Marian Priyanthi Kumarasinghe

Clinicopathological features of patients with concomitant intraductal papillary mucinous neoplasm of the pancreas and pancreatic endocrine neoplasm.

Background/Aims: The occurrence of concomitant pancreatic endocrine neoplasm (PEN) and intraductal papillary neoplasm (IPMN) of the pancreas has rarely been reported. We describe our experience with 3 patients with this association and review the existing literature. Methods: From 1990 to 2005, 65 patients who underwent surgery for a PEN or IPMN were retrospectively reviewed. Forty-three patients had a PEN, 19 had an IPMN and 3 had both an IPMN and PEN. The 3 patients with concomitant IPMN and PEN are the focus of the current study and their clinicopathological features are reported together with 7 patients previously reported in the literature. Results: There were 10 patients with a median age of 62 years (range 40–73). The male:female ratio was equal. Seven of 10 patients were symptomatic and the most common symptoms were abdominal pain (n = 5), jaundice (n = 2) and loss of weight (n = 2). The median size of the endocrine neoplasms was 14 mm (range 2–30) and they occurred in the head (n = 3), body (n = 2) and tail (n = 5). Seven of the PENs were classified as benign, 2 were potentially malignant, and 1 was frankly malignant with lymph node involvement. None of the endocrine neoplasms were functioning. The IPMNs were found in the tail (n = 4), head (n = 3), head and body (n = 1), body (n = 1) and the entire pancreas (n = 1). Five of these neoplasms were benign, 2 were borderline and 3 were malignant (1 carcinoma in situ). Conclusion: The occurrence of concomitant IPMN and PEN is more frequent than would be expected. However, it is difficult in the present analysis to determine if this association is more than just fortuitous.

Modulation of iron-regulatory genes in human hepatocellular carcinoma and its physiological consequences

Hepatocellular carcinoma (HCC) commonly develops in patients with underlying chronic liver disease. Additionally, the tumorous lesions of HCC patients are consistently characterized by the lack of iron accumulation even when arising in iron-loaded liver. However, the molecular mechanism leading to this observed phenomenon is currently poorly understood. In this study, all tumorous tissues from 24 HCC patients with chronic HBV infection were stained negative for iron when histologically assessed by Perls’ Prussian blue stain, whereas excess iron deposits were present in 17 of the 24 adjacent non-tumorous liver tissues. To elucidate the concerted regulation of iron homeostasis in these patients, we studied the gene expression profiling of 42 relevant iron-regulatory genes in the tumorous and adjacent non-tumorous liver tissues of these HCC patients along with 10 normal liver controls. Expression for most of the iron-regulatory genes, including hepcidin, transferrin receptor 2 (TfR2), transferrin (Tf), ceruloplasmin (Cp) and iron regulatory protein 1 (IRP1), were significantly down-regulated in the tumorous tissues of these patients compared to the adjacent non-tumorous liver tissues and normal liver controls. On the other hand, expression of hepcidin, TfR2, ferroportin 1 and DMT1 were significantly up-regulated in iron-loaded non-cirrhotic non-tumorous liver tissues as compared with normal liver controls. Hence, the reduction of hepcidin expression within the iron-depleted tumorous lesions likely reflects the physiological consequence of the obligate demand for iron in the rapidly growing neoplastic cells, whereas the up-regulation of hepcidin expression in the iron-loaded adjacent non-tumorous liver tissues is likely a physiological response.

DNA mismatch repair enzyme immunohistochemistry in colorectal cancer: a comparison of biopsy and resection material.

Background: Microsatellite instability (MSI) in colorectal cancer (CRC) may be predicted using mismatch repair protein (MMRP) immunohistochemistry (immunostaining), allowing focused genetic investigations and potentially influencing therapeutic interventions. Most laboratories perform immunostaining on surgical resection specimens. Endoscopic biopsy specimens are an alternative tissue source for immunostaining. Given the sensitivity of immunostaining to the degree of tissue fixation, endoscopic biopsy material may produce superior staining, based on faster and more thorough fixation. Moreover, in patients receiving neoadjuvant chemotherapy and/or radiotherapy, endoscopic biopsies may be more useful than surgical resection specimens by allowing assessment of MMR status prior to chemotherapy and/or radiotherapy induced changes in tumours. This study examines whether immunostaining for MMRP expression in CRC is as reliable on endoscopic biopsy material as on surgical resection specimens. Methods: Immunostaining for MLH1, PMS2, MSH2 and MHS6 was performed on 112 unselected CRC cases with both endoscopic biopsy and surgical resection material available. A single observer blindly examined intensity and distribution of staining and assessed MMRP expression. Two consultant histopathologists reviewed challenging cases. Endoscopic biopsies and surgical resections were compared using non‐parametric statistical analysis. Results: Immunostaining for all four MMRPs on all 112 cases produced conclusive (i.e., fully interpretable) results in endoscopic biopsies. In surgical resection specimens, 10 stains from nine cases were inconclusive (stains for two MMRPs were inconclusive in one case). In cases where conclusive immunostaining was achieved, there was complete agreement in MMRP status between the endoscopic biopsy and corresponding surgical resection specimens. Overall, MMRP loss was identified in 13% of cases; 11% MLH1, 12% PMS2, 1% MSH2, and 1% MSH6. Immunostaining intensity was significantly higher (p < 0.0005) and the distribution of staining was significantly more uniform (p < 0.0005) on endoscopic biopsy than on surgical resection. Conclusion: Endoscopic biopsy provides equal accuracy and easier interpretation of MMRP expression immunostaining compared to surgical resection specimens.

Pathological features and their prognostic implications in colorectal endocrine cell tumours: a long‐term follow‐up study

Aims: Long‐term follow‐up studies of colorectal endocrine cell tumours (CRECTs) are rare. Our aim was to correlate pathological features with metastatic potential and long‐term survival of CRECTs. Methods: Pathological features of 35 CRECTs were reviewed. Features assessed were the tumour size, local and angio‐invasion, growth pattern, cyto‐nuclear morphology, mitotic count, mucin production and proliferative activity. CRECTs were also re‐classified according to the World Health Organization (WHO) 2000 criteria. The follow‐ups ranging from 60 to 132 months was obtained from Singapore National Cancer Registry data. Results: There were five metastatic and 30 non‐metastatic tumours. Three of five metastatic tumours resulted in death within 1 year of diagnosis. Features exclusively seen in these three tumours were large size (25mm or more), mitoses >6/10 high power fields with abnormal forms necrosis and large cell morphology. The features which correlated significantly with metastases were size, local and angioinvasion, primitive growth pattern, coarse chromatin and mitotic count (p<0.0005), large cells and prominent nucleoli (p=0.017), MIB1 proliferative index (p=0.001) and abnormal mitoses and necrosis (p=0.02). Thirty tumours were reclassified as well‐differentiated endocrine cell tumours (WETs), three as well‐differentiated endocrine cell carcinomas (WECs) and two were large cell neuroendocrine cell carcinomas (LECs) according to WHO criteria. One of the WECs and both LECs resulted in death. Conclusions: All patients whose tumour was 25mm or more, showing mitoses of more than 6 per 10 high power fields, with abnormal forms, necrosis and large cell morphology, died of the disease. Size, invasion, presence of discernible mitoses, coarse chromatin, ‘primitive’ growth pattern and MIB1 index of 4% or more were associated with metastases. LECs are rare but aggressive tumours resulting in early death. All WECs do not behave in the same fashion.