Morphological study of 391 cases of exocrine pancreatic tumours with special reference to the classification of exocrine pancreatic carcinoma

Three hundred and ninety-one cases of primary pancreatic tumours, excluding endocrine tumours, were studied histologically. Carcinoma of the exocrine pancreas formed the largest group (98.5 per cent), benign tumours (1.25 per cent) and other malignant tumours (0.25 per cent) formed the remainder. Ductal adenocarcinoma was the commonest type and was divided into four sub-types, papillary, well, moderately and poorly differentiated duct adenocarcinoma. The moderately and poorly differentiated tumours were the commonest types. Papillary carcinoma was separated from the well differentiated tumours by its different morphological appearances and was found to exhibit different behaviour. Other special morphological types of pancreatic carcinoma, pleomorphic, mucinous, adenosquamous, acinar, microadenocarcinoma, cystadenocarcinoma and oncocytic carcinoma were also represented. Benign microcystadenomata (four cases) were considered because of their interesting morphological features and their significance in the differential diagnosis of carcinoma. Based on the morphology and behaviour of these 391 tumours, the classification of pancreatic carcinoma is discussed and some rare types are compared with previously reported cases and discussed.     

Oncocytic non-functioning endocrine tumor of the pancreas

Herein is presented the case of a malignant non-functioning endocrine tumor of the pancreas with oncocytic features, and a discussion on the high incidence of malignancy in oncocytic endocrine pancreatic tumors. The patient was a 65-year-old woman who showed no paraneoplastic symptoms produced by functioning pancreatic endocrine tumors. The primary tumor was located in the body and tail of the pancreas, and had metastasized to the liver. Tumor cells were arranged in a ribbon-like or trabecular pattern and had an abundant eosinophilic cytoplasm containing numerous mitochondria and neurosecretory granules. The cytoplasm of the tumor cells was intensely stained with an antimitochondrial antigen antibody. Most tumor cells stained positively with Grimelius stain and for chromogranin A. Some tumor cells also stained for synaptophysin. However, the tumor cells negatively stained for hormones such as insulin, glucagon, somatostatin, gastrin, vasoactive intestinal peptide and pancreatic polypeptide, for serotonin, and for pancreatic enzymes such as amylase and trypsin. Analysis of 18 oncocytic pancreatic endocrine tumors, consisting of those reported previously and that in the present case, suggests that the high incidence of malignancy in oncocytic endocrine tumors is associated with the high incidence of non-functioning endocrine tumors among them, most of which are malignant.     

Telomerase activity in pancreatic endocrine tumours: a potential marker for malignancy.

AIMS: Telomerase activation is known to be a common event in human cancer and may be a useful marker for malignancy. In general, the histological features of pancreatic endocrine tumours cannot be used to determine their malignant potential. The aim of this study was to investigate the role of testing telomerase activity in pancreatic endocrine tumours. METHODS: Prospectively collected fresh frozen tissue specimens from 10 patients with pancreatic endocrine tumours (nine insulinomas, one adrenocorticotrophin producing pancreatic endocrine tumour) were examined by a highly sensitive polymerase chain reaction (PCR) based telomerase repeat protocol (TRAP). RESULTS: Of the 10 pancreatic endocrine tumours, three had telomerase activity. The positive cases included two frankly malignant tumours with liver metastases and one pancreatic endocrine tumour occurring in the setting of multiple endocrine neoplasia type 1. The latter had an infiltrative border. Vascular and perineural tumour infiltration was noted. In the two malignant pancreatic endocrine tumours with liver metastases, telomerase activity was noted in the tumour and the adjacent morphologically non-neoplastic pancreas. CONCLUSION: To our knowledge, this is the first report of the role of telomerase activity in pancreatic endocrine tumours. Telomerase activity might be useful for distinguishing between benign and malignant pancreatic endocrine tumours.     

Multicentric encapsulated papillary oncocytic neoplasm of the thyroid: A case diagnosed by a combined cytological, histological, immunohistochemical, and molecular approach

Fine-needle aspiration (FNA) diagnosis of oncocytic lesions is challenging. In fact, oncocytic changes occur in inflammatory, hyperplastic, and neoplastic settings, including both benign and malignant tumors. The rare oncocytic variant of papillary thyroid carcinoma (PTC), shows papillae composed by cells with large oncocytic granular cytoplasm featuring clear PTC nuclear features. A morphological similar, but biologically distinct lesion, is the encapsulated papillary oncocytic neoplasia. Here, we first report on FNA, its cytological features together with histological, immunohistochemical, and molecular correlates.     

Oncocytic myoepithelioma and pleomorphic adenoma of the salivary glands

 Twenty oncocytic myoepitheliomas (MEs) and pleomorphic adenomas (PAs) were composed of interlacing fascicles of swollen spindle-shaped or/and epithelioid oncocytic myoepithelial cells showing intense finely granular immunoreactivity with anti-mitochondrial antibody. Focal vacuolation of the cytoplasm of oncocytic myoepithelial cells and their gradual transition into sebaceous metaplasia were observed in 3 cases. Another unusual feature found in 5 cases was the presence of slit-like adenomatoid spaces lined with double-layered oncocytic myoepithelium closely resembling Warthin’s tumour. The nuclei of oncocytic cells were characterized by enlargement, hyperchromasia and polymorphism, which should not be confused with malignancy. Oncocytic change in myoepithelial cells in MEs and PAs can cause pitfalls in the differential diagnosis of salivary gland tumours. We describe some unusual histological features associated with onococytic metaplasia in benign myoepithelial cell-derived salivary gland tumours, hoping to help to avoid the overdiagnosis of malignancy. Received: 24 September 1998 / Accepted: 31 January 1999     

Adrenal Oncocytic Phaeochromocytoma with Putative Adverse Histologic Features: a Unique Case Report and Review of the Literature

Oncocytic phaeochromocytomas are exceedingly rare tumours. To date, there are three reported cases in the literature. This report describes a case of adrenal oncocytic phaeochromocytoma with unique features and malignant potential in a 68-year-old man. The patient presented with an incidental non-functional mass discovered on routine radiological investigation, which was subsequently excised. Histologically, the tumour cells showed oncocytic features with high-grade nuclear abnormalities and foci of extension to the peri-adrenal fat. Immunohistochemistry performed was positive for chromogranin, CD56, S-100 and p53 and negative for inhibin, HMB-45, EMA, AE1/AE3, Cam 5.2 and calretinin. Electron microscopy showed electron dense granules of neurosecretory type, which confirmed the diagnosis. The malignant potential of the tumour was assessed on available histologic scoring systems, which demonstrated a high malignant potential. However, no recurrence was detected after 5 years of follow-up. Compared to all the previously reported cases of oncocytic phaeochromocytoma, this patient was the oldest on presentation, was the only case with identified high malignant potential and has the longest follow-up. A review of the literature showed that all the oncocytic phaeochromocytomas reported were non-functional, non-metastasizing and were described in women. To conclude, oncocytic phaeochromocytoma should be in the differential diagnoses of oncocytic tumours of the adrenal gland. Additional studies are needed to predict the behaviour of this entity.     

Salivary gland-like tumours of the breast: surgical and molecular pathology

Breast glands and salivary glands are tubulo-acinar exocrine glands that can manifest as tumours with similar morphological features, but that differ in incidence and clinical behaviour depending on whether they are primary in breast or salivary glands. Salivary gland-like tumours of the breast are of two types: tumours with myoepithelial differentiation and those devoid of myoepithelial differentiation. The first and more numerous group comprises a spectrum of lesions ranging from "bona fide" benign (such as benign myoepithelioma and pleomorphic adenoma), to low grade malignant (such as adenoid cystic carcinoma, low grade adenosquamous carcinoma, and adenomyoepithelioma), to high grade malignant lesions (malignant myoepithelioma). The second group comprises lesions that have only recently been recognised, such as acinic cell carcinoma, oncocytic carcinoma of the breast, and the rare mucoepidermoid carcinoma.     

Cytokeratin 14 immunoreactivity distinguishes oncocytic tumour from its renal mimics: an immunohistochemical study of 63 cases

AIMS: The cytokeratin 14 (CK14) expression in oncocytomas or oncocytic tumours of various tissue origins has not been established. We have studied CK14 expression in 30 cases of oncocytic tumours of various tissue origins and 33 cases of renal cell carcinoma with overlapping features (mimics) by immunohistochemistry. METHODS AND RESULTS: Immunohistochemistry (ABC-HRP method) was performed for detection of CK14 in 30 cases of oncocytic tumour and 33 cases of renal mimics. To demonstrate CK14 specificity and sensitivity in oncocytic tumours, mES-13 (an anti-mitochondrial monoclonal antibody) immunohistochemistry was also performed in 20 of 30 cases on oncocytic tumour and all 33 cases of renal mimics. We found that all 30 cases of oncocytic tumour showed cytoplasmic CK14 positivity. All 20 cases of oncocytic tumour studied with mES-13 were positive. CK14 immunoreactivity was identified in only four cases of renal cell carcinoma (one conventional renal cell carcinoma with granular cytoplasm and three chromophobe renal cell carcinomas with eosinophilic cytoplasm). In contrast, all 33 cases of renal cell carcinoma were positive for mES-13 to varying degrees. CONCLUSION: The homogeneous, cytoplasmic, and granular CK14 immunoreactivity is sensitive and specific for oncocytic tumours, whereas CK14 immunoreactivity in renal mimics is light and sporadic with peripheral accentuation.     

Oncocytic lesions of the neuroendocrine system.

Oncocytic tumors are rare tumors that have been described in many organs throughout the body, mainly in salivary, parathyroid, thyroid, and adrenal glands and in the kidney. A wide spectrum of benign and malignant oncocytic tumors can arise in various organs of the neuroendocrine system. They are usually defined as tumors that are composed predominantly or exclusively of oncocytic cells. A majority of these tumors are benign; however, in some endocrine organs such as the thyroid the diagnosis of oncocytic/Hürthle cell carcinoma portends a more aggressive clinical course than non-Hürthle cell follicular carcinoma. Therefore, it is important to follow strict criteria to diagnose and differentiate between benign and malignant oncocytic tumors. In this review we will discuss the clinicopathologic features of various oncocytic tumors of the endocrine glands.     

Metastatic papillary oncocytic carcinoma of the pancreas to the liver diagnosed by fine-needle aspiration

A 37-year-old white male with a large pancreatic mass was referred to our institution with a hypodense liver lesion detected on CT scan. A fine-needle aspiration (FNA) was performed on the liver lesion. Diff-Quik smears demonstrated scattered papillary structures and single neoplastic cells with abundant well-defined dense granular cytoplasm. Eccentrically located nuclei were noted with single prominent nucleoli. Cell block preparations showed papillary structures lined by cells with abundant pink granular cytoplasm, hyperchromatic nuclei, and prominent single nucleoli. Electron microscopic examination displayed numerous but poorly preserved mitochondria. The diagnosis of papillary carcinoma with oncocytic features was made. Only two previous cases of pancreatic oncocytic tumors diagnosed by FNA have been reported in the literature. We present an additional case, notable in that the diagnosis was made in a metastatic liver nodule. Diagn. Cytopathol. 1998;18:291–296. © 1998 Wiley-Liss, Inc.     

Oncocytic adrenocortical neoplasms--a clinicopathologic study of 13 new cases emphasizing the importance of their recognition

Oncocytic adrenocortical neoplasms (OANs) are a rare but important subtype of adrenal tumors with unique clinical and morphological features. We present 13 previously unpublished cases, of which 3 were classified as benign, 2 as having borderline malignant potential, and 8 as malignant according to the Lin-Weiss-Bisceglia criteria. Seven tumors (54%) showed evidence of endocrine activity. All were composed of more than 90% oncocytes confirmed immunohistochemically using the antimitochondrial antibody mES-13 and ultrastructurally in 4 cases. Small oncocytes were a frequent finding that challenges the conventional notion of oncocytes as necessarily having abundant cytoplasm. Most cases were immunoreactive for vimentin, synaptophysin, inhibin-α, melan A, and calretinin, the latter being a novel finding in this group of neoplasms. Cytokeratin positivity with AE1/AE3 and CAM5.2 was variable. The literature was comprehensively reviewed to identify all cases of OANs reported to date. Hormone production is not as uncommon as previously believed, occurring in 30%. The Lin-Weiss-Bisceglia criteria were retrospectively applied to all published cases with sufficient information and were shown to effectively separate tumors according to their future risk of recurrence and survival using Kaplan-Meier survival curves (log-rank test, P < .001 for both). The estimated overall median survival for malignant oncocytic neoplasms is 58 months (95% confidence interval = 27.5-88.5 months), providing the first preliminary evidence that the prognosis of malignant OANs is likely to be more favorable than conventional adrenocortical carcinomas, in which the reported median survival is between 14 and 32 months.     

鼻嗜酸性细胞乳头状瘤的临床和病理学特点

目的探讨鼻嗜酸性细胞乳头状瘤的临床及病理组织学特点。方法回顾性分析9例鼻嗜酸性细胞乳头状瘤的临床和病理学特征,并对手术标本进行免疫组织化学染色。结果患者年龄48～66岁,6例发生于上颌窦、2例发生于筛窦、1例发生于鼻腔。镜下见乳头状排列的多层柱状上皮细胞,胞浆内含有嗜酸性颗粒,上皮内含有充满粘液的微囊,有的微囊内聚集多少不等的中性粒细胞形成微脓肿。手术后3例复发,1例恶变。结论鼻嗜酸性细胞乳头状瘤是一种罕见的良性肿瘤,易误诊,术后易复发及恶变,需积极治疗和精心的术后监测。     

Hybrid oncocytic/chromophobe renal cell tumours do not display genomic features of chromophobe renal cell carcinomas

Hybrid oncocytic/chromophobe tumours (HOCT) are renal tumours recently described displaying histological features of both renal oncocytoma (RO) and chromophobe renal cell carcinoma (ChRCC), raising the question of their precise signification in the RO/ChRCC group. This study aimed to describe clinicopathological features of so called HOCT and to characterise their genomic profile. Five hundred and eighty-three tumours belonging to the ChRCC/RO group were retrospectively reviewed. Twelve tumours that could not be classified as RO or CHRC were considered as HOCT. Hale staining and cytokeratin 7 (CK7) immunostaining were performed. Genomic profile was established by array comparative genomic hybridisation (array-CGH) on frozen samples. Mean age at diagnosis was 70 years (range 46–83). No recurrence was observed (median follow-up: 18 months; range 9–72). Tumour size ranged from 1 to 11 cm. HOCT showed an admixture of RO- and ChRCC-like areas and/or “hybrid” cells with overlapping cytonuclear and/or histochemical features. Hale staining was apical in 50 to 100 % of cells, and CK7 was expressed in 10 to 100 % of cells. Genomic profile was balanced in seven cases or showed a limited number of random imbalances in five cases, as observed in RO. In no instances were observed the characteristic chromosome losses of ChRCC. These results suggest that so called HOCT are not true hybrid tumours and rather could represent a morphological variant of RO. From a diagnostic perspective, an array-CGH analysis could be performed in ambiguous ChRCC/RO cases to formally exclude the diagnosis of ChRCC.     

Oncocytic and oncocytoid tumors of the exocrine pancreas, liver, and gastrointestinal tract.

Tumors having typical oncocytic features very rarely affect the gastrointestinal (GI) tract, liver, and pancreas, although several tumors with prominent "pink" (eosinophilic) cytoplasm are recognizable in the digestive tract. From a practical point of view, interest in the former lesions is limited to the differential diagnosis of a primary neoplasm versus metastatic deposits of malignant oncocytic tumors from other sites. This article briefly reviews the diagnostic features and clinical significance of the currently known tumors of the alimentary tract displaying a prominent oxyphilic character.     

Malignant potential of aneuploid pancreatic endocrine tumours

Evaluation of the malignant potential of pancreatic endocrine tumours is difficult by histological criteria alone. Nuclear deoxyribonucleic acid (DNA) cytometric analysis can provide significant prognostic and biological information in a number of solid human tumours. Thus, the DNA profiles and nuclear parameters of 39 patients with pancreatic endocrine tumours diagnosed from 1969 to 1989 were studied, using computerized video image analysis. Of the 39 patients with tumours, 27 cases did not have evidence of metastatic disease at the time of investigation. The majority of these (N=21) showed a diploid profile. Five were aneuploid and one was tetraploid. In the 12 tumours that proved malignant, three had tissue of both the primary tumour and the metastases analysed; six had material only from the primary tumour, although metastatic disease was established clinically; and another three only had tissue from the secondary tumour studied. The majority of the malignant cases were aneupioid (N =7); three were dipioid; one showed a diploid primary but an aneuploid secondary; and one showed a hyperdiploid pattern. The percentage of nuclei with a DNA content greater than 5N (5CER) did not seem to contribute further to the assessment nor did the means of the nuclear areas and shape factors. It appears that ploidy studies may be useful in predicting malignant potential of pancreatic endocrine tumours. There is a high rate of immunostaining for insulin by benign pancreatic endocrine tumours and this may be a useful adjunct to distinguish them from their malignant counterparts. However, there is no statistically significant correlation between the expression of various hormones and the DNA ploidy of tumour cells.     

Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours

The fourth edition of the World Health Organization (WHO) classification of endocrine tumours contains substantial new findings for the adrenal tumours. The tumours are presented in two chapters labelled as “Tumours of the adrenal cortex” and “Tumours of the adrenal medulla and extra-adrenal paraganglia.” Tumours of the adrenal cortex are classified as cortical carcinoma, cortical adenoma, sex cord stromal tumours, adenomatoid tumour, mesenchymal and stromal tumours (myelolipoma and schwannoma), haematological tumours, and secondary tumours. Amongst them, schwannoma and haematological tumours are newly documented. The major updates in adrenal cortical lesions are noted in the genetics of the cortical carcinoma and cortical adenoma based on the data from The Cancer Genome Atlas (TCGA). Also, a system for differentiation of oncocytoma from oncocytic cortical carcinoma is adopted. Tumours of the adrenal medulla and extra-adrenal paraganglia comprise pheochromocytoma, paraganglioma (head and neck paraganglioma and sympathetic paraganglioma), neuroblastic tumours (neuroblastoma, nodular ganglioneuroblastoma, intermixed ganglioneuroblastoma, and ganglioneuroma), composite pheochromocytoma, and composite paraganglioma. In this group, neuroblastic tumours are newly included in the classification. The clinical features, histology, associated pathologies, genetics, and predictive factors of pheochromocytoma and paraganglioma are the main changes introduced in this chapter of WHO classification of endocrine tumours. The term “metastatic pheochromocytoma/paraganglioma” is used to replace “malignant pheochromocytoma/paraganglioma.” Also, composite pheochromocytoma and composite paraganglioma are now documented in separate sections instead of one. Overall, the new classification incorporated new data on pathology, clinical behaviour, and genetics of the adrenal tumours that are important for current management of patients with these tumours.     

Oncocytic neuroendocrine tumors of the lung: histopathologic spectrum and immunohistochemical analysis of 15 cases

Oncocytic neuroendocrine tumor of the lung is rare. To reveal the clinicopathologic features of oncocytic neuroendocrine tumor, we reviewed surgical resections from 80 patients diagnosed with carcinoid tumors and 35 high-grade neuroendocrine carcinomas. We discovered 7 cases from the 80 carcinoid tumors and added 8 patients from personal consultation files. There were no statistically significant differences among the clinical features (such as age, location, and survival). Although most oncocytic neuroendocrine tumors were low-grade neuroendocrine carcinomas, we found that they could be of any grade. Tumor cells showed an ample amount of granular oncocytic cytoplasm and had a round-to-oval nucleus with coarse chromatin. Two cases mainly consisted of small-sized to medium-sized cells resembling plasma cells. This tumorous area intermingled with the conventional oncocytic area. Other histologic features were a large conspicuous nucleolus in 9 cases and the presence of giant cells in 8 cases. In the 80 carcinoid cases, bone formation (P = .034), the presence of giant cells (P?=?.021), and tumor cells with a conspicuous nucleolus (P = .021) were more frequently observed. Immunohistochemical analysis revealed that oncocytic cells were positive for antimitochondria antibody. In conclusion, most of the tumors were low-grade neuroendocrine carcinomas, but we found that oncocytic neuroendocrine tumor can display features of high-grade neuroendocrine carcinoma. The oncocytic change was induced by accumulation of mitochondria. Although this variant does not differ in clinical features of nononcocytic neuroendocrine tumors, histologic features of the oncocytic neuroendocrine tumor can be a potential cause of diagnostic error.     

Intraductal oncocytic papillary carcinoma of the pancreas showing numerous hyaline globules in the lumen

Two cases of intraductal oncocytic papillary carcinoma (IOPC) treated surgically were analyzed on light microscopy and immunohistochemistry: that of a 61-year-old man and that of a 55-year-old man. There were no clinical symptoms in either case. Pancreatic abnormalities were discovered incidentally on CT. Various clinical examinations were carried out, and the preoperative diagnosis was intraductal papillary mucinous carcinoma (IPMC) in both cases. Surgery was performed. Macroscopic observation of tissue cross-sections indicated multilocular cystic mass containing polypoid lesions encapsulated by the dilated pancreatic duct. Histologically, the cyst walls were lined by columnar epithelial cells with complex papillary projections associated with oxyphilic cytoplasm, and they were strongly immunoreactive with anti-mitochondrial antibody in the cytoplasm. Electron microscopy showed numerous mitochondria in the cytoplasm. IOPC was diagnosed. Interestingly, amorphous hyaline globules were produced from the oxyphilic cells, which exhibited a bud-like appearance. The hyaline globules were not positive for mucin staining. No case of IPMC with hyaline globules has been reported to date. The production of hyaline globules may be related to oncocytic differentiation. It is suggested that hyaline globules should be regarded as a characteristic of IOPC.     

Immunocytochemical characterization of 10 pancreatic tumours, associated with the glucagonoma syndrome, using antibodies to separate regions of the pro-glucagon molecule and other neuroendocrine markers

Histological diagnosis of neuroendocrine tumours can be hampered by their lack of peptide or amine immunoreactivity. In order to assess the usefulness of a range of specific and general markers of neuroendocrine differentiation, 10 pancreatic endocrine tumours, associated with high levels of circulating glucagon, were studied using histology, histochemistry, immunocytochemistry and electron microscopy. All cases showed immunoreactivity for one or other of the peptides derived from pro-glucagon, although only seven were found to contain immunoreactive pancreatic glucagon. The presence of secretory granules in eight of the tumours was demonstrated by electron microscopy, argyrophilia or chromogranin immunoreactivity. Not only was neuron specific enolase positively immunostained in all the tumours, thereby revealing their neuroendocrine nature, but also the intensity of the immunostain was higher in four of the five malignant ones than in the rest of the cases. Pancreatic polypeptide was present in non-glucagon cells in six out of 10 cases. Our results emphasize the importance of the use, not only of general histochemical and immunocytochemical tests but also antibodies to all possible derivatives of the precursor form of the active tumour product in the diagnosis of possible endocrine tumours. In this way, any abnormal molecular forms of the peptide synthesized by tumour cells with altered synthetic and secretory mechanisms may be detected.     

Gastrointestinal stromal tumours: An update

Gastrointestinal stromal tumours (GISTs) comprise the largest subset of mesenchymal tumours of the digestive tract. These tumours have been the subject of considerable debate in the literature regarding their histogenesis, criteria for diagnosis, prognostic features and biological behaviour.The majority of GISTs express CD117 immunostaining and show various degrees of differentiation towards the phenotype of interstitial cell of Cajal.Clinically and histologically, GISTs represent a spectrum that includes benign and malignant variants. The prediction of clinical behaviour is best achieved by evaluation of multiple parameters including clinical, morphological and cytogenetic features.The recognition of the central role played by activating mutations of c-kit and platelet derived growth factor receptor alpha in the pathogenesis of GISTs and the introduction of STI-571, a receptor tyrosine kinase inhibitor that has proved extremely effective in the treatment of GISTs, have not only have focused attention on these tumours but also made it necessary to accurately define these tumours and separate them from other mesenchymal lesions. This review discusses the definition, histogenesis, epidemiology, clinical presentation, morphological and immunohistochemical features and the differential diagnosis of GISTs and addresses predictors of malignancy and management of GISTs.