiamento diagnóstico T4/N2 para mudar o estadiamento N2 obtido por MDCT para estadiamento N3A aumentaria a acuidade do estadiamento N para 59% e a sensibilidade para 58,1% e baixaria a especificidade para 61,5%, embora essa mudança não fosse estatisticamente significativa (Teste exato de Fisher 0,159). Em conclusão a acuidade de uma técnica simples de MDCT com distensão gástrica no estadiamento T e N do GA está dentro dos valores citados na literatura e fatores de substituição/representação como o estadiamento T4 e o tipo Difuso da classificação de Lauren podem melhorar a acuidade do estadiamento N.-------------- ABSTRACT: Recent innovations in medical sectional imaging have allowed a major role of multi-detector computed tomography (MDCT) in staging of gastric adenocarcinoma (GA). The purpose of this study was to evaluate the accuracy of this technique in depth of mural invasion (T) and nodal (N) staging of GA and to evaluate prognostic factors as surrogate factors to improve such accuracy. Sixty nine patients operated to GA between January 2010 and July 2012 that underwent Computed Tomography, the majority through Multidetector Computed Tomography (MDCT) with gastric distention, were staged retrospectively by three imagiologists with state-of-the-art criteria and surrogate prognostic factors were analyzed for less accurate stages. MDCT T-staging was 66,7 % accurate with a sensibility of 92 % and there was a 49 % accuracy, 40,9 % sensibility and 64 % specificity for N Staging. Using a surrogate factor of T4/N2 diagnostic staging to change diagnostic MDCT N2 disease to N3A disease would increase accuracy of N staging to 59% and sensibility to 58,1% and would decrease specificity to 61,5 %, although that change was not statistically significant (Fisher´s Exact Test 0,159)In conclusion the accuracy of a simple hydro-MDCT technique in T and N staging of GA is in the range of values cited in the literature and surrogate factors as diagnostic T4 disease and diffuse type of Lauren´s Classification may improve the accuracy of N staging.

Adenocarcinoma do Colon Revelado por Endocardite por Estreptococos Bovis

A associação da endocardite por Estreptococos bovis com neoplasias do colon tem sido referida na literatura. Descreve-se um doente cuja endocardite por estreptococos bovis, determinou uma avaliação colonoscóspica, que permitiu o diagnóstico e tratamento cirúrgico de um adenocarcinoma do colon.

Adenocarcinoma of the Ileum: A Rare and Challenging Entity

INTRODUCTION: Primary small bowel malignancy is unusual and accounts for 1-3% of all gastrointestinal tract neoplasms. Adenocarcinoma is one of the most common histologic types, but its frequency decreases with more distal locations. Its clinical presentation is nonspecific and is usually associated with advanced disease, which contributes to delayed diagnosis. PRESENTATION OF CASE: A 66-year-old woman was admitted to the hospital with a 6-day history of progressively worsening abdominal pain localized in the right lower quadrant, nausea, and vomiting. Investigation revealed an inflammatory appendiceal tumor. The patient underwent surgery and an unexpected tumor involving the distal ileal segment and ileocecal appendix was found. Right radical hemicolectomy with en bloc resection of the distal ileum was performed. Histopathological examination revealed adenocarcinoma of the ileum. DISCUSSION: This rare entity is associated with a nonspecific clinical presentation that contributes to delayed diagnosis and treatment, and consequently to a worse prognosis. Approximately half of the cases are only diagnosed at surgery. Primary treatment consists of wide resection with locoregional lymphadenectomy. The role of adjuvant chemotherapy has yet to be determined. CONCLUSION: This case demonstrates an unusual condition characterized by late and challenging diagnosis. We highlight the importance of an earlier diagnosis and optimal treatment for improved patient outcomes.

Henoch-Schönlein Purpura Associated with Pulmonary Adenocarcinoma

Introduction: The Henoch-Schönlein purpura (HSP) is an immunoglobulin A (IgA)-mediated smallvessel systemic vasculitis, rare in adults. The association with solid tumours has been described, especially with lung cancer. Case Report: We present the case of a 60-year-old Caucasian male, diagnosed with lung adenocarcinoma that underwent surgical resection without (neo)adjuvant theraphy. Two months latter he was admitted for abdominal pain, purpuric rash on his lower extremities and acute kidney injury, with serum creatinine (Scr) of 2 mg/dl. Urinalysis revealed haematuria and 24h proteinuria (P24h) of 1.5 g. The serum protein electrophoresis, complement components C3 and C4, circulating immune complexes, cryoglobulins, ANCA, ANA, anti-dsDNA and the remaining immunologic study as screening for viral infections (HCV, HBV and HIV) were negative. Renal ultrasound was normal and kidney biopsy revealed mild mesangial proliferation; 2 cellular glomerular crescents and 1 fibrinoid necrosis lesion; large amounts of red blood cell casts; lymphocytic infiltration in the intertubular interstitial capillaries; moderate arteriolar hyalinosis. Immunofluorescence demonstrated mesangial and parietal deposits of IgA. The diagnosis of HSP was assumed, and the patient started prednisolone 1 mg/kg/day. Ten months after diagnosis the patient’s baseline Scr is 1.4 mg/dl with P24h of 0.18g, without haematuria. Conclusion: Although this is a rare association and the exact mechanism behind the disease is yet unknown, physicians should be aware of it. The early recognition and treatment may prevent renal disease progression.

Effects of circular myotomy on the healing of esophageal suture anastomosis: an experimental study

For esophageal reconstruction in newborns with esophageal atresia, esophageal reunion with an end-to-end anastomosis is the ideal procedure, although it may result in leaks and strictures due to tension on the suture line, mainly in cases with a wide gap between the ends. Circular myotomy (Livaditis' procedure) is the best method to elongate the proximal esophageal pouch and reduce anastomotic tension. This experimental investigation in dogs was undertaken to attempt to verify that circular myotomy decreases the anastomotic leak rate in newborns with wide gap esophageal atresia, and to analyze whether the technique promotes morphologic changes in the anastomotic scar. A pilot study demonstrated that it is necessary to resect more than 8 cm (40% of the total esophageal length) in order to obtain high leak rates. In the experimental project, such resection was performed in dogs divided into two groups (control group, anastomosis only, and experimental group, anastomosis plus circular myotomy in the proximal esophageal segment). The animals were killed in the 14th postoperative day, submitted to autopsy, and were evaluated as to the presence of leaks and strictures, as well as to the features (macroscopic and microscopic aspects) of the anastomosis. Leak rates were the same in both groups. Morphometric analysis revealed that in animals in the experimental group, the anastomotic scar was thinner than the control animals, and the isolated muscular manchette distal to the site of myotomy was replaced by fibrous tissue. Correspondingly, a decreased number of newly formed small vessels were noted in the experimental animals, compared to control animals. We concluded that circular myotomy does not decrease the incidence of anastomotic leaks, and it also promotes deleterious changes in anastomotic healing.

Fatal pulmonary thromboembolism in gastrectomy intraoperative procedures by gastric adenocarcinoma: case report

The case of a patient with gastric adenocarcinoma with indication for gastrectomy is reported. The surgery took place without complications. A palliative, subtotal gastrectomy was performed after para-aortic lymph nodes compromised by neoplasm were found, which was confirmed by pathological exam of frozen sections carried out during the intervention. At the end of the gastroenteroanastomosis procedure, the patient began to show intense bradycardia: 38 beats per minute (bpm), arterial hypotension, changes in the electrocardiogram's waveform (upper unlevelling of segment ST), and cardiac arrest. Resuscitation maneuvers were performed with temporary success. Subsequently, the patient had another circulatory breakdown and again was recovered. Finally, the third cardiac arrest proved to be irreversible, and the intra-operative death occurred. Necropsy showed massive pulmonary embolism. The medical literature has recommended heparinization of patients, in an attempt to avoid pulmonary thromboembolism following major surgical interventions. However, in the present case, heparinization would have been insufficient to prevent death. This case indicates that it is necessary to develop preoperative propedeutics for diagnosing the presence of venous thrombi with potential to migrate, causing pulmonary thromboembolism (PTE). If such thrombi could be detected, preventative measures, such as filter installation in the Cava vein could be undertaken.

Widespread hematogenous metastases and Trousseau's syndrome in gastric adenocarcinoma

A case of widespread hematogenous metastases and Trousseau's syndrome is reported in a 40 year-old white housewife with gastric cancer, presenting subdural hematoma, ecchymoses, epistaxis, stomach and uterine bleeding. After undergoing hematoma drainage, she was unsuccessfully treated with platelets, red blood cells, plasma cryoprecipitate transfusions, and antibiotics. Necropsy disclosed gastric ring-signet adenocarcinoma invading the serous layer, with massive disseminated intravascular coagulation and systemic neoplastic embolism. Multiple old and recent hyaline (rich in fibrin and platelets) microthrombi, and tumor emboli were observed in the bone marrow, meninges, liver, lungs, kidneys, lymph nodes, adrenals, thyroid, heart, pancreas, and ovaries (Krukenberg tumor).

Prognostic factors influencing morbidity and mortality in esophageal carcinoma

PURPOSE: In 1980, operative mortality for esophageal resection was 29%. Over the last 15 years, technical and critical care improvements contributed to the reduction of postoperative mortality rate to 8%. The aim of this study is to analyze retrospectively the role of different factors (surgical procedure, stage of the disease, and anesthetic risk) on the postoperative mortality of 63 patients that underwent esophagectomy with gastric interposition for cancer. METHODS: Seventy-two patients underwent esophagectomy. The stomach was the esophageal substitute in 63 cases. Surgical procedures included transthoracic esophagectomy in 49 patients and transhiatal esophagectomy in 14 cases. Among the 49 transthoracic esophagectomy patients, there were 18 patients with a high anesthetic risk (ASA III). Among the patients that underwent transhiatal esophagectomy, there were 10 patients with a high anesthetic risk (ASA III). RESULTS: The operative mortality rate was 14% (2/14) in transhiatal esophagectomy group and 22% (11/49) in transthoracic esophagectomy group (P = ns). The postoperative mortality of patients with a high anesthetic risk (ASA III) was 47% (8/17) after transthoracic esophagectomy and 10% (1/10) after transhiatal esophagectomy (P <0.05). DISCUSSION: In our experience, the operative mortality was nearly 18% (16.6% after transhiatal esophagectomy and 20.8% after transthoracic esophagectomy). Among the patients with a high anesthetic risk (ASA III) that underwent surgery, the postoperative mortality was significantly lower after transhiatal esophagectomy (10%) compared to transthoracic esophagectomy (47%) (P <0.05).

Meningeal carcinomatosis as the initial manifestation of a gallbladder adenocarcinoma associated with a Krukenberg tumor

A case of malignant neoplasm is described in which the initial manifestations were mental dysfunction and meningeal irritation, mimicking chronic or subacute meningitis. Physical examination showed cranial nerve involvement and a pelvic tumor. There was progressive deterioration, and death occurred in 2 weeks. The autopsy revealed a gallbladder adenocarcinoma, meningeal carcinomatosis, and ovarian metastasis presenting as a Krukenberg tumor. The authors emphasize the importance of including meningeal carcinomatosis as a possibility in the differential diagnosis of non-characteristic clinical pictures, as well as the importance of the cerebrospinal fluid cytologic examination, repeated as needed, in order to confirm this diagnosis.

Analysis of outcome and cancer stem cells status in patients with resectable pancreatic adenocarcinoma

RESUMO: Actualmente, a única possibilidade de cura para doentes com adenocarcinoma do pâncreas (PDAC) é a ressecção cirúrgica, no início deste estudo, perguntamo-nos se os predictores clínico-patológicos clássicos de prognostico poderiam ser validados em uma grande cohort de doentes com cancro do pâncreas ressecável e se outros predictores clínicos poderiam ter um papel na decisão de que doentes beneficiariam de ressecção cirúrgica. No capítulo 2, observamos que até 30% dos doentes morrem no primeiro ano após a ressecção cirúrgica, pelo que o nosso objectivo foi determinar factores pré-operatórios que se correlacionam com mortalidade precoce após ressecação cirúrgica com recurso a um instrumento estatisticamente validado, o Charlson-Age Comorbidity Index (CACI), determinamos que um CACI score superior a 4 foi preditivo de internamentos prolongados (p <0,001), complicações pós-operatórias (p = 0,042), e mortalidade em 1 ano pós- ressecção cirúrgica (p <0,001). Um CACI superior a 6 triplicou a mortalidade no primeiro ano pós-cirurgia e estes doentes têm menos de 50% de probabilidade de estarem vivos um ano após a cirurgia. No capítulo 3, o nosso objectivo foi identificar uma proteína de superfície que se correlacionasse estatisticamente com o prognostico de doentes com adenocarcinoma do pâncreas e permitisse a distinção de subgrupos de doentes de acordo com as suas diferenças moleculares, perguntamo-nos ainda se essa proteína poderia ser um marcador de células-estaminais. No nosso trabalho anterior observamos que as células tumorais na circulação sanguínea apresentavam genes com características bifenotípica epitelial e mesenquimal, enriquecimento para genes de células estaminais (ALDH1A1 / ALDH1A2 e KLF4), e uma super-expressão de genes da matriz extracelular (colagénios, SPARC, e DCN) normalmente identificados no estroma de PDAC. Após a avaliação dos tumores primários com RNA-ISH, muitos dos genes identificados, foram encontrados co-localizando em uma sub-população de células na região basal dos ductos pancreáticos malignos. Além disso, observamos que estas células expressam o marcador SV2A neuroendócrino, e o marcador de células estaminais ALDH1A1/2. Em comparação com tumores negativos para SV2, os doentes com tumores SV2 positivos apresentaram níveis mais baixos de CA 19-9 (69% vs. 52%, p = 0,012), tumores maiores (> 4 cm, 23% vs. 10%, p = 0,0430), menor invasão de gânglios linfáticos (69% vs. 86%, p = 0,005) e tumores mais diferenciados (69% vs. 57%, p = 0,047). A presença de SV2A foi associada com uma sobrevida livre de doença mais longa (HR: 0,49 p = 0,009) bem como melhor sobrevida global (HR: 0,54 p = 0,018). Em conjunto, esta informação aponta para dois subtipos diferentes de adenocarcinoma do pâncreas, e estes subtipos co-relacionam estatisticamente com o prognostico de doentes, sendo este subgrupo definido pela presença do clone celular SV2A / ALDH1A1/2 positivo com características neuroendócrinas. No Capítulo 4, a expressão de SV2A no cancro do pâncreas foi validado em linhas celulares primárias. Demonstramos a heterogeneidade do adenocarcinoma do pâncreas de acordo com características clonais neuroendócrinas. Ao comparar as linhas celulares expressando SV2 com linhas celulares negativas, verificamos que as linhas celulares SV2+ eram mais diferenciadas, diferindo de linhas celulares SV2 negativas no que respeita a mutação KRAS, proliferação e a resposta à quimioterapia. No capítulo 5, perguntamo-nos se o clone celular SV2 positivo poderia explicar a resistência a quimioterapia observada em doentes. Observamos um aumento absoluto de clones celulares expressando SV2A, em múltiplas linhas de evidência - doentes, linhas de células primárias e xenotransplantes. Embora, tenhamos sido capazes de demonstrar que o adenocarcinoma do pâncreas é uma doença heterogénea, consideramos que a caracterização genética destes clones celulares expressando SV2A é de elevada importância. Pretendemos colmatar esta limitação com as seguintes estratégias: Após o tratamento com quimioterapia neoadjuvante na nossa coorte, realizamos microdissecação a laser das amostras primarias em parafina, de forma a analisar mutações genéticas observadas no adenocarcinoma pancreático; em segundo lugar, pretendemos determinar consequências de knockdown da expressão de SV2A em nossas linhas celulares seguindo-se o tratamento com gemicitabina para determinação do papel funcional de SV2A; finalmente, uma vez que os nossos esforços anteriores com um promotor - repórter e SmartFlare ™ falharam, o próximo passo será realizar RNA-ISH PrimeFlow™ seguido de FACS e RNA-seq para caracterização deste clone celular. Em conjunto, conseguimos provar com várias linhas de evidência, que o adenocarcinoma pancreático é uma doença heterogénea, definido por um clone de células que expressam SV2A, com características neuroendócrinas. A presença deste clone no tecido de doentes correlaciona-se estatisticamente com o prognostico da doença, incluindo sobrevida livre de doença e sobrevida global. Juntamente com padrões de proliferação e co-expressão de ALDH1A1/2, este clone parece apresentar um comportamento de células estaminais e está associado a resistência a quimioterapia, uma vez que a sua expressão aumenta após agressão química, quer em doentes, quer em linhas de células primárias.----------------------------- ABSTRACT: Currently, the only chance of cure for patients with pancreatic adenocarcinoma is surgical resection, at the beginning of my thesis studies, we asked if the classical clinicopathologic predictors of outcome could be validated in a large cohort of patients with early stage pancreatic cancer and if other clinical predictors could have a role on deciding which patients would benefit from surgery. In chapter 2, we found that up to 30% of patients die within the first year after curative intent surgery for pancreatic adenocarcinoma. We aimed at determining pre-operative factors that would correlate with early mortality following resection for pancreatic cancer using a statistically validated tool, the Charlson-Age Comorbidity Index (CACI). We found that a CACI score greater than 4 was predictive of increased length of stay (p<0.001), post-operative complications (p=0.042), and mortality within 1-year of pancreatic resection (p<0.001). A CACI score of 6 or greater increased 3-fold the odds of death within the first year. Patients with a high CACI score have less than 50% likelihood of being alive 1 year after surgery. In chapter 3 we aimed at identifying a surface protein that correlates with patient’s outcome and distinguishes sub-groups of patients according to their molecular differences and if this protein could be a cancer stem cell marker. The most abundant class of circulating tumor cells identified in our previous work was found to have biphenotypic features of epithelial to mesenchymal transition, enrichment for stem-cell associated genes (ALDH1A1/ALDH1A2 and KLF4), and an overexpression of extracellular matrix genes (Collagens, SPARC, and DCN) normally found in the stromal microenvironment of PDAC primary tumors. Upon evaluation of matched primary tumors with RNA-ISH, many of the genes identified were found to co-localize in a sub-population of cells at the basal region of malignant pancreatic ducts. In addition, these cells expressed the neuroendocrine marker SV2A, and the stem cell marker ALDH1A1/2. Compared to SV2 negative tumors, patients with SV2 positive tumors were more likely to present with lower CA 19-9 (69% vs. 52%, p = 0.012), bigger tumors (size > 4 cm, 23% vs. 10%, p= 0.0430), less nodal involvement (69% vs. 86%, p = 0.005) and lower histologic grade (69% vs. 57%, p = 0.047). The presence of SV2A expressing cells was associated with an improved disease free survival (HR: 0.49 p=0.009) and overall survival (HR: 0.54 p=0.018) and correlated linearly with ALDH1A2. Together, this information points to two different sub-types of pancreatic adenocarcinoma, and these sub-types correlated with patients’ outcome and were defined by the presence of a SV2A/ ALDH1A1/2 expressing clone with neuroendocrine features. In Chapter 4, SV2A expression in cancer was validated in primary cell lines. We were able to demonstrate pancreatic adenocarcinoma heterogeneity according to neuroendocrine clonal features. When comparing SV2 expressing cell lines with SV2 negative cell lines, we found that SV2+ cell lines were more differentiated and differ from SV2 negative cell lines regarding KRAS mutation, proliferation and response to chemotherapy. In Chapter 5 we aimed at determining if this SV2 positive clone could explain chemoresistance observed in patients. We found an absolute increase in SV2A expressing cells, with multiple lines of evidence, in patients, primary cell lines and xenografts. Although, we have been able to show evidence that pancreatic adenocarcinoma is a heterogeneous disease, our findings warrant further investigation. To further characterize SV2A expressing clones after treatment with neoadjuvant chemotherapy in our cohort, we have performed laser capture microdissection of the paraffin embedded tissue in this study and will analyze the tissue for known genetic mutations in pancreatic adenocarcinoma; secondly, we want to know what will happen after knocking down SV2A expression in our cell lines followed by treatment with gemcitabine to determine if SV2A is functionally important; finally, since our previous efforts with a promoter – reporter and SmartFlare™ have failed, we will utilize a novel PrimeFlow™ RNA-ISH assay followed by FACS and RNA sequencing to further characterize this cellular clone. Overall our data proves, with multiple lines of evidence, that pancreatic adenocarcinoma is a heterogeneous disease, defined by a clone of SV2A expressing cells, with neuroendocrine features. The presence of this clone in patients’ tissue correlates with patient’s disease free survival and overall survival. Together with patterns of proliferation and ALDH1A1/2 co-expression, this clone seems to present a stem-cell-like behavior and is associated with chemoresistance, since it increases after chemotherapy, both in patients and primary cell lines.

Clear cell adenocarcinoma of the cervix in a young woman: a diagnostic challenge

Clear cell adenocarcinoma of the cervix is a rare tumor, classically related with in utero diethylstilbestrol (DES) exposure. The authors report a rare case of clear cell adenocarcinoma of the cervix in a 21-yearold woman who had no history of in utero DES exposure, presenting with intermittent vaginal bleeding. It stresses the relevance to always clarify the etiology of abnormal genital bleeding and consider the possibility of cervicovaginal tumors.