Histopathological evaluation of minor salivary gland papillary-cystic tumours: focus on genetic alterations in sialadenoma papilliferum and intraductal papillary mucinous neoplasm.

AIMS: Minor salivary gland tumours showing a predominant papillary-cystic structure are rare, and constitute a mixture of various types of neoplasm; thus, the histopathological assessment of these tumours poses a significant diagnostic challenge. We aimed to delineate the histological characteristics of these tumours and further mutational aspects with a particular focus on sialadenoma papilliferum (SP) and intraductal papillary mucinous neoplasm (IPMN). METHODS AND RESULTS: We retrieved 28 papillary-cystic tumours of the minor salivary glands, and performed histological re-evaluation and mutation analyses of several key oncogenes. The histological classifications were as follows: SP (n = 10), SP-like intraductal papillary tumour (SP-IPT) (n = 2), IPMN (n = 9), intraductal papilloma, cystadenoma, and cystadenocarcinoma (two, three and two respectively). Whereas SP typically consisted of a combination of exophytic squamous epithelium and endophytic intraductal papillary infoldings, SP-IPT lacked the exophytic component. SP and SP-IPT frequently harboured BRAF V600E mutations (75.0%), which were identified in both squamous and ductal components. IPMN was characterised by a well-demarcated cystic lesion filled exclusively with a papillary proliferation of mucinous cells and a high rate of AKT1 E17K mutations (88.9%). Intraductal papillomas were unilocular cystic lesions with intraluminal papillary growth of bland columnar cells. In contrast, both cystadenomas and cystadenocarcinomas showed a multicystic appearance with a papillary configuration. Cystadenocarcinomas invaded the surrounding tissue and were composed of markedly atypical tumour cells. CONCLUSION: The appropriate interpretation of histological findings and specific genetic alterations (e.g. BRAF V600E and AKT1 E17K in SP and IPMN) would be useful for the correct diagnosis of minor salivary gland papillary-cystic tumours.

Latest advances in the pathological understanding of cholangiocarcinomas.

Cholangiocarcinomas (CCAs) are anatomically classified into intrahepatic, perihilar, and distal types. The gross pathological classification of intrahepatic CCAs divides them into mass-forming, periductal-infiltrating, and intraductal-growth types; and perihilar/distal CCAs into flat- and nodular-infiltrating and papillary types. Unique preinvasive lesions appear to precede individual gross types of CCA. Biliary intraepithelial neoplasia, a flat lesion, precedes periductal-, flat-, and nodular-infiltrating CCAs, whereas intraductal papillary neoplasm of the bile duct (IPNB) precedes the intraductal-growth and papillary type of CCAs. IPNBs are heterogeneous in their histological and pathological profiles along the biliary tree. Hepatobiliary cystadenomas/adenocarcinomas are reclassified as cystic IPNBs and hepatic mucinous cystic neoplasms. Peribiliary glands may participate in the development of CCAs. These latest findings present a new challenge for understanding the pathology of CCAs.

Searching for mammary analogue [corrected] secretory carcinoma of salivary gland among its mimics.

Mammary analog secretory carcinoma of salivary gland is a recently described entity with unique morphologic, clinical, and genetic characteristics, including the characteristic t(12;15)(p13;q25) with ETV6-NTRK3 translocation found in secretory carcinomas of the breast. Before their initial description, these salivary gland tumors were generally diagnosed as acinic cell carcinoma or adenocarcinoma. For the purpose of this study, all cases of salivary gland acinic cell carcinoma, cribriform cystadenocarcinoma, and adenocarcinoma, not otherwise specified (NOS), diagnosed over a 10-year period were retrieved from our surgical pathology files. There were a total of 11 cases diagnosed as acinic cell carcinoma, 10 cases of adenocarcinoma, NOS, and 6 cases of cribriform cystadenocarcinoma. All slides were reviewed by two pathologists (AP, CGF) and tumors that show morphologic features of mammary analog secretory carcinoma according to the recent literature were selected. This process narrowed down the initial number to six cases originally diagnosed as acinic cell carcinoma, three cases originally diagnosed as adenocarcinoma, NOS, and one case originally diagnosed as cribriform cystadenocarcinoma. The 10 cases were subjected to immunohistochemistry for S-100, mammaglobin, and ANO1, as well as fluorescence in situ hybridization analysis for t(12;15)(p13;q25) with ETV6-NTRK3 fusion rearrangement. The ETV6-NTRK3 gene rearrangement was detected in three tumors. These three tumors, initially diagnosed as acinic cell carcinomas, stained positive for S-100 and mammaglobin, and negative for ANO1 by immunohistochemistry. Two of the three patients were male (2/3). In summary, mammary analog secretory carcinoma is a newly described diagnostic entity that should be in the differential diagnosis of salivary gland tumors that morphologically mimic other neoplasms, mainly acinic cell carcinomas. They differ from conventional acinic cell tumors immunohistochemically and molecularly. Positivity for mammaglobin and S-100, and negativity for ANO1 are useful screening tools before confirmatory molecular studies.

Current issues in the pathology of ovarian cancer.

The majority of primary ovarian tumors are histologically classified as surface epithelial-stromal neoplasms. The malignant potential of such neoplasms may be categorized, on the basis of the extent of epithelial proliferation and stromal invasion, as benign, borderline or malignant. Recent efforts to further classify the malignant potential of such neoplasms have produced a new system for the histologic grading of ovarian carcinoma as well as new potential histologic predictors of behavior, including micropapillary morphology and stromal microinvasion in serous tumors. Among mucinous ovarian neoplasms, new criteria have been proposed to distinguish primary ovarian from metastatic carcinomas; the distinction may be difficult but has great clinical significance. The origin of ovarian mucinous tumors associated with pseudomyxoma peritonei has been reassessed. Finally, recent pathologic findings from prophylactic salpingo-oophorectomy specimens in patients with hereditary risks for ovarian carcinoma have highlighted the additional risk for fallopian tube carcinoma and primary peritoneal carcinoma. Special processing of the pathologic specimens is required to detect early and minimal neoplasia in this setting. These current issues in the pathology of ovarian carcinoma and their clinical significance form the basis of this review.

Borderline ovarian tumors: diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images.

The National Cancer Institute sponsored a Borderline Ovarian Tumor Workshop held in August 2003 in Bethesda, MD. This report was developed from discussions at the Workshop. The participants acknowledged several areas of disagreement on basic terminology issues and agreed that a glossary with example images would help clarify many commonly misunderstood issues. This report defines terminology used in the pathological description of borderline tumors and their variants, and illustrates examples of each of the most common entities. It also addresses controversial aspects of the definitions and issues involving specimen handling and reporting. For those issues where there is disagreement, the terminology and diagnostic approaches reflecting the differing views are presented.

[Tumors of borderline malignancy or atypical proliferative tumors of the ovary?]. / Guzy o granicznej zlosci czy atypowe proliferacyjne guzy jajnika?

Nearly sixty years have passed since Taylor first published the concept of ovarian epithelial semimalignant tumors. After confirmation of this suggestion by FIGO and WHO these tumors became the subject of analyses which helped to separate unfavourable prognostic cases in this group. We would like to present a description of basic and latest papers on borderline ovarian tumors.

Histopathology of malignant salivary gland tumours.

This report is based upon the Salivary Gland Register in Hamburg and on the second revised edition of the WHO Histological Typing of Salivary Gland Tumours. The group of malignant salivary gland tumours contains carcinomas, malignant non-epithelial tumours, malignant lymphomas and secondary tumours. The various carcinomas are classified in a continuous separate listing because the different types are distinguished not only by histopathology, but also by differences in prognosis and treatment. The term "tumour" is replaced by "carcinoma" in two entities: acinic cell carcinoma and mucoepidermoid carcinoma. New entities are: polymorphous low-grade adenocarcinoma, basal cell adenocarcinoma, salivary duct carcinoma and malignant myoepithelioma. Carcinoma in pleomorphic adenoma can be distinguished as non-invasive and invasive carcinoma, and carcinosarcoma. Malignant non-epithelial tumours are mostly malignant fibrous histiocytoma, malignant schwannoma and rhabdomyosarcoma. The large majority of malignant lymphomas are non-Hodgkin-lymphomas with high differentiation. Many lymphomas are associated with chronic immunosialadenitis (Sjögren's syndrome). Secondary tumours are mostly metastases from primary squamous cell carcinomas or from melanomas of the skin (head and neck area). Haematogeneous metastases are very rare (mainly from lung, kidney or breast).

Spectrum of cystic tumors of the pancreas.

The pathologic and clinical classification, as well as the behavior, of cystic tumors of the pancreas has been the subject of controversy. We retrospectively reviewed 50 patients with a diagnosis of cystic tumor of the pancreas observed at The Johns Hopkins Hospital from 1984 to 1991. These tumors were classified into three broad groups: I, cystadenoma; II, cystadenocarcinoma; and III, adenocarcinoma with mucin production or an associated cyst. The three groups did not differ with respect to age or sex. The most common clinical presentation was abdominal pain. Symptoms and signs among the three groups were similar except that patients with cystadenomas were less likely (p less than 0.05) to be jaundiced and more likely (p less than 0.05) to be asymptomatic. Radiologic findings on computerized tomography, cholangiography, and arteriography also overlapped, making precise preoperative determination of tumor type difficult. Operative classification was also often not possible. The resectability rate (Group I, 91%; Group II, 67%; Group III, 53%) and 5-year survival rate (Group I, 90%; Group II, 72%; Group III, 14%) correlated with careful pathologic determination. Cystic tumors of the pancreas represent a spectrum of disease ranging from benign cystadenoma to adenocarcinoma masquerading as cystadenocarcinoma. We recommend resection whenever possible, even when preoperative evaluation suggests benign disease.

A report of 5 cases of cystic bile duct carcinoma of the liver and proposal of a new classification.

Primary biliary cystadenocarcinoma of the liver is rare. Among 239 patients with primary liver cancer admitted to our service during the last 13 years, there were 5 cases of cystic bile duct carcinoma of the liver. Three of these were cystadenocarcinoma, one was adenocarcinoma arising from a liver cyst, and one was carcinoma of the intrahepatic bile ducts with cystic dilatation. A better classification of these entities seems necessary, and it is suggested that malignant cystic tumors of the liver should be divided into 3 groups: Group A is cystic adenocarcinoma, group B is bile duct carcinoma with primary or secondary intrahepatic bile duct, and group C is degenerative cyst formation by other types of malignant tumors. Cystic adenocarcinoma (Group A) can then be further subdivided into cystadenocarcinoma, cystadenocarcinoma with cystadenoma, and carcinoma in a simple cyst of the liver.

[A clinicopathological study of mucus producing bile duct carcinoma].

Bile duct carcinoma, which produces clinically recognizable mucus, was defined as "mucus producing bile duct carcinoma", and clinicopathological study was carried out in 7 cases of bile duct carcinoma suitable for the definition. All the tumors arose from the intrahepatic bile duct. There were no tumors arising from the extrahepatic bile duct. Superficially spreading mucosal infiltration of carcinoma was recognized in 6 cases out of 7, and accordingly distinct cholangiography after draining mucus through percutaneous transhepatic cholangio-drainage (PTCD) and percutaneous transhepatic cholangioscopy (PTCS) were indispensable for accurate diagnosis of the extent of carcinoma. The prognosis of patients with mucus producing bile duct carcinoma were almost satisfactory if rational operation had been performed according to accurate diagnosis. On the other hand, since mucus producing bile duct carcinoma frequently has a cystic lesion, the relation to biliary cystadenocarcinoma may become a subject of question. We advocate that biliary cystadenocarcinoma should be included in mucus producing bile duct carcinoma since biliary cystadenocarcinoma originally arises from the intrahepatic bile duct and very rarely from the extrahepatic bile duct. But now the concept of biliary cystadenocarcinoma is equivocal and further investigations will be requested.

Cystic neoplasms and true cysts of the pancreas.

As the spectrum of pancreatic cysts evolves, sped by the increasing utilization of CT scanning, it becomes apparent that the surgeon must gain information preoperatively about the family history, as well as the personal history of the patient. The presence of cysts in the liver or kidney should be sought. The relation of the lesion to the duodenum and biliary tract needs to be defined. The possibility that the "cyst" represents necrosis of a primary adenocarcinoma of the pancreatic duct should be considered prior to laparotomy. At the time of operation, biopsy of the cyst wall and frozen-section study are fundamental to a decision whether resection or drainage is the treatment of choice. Resection is generally the treatment of the cystic neoplasms, drainage the treatment of pseudocysts. The failure of the surgeon to distinguish between the two groups may be catastrophic. The true cysts and cystic neoplasms of the pancreas are rare lesions. The clinical and radiologic characteristics, the pathologic features, and the natural history of these lesions are not fully documented. Therefore, when they are encountered, the clinician who will carefully document their characteristics can make a contribution to our knowledge.

Epidemiology of borderline ovarian tumors.

Ovarian tumors of low malignant potential, often termed "borderline tumors," have been defined as those that have some but not all of the morphologic features of malignancy (i.e., they are not invasive). With the use of data obtained by the western Washington population-based Cancer Surveillance System for 1975-83, the incidence of serous and mucinous borderline epithelial ovarian tumors was analyzed, as well as the survival of women who developed them. The incidence of borderline tumors increased with increasing age, although at a pace somewhat slower than that of malignant ovarian tumors. There was an upward trend in the incidence of borderline tumors starting in the late 1970's, a trend not present for malignant tumors. Only 12% of borderline tumors were not confined to the ovary, as opposed to 40% of malignant Grade I and 73% of other malignant ovarian neoplasms. At 5 years following diagnosis, the survival of women with borderline tumors was 93% that of the general female population. This percentage varied little by stage or histologic type. Given the reduced survival of women with these ovarian tumors and the lack of a sharp histologic distinction between borderline and Grade I malignant lesions, it is recommended that borderline ovarian tumors be routinely ascertained by population-based cancer registries.

Morphological behavior of carcinoma of the pancreas. 1. Histological classification and electron microscopical observation.

A total of 84 autopsied and 10 operative pancreatic carcinoma cases were studied to investigate their morphological behavior, by light and electron microscopies. The autopsied materials were classified into 70 duct cell carcinomas, 11 undifferentiated carcinomas including 2 giant cell carcinomas simulating giant cell tumor of bone, and 3 endocrine cell carcinomas which might be called carcinoid or oat cell carcinoma. No acinar cell carcinoma was found. Duct cell carcinomas were further subclassified into 37 large and 24 small duct-forming adenocarcinomas, 8 adenosquamous carcinomas, and 1 cystadenocarcinoma. The majority of undifferentiated carcinomas were considered to be of ductal or ductular cell origin. Rare tumors, such as cystadenocarcinoma, giant cell carcinoma, and endocrine cell carcinoma, were shown as case presentations. Electron microscopic features of duct cell carcinoma and its related findings were also presented. These studies should be pursued, because it may be important clinically and disclose, in the future, possible differences in etiology or effective therapeutic agents among the categories, although the classification, made from a viewpoint of histogenesis, did not reflect prognostic differences at the present.

Importance of histologic grading in the prognosis of epithelial ovarian carcinoma.

Ovarian epithelial carcinomas still have a poor prognosis. Great efforts are being made to improve treatment modalities; chemotherapy in particular is in a period of dynamic development. A basic requirement for the necessary research is a thorough knowledge of the natural history of ovarian cancer and its prognostic influence. In this report the importance of tumor stage, histologic type, and degree of differentiation is analyzed in an unselected and well-controlled Swedish ovarian cancer series comprising 501 cases. The great prognostic significance of tumor grade for survival is demonstrated and it is proposed that this histopathologic factor, as well as tumor stage and histologic type, should be included in the international classification of primary epithelial tumors of the ovary.