Giovanni Serio

Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: A comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables

Prediction for malignancy of pancreatic endocrine tumors (PET) is often a formidable challenge for the pathologist. The authors evaluated the role of the proliferative activity and progesterone receptor protein (PgRP) in predicting prognosis and survival of PET. Twenty-three functioning (FT) and 31 nonfunctioning tumors (NFT) were evaluated for mitotic activity and immunostaining for Ki-67 antigen, proliferating cell nuclear antigen (PCNA), and progesterone receptor protein (PgRP) on paraffin sections. The results were expressed as a percentage (index) of immunoreactive or mitosing cells. All 54 cases showed immunostaining for Ki-67 and PCNA, and valuable mitotic index, whereas only a fraction of tumors (25 of 54 cases) exhibited PgRP expression. Ki-67 and PCNA indexes correlated strongly between themselves and to mitotic index, whereas an inverse relationship was observed between cell proliferation and PgRP status in both FT and NFT. Although univariate analysis showed that Ki-67, PCNA, mitotic and PgRP indexes, stage, immunoreactivity for hormones other than insulin, diameter, and nonfunctioning type of tumor were statistically correlated to survival, Coxs regression method let only Ki-67 index emerge as an independent predictor of survival using a cutoff value of 5% in both FT and NFT.

Is there a place for central pancreatectomy in pancreatic surgery

Tumors located in the neck of the pancreas that are not small and superficial enough to be enucleated are usually resected with a pancreaticoduodenectomy or left splenopancreatectomy. Such operations may cause digestive disorders, glucose intolerance, and late postsplenectomy infection. Central pancreatectomy is a segmental resection whereby the cephalic stump is sutured and the distal stump anastomosed with a Roux-en-Y jejunal loop. The purpose of this study was to evaluate whether central pancreatectomy has a place in pancreatic surgery. Thirteen patients with the following tumors underwent central pancreatectomy: five endocrine tumors, one mucinous and six serous cystadenomas, and one solid cysticpapillary tumor. Mean operative time was 250 minutes. Operative mortality was zero. Complications occurred in three patients (23%). At mean follow-up of 68 months, no recurrences were found. Postoperative oral glucose tolerance, pancreolauryl, and fecal fat excretion tests were normal in all patients. We believe that central pancreatectomy does have a place in pancreatic surgery; it is a reliable technique for benign or low-grade malignant tumors and has a surgical risk similar to that of standard operations. Its principal advantage is that it preserves pancreatic parenchyma and the anatomy of the upper gastrointestinal and biliary tract and the spleen better than pancreaticoduodenectomy or distal pancreatic and splenic resection.

Expression of progesterone receptors in solid-cystic tumour of the pancreas : a clinicopathological and immunohistochemical study of ten cases

A role for sex hormones in the pathogenesis of solid-cystic tumour (SCT) of the pancreas is suggested by its predilection for young fertile women. Controversial data have been provided for the presence of progesterone receptors (PR) and/or oestrogen receptors (ER) in SCT. We report the immunohistochemical detection of PR in ten cases of SCT. Eight were from young women. The remaining two were from a post-menopausal woman and a young boy. All cases showed PR immunoreactivity in the large majority of neoplastic cells, whereas none exhibited ER positivity. In one tumour two types of cell populations were noted, the more anaplastic invasivetype being PR negative, whereas the more typical was PR positive. PR immunoreactivity in the absence of ER may simply reflect a lower sensitivity of ER antibody failing to reveal the biochemically detectable ER, or that the PR in cells of SCT are constitutively synthesized in an oestrogen-independent way, as in T47D breast carcinoma cell line, meningioma cells and some gastric cancer cells. Our findings support the hypothesis of a possible pathogenetic role of progesterone in SCT, independent of the patients sex and age.

Immunodetection of proliferating cell nuclear antigen assesses the growth fraction and predicts malignancy in endocrine tumors of the pancreas

Thirty-five endocrine tumors of the pancreas, 17 functioning and 18 nonfunctioning, were immunohistochemically studied for the expression of proliferating cell nuclear antigen (PCNA) using 19A2 and PC10 monoclonal antibodies. The proportion of PCNA-reactive cells (PCNA index) ranged from 0.2 to 27% in functioning tumors and from 0.1% to 55% in nonfunctioning tumors. PCNA index showed a statistically significant correlation with mitotic and Ki67 indexes. The median values of PCNA index identified three groups of patients: group A PCNA ≤ 2%), including 13 functioning and six nonfunctioning tumors; group B (PCNA between 2 and 5%), including three functioning and three nonfunctioning tumors; group C (PCNA > 5%), including one functioning and nine nonfunctioning tumors. All group A tumors were confined to the pancreas. In group B, the functioning tumors were limited to the pancreas, and the nonfunctioning tumors extended to extrapancreatic tissues. All group C patients had extrapancreatic extension of the disease. At follow-up, a PCNA index higher than 5% correlated to a decreased mean survival. Our data suggest that PCNA index is a reliable tool to assess the growth fraction, discern local from advanced diseases, and predict malignancy in pancreatic endocrine tumors.

Small-cell neuroendocrine carcinoma of the ampullary region. A clinicopathologic, immunohistochemical, and ultrastructural study of three cases.

We report the clinicopathologic, immunohistochemical, and ultrastructural features of three small-cell neuroendocrine carcinomas of the ampullary region of the duodenum. All patients were men; their ages were 51, 62, and 66 years. The therapy consisted of pancreatoduodenectomy. All patients died of the disease; median survival was 10 months from the diagnosis. The histological appearance was identical to pulmonary and extrapulmonary small-cell carcinoma. The neuroendocrine differentiation was demonstrated ultrastructurally by the presence of dense-core granules, and by the positive immunoreaction for neuron-specific enolase and Leu-7 in each case. One case expressed a focal positivity for chromogranin A (PHE-5) and argyrophilic granules. The same case showed the presence of neurofilaments on frozen material. Neurofilament proteins could not be demonstrated in any case in paraffin sections. Neoplastic cells exhibited cytoplasmic immunostaining for cytokeratins (CAM 5.2) in all cases. In one case, a large number of neoplastic cells (60–70%) exhibited nuclear Ki-67 positivity. We postulate that the diseases histogenesis was from epithelial stem cell expressing both epithelial and neuroendocrine characteristics. The clinical behavior of small-cell neuroendocrine carcinomas of the ampullary region appears to be extremely aggressive, with early metastases and fatal outcome.

Thoracic Complications of Pancreatitis

Pancreatitis may be associated with thoracic complications, notably chronic massive pleural effusion (CMPE) and, rarely, pseudocysts with mediastinal extension (PME) and enzymatic mediastinitis (EM). Our personal experience with 14 cases of thoracic complications (nine CMPE, two PME associated with pleural effusion, and three EM of 670 patients who underwent surgery; of these, 191 had acute and 479 had chronic pancreatitis) during 16 years (1970–1986) is reported. In the patients with CMPE, the initial symptoms were progressive dyspnea eventually associated with cough and chest pain. In the PME cases, there was dysphagia associated with left subscapular pain and left chest pain. The initial signs in the patients with EM were sudden dyspnea, cyanosis, retrosternal pain, tachycardia, and acute heart failure. A fistula between the pancreatic ductal system and the pleural cavity in seven of the nine patients with CMPE was demonstrated by intraoperative pancreatography and/ or cystography. On the contrary, preoperative endoscopic pancreatography demonstrated the sinus tract in only three of the seven. In both cases of PME, computed tomography (CT) provided a correct diagnosis that was confirmed at surgery. In the patients with EM, the diagnosis was suggested by the clinical appearance and was confirmed by the chest roentgenogram and by CT. All patients had operations after varying periods of unsuccessful 2–4-week-long conservative treatment. One patient with infected ascites died postoperatively. There were no thoracic recurrences of pancreatic disease among the other patients at a 10-month-10-year follow-up observation after surgery.

Results of pancreaticoduodenectomy for pancreatic cancer: extended versus standard procedure.

In Western experience, the long-term survival benefit after extended pancreaticoduodenectomy (EPD) in patients with pancreatic ductal adenocarcinoma is still controversial. The aim of this work was to evaluate weather EPD for pancreatic ductal adenocarcinoma prolongs long-term survival compared to standard pancreaticoduodenectomy (SPD). From November 1992 to September 1996, we performed pancreatic resections in 30 patients affected by stage I–III pancreatic ductal adenocarcinoma: 13 patients underwent SPD and 17 patients underwent EPD, consecutively. The two groups of patients were similar for all the demographic, clinical, and pathological characteristics, and all the intraoperative factors considered except the number of resected lymph nodes (mean number per case=34.2 ± 15.5 in the EPD group versus 12.8 ± 3.6 in the SPD group, p<0.001) and the operative time (median time per case=375 minutes in the EPD group versus 270 minutes in the SPD group, p=0.009). Patients in the two groups experienced a similar postoperative course. The estimated survival probability at 1 and 3 years after operation was 0.76 (95% confidence interval [CI]: 0.49 to 0.90) and 0.24 (95% CI: 0.07 to 0.45) in the EPD group; 0.31 (95% CI: 0.09 to 0.55) and 0.08 (95% CI: 0.00 to 0.29) in the SPD group (p=0.014). According to a Cox model, the treatment was associated with R0 patients’ long-term survival (SPD versus EPD: hazard ratio (HR)=4.82, 95% CI: 1.66 to 14.00, p=0.004). Grading of tumor differentiation was confirmed to be a relevant prognostic factor (poor versus moderate: HR=4.33, 95% CI: 1.49 to 12.61, p=0.007), whereas type of resection had no significant effect (pylorus-preserving versus hemigastrectomy: HR=1.49, 95% CI: 0.56 to 3.95, p=0.42). The proportion of R0 patients with local recurrence was lower in the EPD group (20.0% versus 70.0%, p=0.034).RésuméDans l’Occident, les bénéfices à long terme en termes de survie, après duodénopancréatectomie céphalique étendue (DPCE) chez les patients présentant un adénocarcinome du pancréas, sont toujours controversés. Le but de cette étude a été d’évaluer si la DPCE augmentait la survie comparée aux DPC conventionnelles (DPCC). Entre novembre 1992 et septembre 1996, nous avons opéré 30 patients atteints d’adénocarcinome pancréatique stades I–III: 13 patients ont eu une DPCC et 17 patients, une DPCE, consécutivement. Les deux groupes de patients étaient comparables en ce qui concernaient les données démographiques, cliniques et pathologiques ainsi que les facteurs peropératoires sauf pour le nombre d’adénopathies réséquées (nombre moyen par cas=34.2 ± 15.5 dans le groupe DPCE versus 12.8 ± 3.6 dans le groupe DPCC, p<0.001) et la durée opératoire (temps médiane par cas=375 minutes pour la DPCE versus 270 minutes pour la DPCC, p=0.009), et les deux groupes ont eu une évolution postopératoire similaire. La probabilité de survie estimée à un et à trois ans après l’intervention a été de 0.76 (intervalle de confiance à 95% [IC]: 0.49–0.90) et 0.24 (95% IC: 0.07–0.45) dans le groupe DPCE et de 0.31 (95% IC: 0.09–0.55) et 0.08 (95% IC: 0.00–0.29) dans le groupe DPCC (p=0.014). Selon le modèle de Cox, deux facteurs influençaient la survie à long terme: les résection R0 (DPCC vs DPCE: Rapport de risque=4.82, 95% IC: 1.66–14.00, p=0.004), le degré de dédifférenciation tumorale (mal différencié vs modérément différencié: rapport de risque=4.33, 95% IC: 1.49–12.61, p=0.007), alors que le type de résection n’avait aucun effet significatif: pancréatectomie avec conservation du pylore versus hémi-gastrectomie: rapport de risque=1.49, 95% IC: 0.56–3.95, p=0.42). La proportion de patients réséqués R0 avec récidive locale a été plus bas dans le groupe DPCE (20.0% versus 70.0%, p=0.034).ResumenEn Occidente, siguen sujetos a discusión los resultados tardíos de la duodenopancreatectomía ampliada (EPD) en pacientes con adenocarcinoma ductal pancreático. El objetivo del trabajo fue determinar si la EPD prolonga la supervivencia tardía más que la duodenopancreatectomía estándar (SPD). De noviembre de 1992 a septiembre de 1996 se resecaron 30 adenocarcinomas ductales pancreáticos en estadio I–III. En 13 se practicó una SPD y en 17 una EPD. Ambos grupos eran homogéneos tanto desde el punto de vista demográfico, clínico y anatomopatológico como por lo que a la evolución postoperatoria y hallazgos intraoperatorios se refiere, excepción hecha de: el número de ganglios linfáticos extirpados (media por caso=34.2 ± 15.5 en el grupo EPD vs 12.8 ± 3.6 en el SPD, p<0.001) y la duración de la intervención (media por caso=375 minutos en el grupo EPD vs 270 m. en el SPD, p=0.009). Tras la operación la probabilidad estimada de supervivencia a 1 y 3 años fue: 0.76 (95% CI: 0.49–0.90) y 0.24 (95% CI: 0.07–0.45) en el grupo EPD. En el grupo SPD estos valores fueron: 0.31 (95% CI: 0.09–0.55) y 0.08 (95% CI: 0.00–0.29), p=0.014. De acuerdo con el modelo de Cox la modalidad de tratamiento, en pacientes RO, influye en la supervivencia tardía (SPD vs EPD: cociente de azar (HR)=4.82, 95% CI: 1.66–14.00, p=0.004); el estadio tumoral es el factor pronóstico más importante (poco diferenciados vs moderadamente diferenciados: HR=4.33, 95% CI: 1.49–12.61, p=0.007). Sin embargo, la técnica quirúrgica no tiene importancia alguna (preservación del píloro vs hemigastrectomía: HR=1.49, 95% CI: 0.56–3.95, p=0.42). En pacientes R0 la recidiva local fue menor en el grupo EPD (20% vs 70%, p=0.034).

Cystic tumors of the pancreas: Evaluation by ultrasonography and computed tomography

The personal series of 30 cystic tumors of the pancreas [12 serous cystic tumors (SCT) and 18 mucinous cystic tumors (MCT)] is presented. All neoplasms were evaluated with ultrasonography (US) 28 of 30 with computed tomography (CT); the tumoral histotype could be correctly defined in 73% of cases (seven of 12 SCT and 15 of 18 MCT). Percutaneous fine-needle aspiration (FNA) with diagnostic aims (preparation of cytological smears and/or biochemical assays) was performed in only 10 of 30 cases, yielding a 100% sensitivity; on the whole, the combined use of imaging modalities and FNA allowed correct characterization of the cystic tumors in 27 of 30 cases (90%). The usefulness of a precise diagnostic workup of these neoplasms is emphasized, due to their prognostic and therapeutic outcome.

Cystic islet cell tumors of the pancreas. A clinico-pathological report of two nonfunctioning cases and review of the literature

SummaryCystic islet cell tumors of the pancreas are extremely rare. The authors report their personal experience with two cases of nonfunctioning cystic endocrine neoplasms. The tumor was diagnosed preoperatively in one case by ultrasonography (US)-guided fine-needle aspiration cytology, while in the other it was identified only in the surgical specimen after a clinical-radiologic diagnosis of pancreatic mucinous cystic tumor. Immunohistochemical assay showed positivity for the generic neuroendocrine markers (neuron specific enolase, or NSE, synaptophysin, and chromogranin A) in both cases and also for glucagon in one case. The neoplasms were resected by distal pancreatectomy with splenectomy and intermediate pancreatectomy respectively. Both patients are alive and recurrence-free 6 mo and 2.5 yr, respectively, after surgery. The authors also review the existing literature, discussing the pathogenesis of such tumors and the imaging techniques and surgical strategies adopted in their management.

Gastroduodenal artery stump haemorrhage following pylorus-sparing Whipple procedure: treatment with covered stents.

Background/Aims: To report a case of bleeding after pancreatoduodenectomy in a patient with pancreatic leak and portal thrombosis who was successfully treated with an endovascular approach. Methods: A 58-year-old male, suffering from neoplasm of the distal bile duct, underwent a pylorus-preserving Whipple procedure. On the 18th day, following a sudden drop in pressure and low haematocrit values, the patient underwent surgery. The source of the bleeding was not found. Six days later, following the appearance of bleeding from the abdominal drainage and haematemesis with shock, the patient had an immediate angiography. Bleeding from the gastroduodenal artery stump was evident, the portography showed no portal flow. With respect to the shortness of the stump, safe embolisation with coils, while preserving the common hepatic artery patency, was difficult to obtain. Results: By transcatheter placement of covered stents into the hepatic artery and thereby occluding the origin of the gastroduodenal artery, the bleeding was stopped. After 2 months, CT angiography showed patency of both the common and proper hepatic arteries. Nine months after the procedure the patient is in good health. Conclusions: Percutaneous placement of covered stents can be the solution in cases where transcatheter embolisation is not recommendable because of portal vein thrombosis.