Giuseppe Zamboni

Consensus statement on the pathology of IgG4-related disease.

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and—often but not always—elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4–7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4+ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

Whole genomes redefine the mutational landscape of pancreatic cancer

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors

The clinicopathological features of 56 patients with mucinous cystic tumors (MCTs) of the pancreas were studied. Particular attention was paid to the prognosis of MCTs and the relationship to their ovarian, hepatic, and retroperitoneal counterparts. To distinguish MCTs from pancreatic intraductal papillary-mucinous tumors, MCTs were defined as tumors lacking communication with the duct system and containing mucin-producing epithelium, usually supported by ovarian-like stroma. All 56 tumors occurred in women (mean age 48.2 years) and were preferentially (93%) located in the body and tail of the pancreas. In accordance with the WHO classification, MCTs were divided into adenomas (n = 22), borderline tumors (n= 12), and noninvasive and invasive carcinomas (n = 22). Survival analysis revealed the extent of invasion to be the most significant prognostic factor (p<0.0001). Malignancy correlated with multilocularity and presence of papillary projections or mural nodules, loss of ovarian-like stroma, and p53 immunoreactivity. Stromal luteinization with expression of tyrosine hydroxylase, calretinin, or alpha inhibin was found in 66% of the cases. We conclude that the biologic behavior of MCTs is predictable on the basis of the extent of invasion. The similarities (i.e. gender, morphology, stromal luteinization) between pancreatic MCT and its ovarian, hepatobiliary, and retroperitoneal counterparts suggest a common pathway for their development.

Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations

John H. Stone, Arezou Khosroshahi, Vikram Deshpande, John K. C. Chan, J. Godfrey Heathcote, Rob Aalberse, Atsushi Azumi, Donald B. Bloch, William R. Brugge, Mollie N. Carruthers, Wah Cheuk, Lynn Cornell, Carlos Fernandez-Del Castillo, Judith A. Ferry, David Forcione, Gunter Kloppel, Daniel L. Hamilos, Terumi Kamisawa, Satomi Kasashima, Shigeyuki Kawa, Mitsuhiro Kawano, Yasufumi Masaki, Kenji Notohara, Kazuichi Okazaki, Ji Kon Ryu, Takako Saeki, Dushyant Sahani, Yasuharu Sato, Thomas Smyrk, James R. Stone, Masayuki Takahira, Hisanori Umehara, George Webster, Motohisa Yamamoto, Eunhee Yi, Tadashi Yoshino, Giuseppe Zamboni, Yoh Zen, and Suresh Chari

Intraductal papillary-mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26 patients

Intraductal papillary growth of mucin producting hypersecreting, columnar cells characterizes a group of rare pancreatic exocrine neoplasms which we propose to call intraductal papillary-mucinous tumors (IPMT). We analysed the histopathology of 26 IPMT in relation to gastro-enteropancreatic marker expression, genetic changes and biology. Four IPMT showing only mild dysplasia were considered to be adenomas. Nine tumours displayed moderate dysplasia and were regarded as borderline. Severe dysplasia-carcinoma in situ changes were found in 13 IPMT which were therefore classified as intraductal carcinomas. Six of these carcinomas were frankly invasive and two of these had lymph node metastases. The invasive component resembled mucinous noncystic carcinoma in all but one tumour which showed a ductal invasion pattern. Immunohistochemically, an intestinal marker type was found in most carcinomas, while gastric type differentiation prevailed among adenomas or borderline tumours. K-ras mutations (seven at codon 12 and one at codon 13) were found in 31% of IPMT (2 adenomas, 1 borderline, 5 carcinomas). Nuclear p53 overexpression was detected in 31% of IPMT (6 carcinomas and 2 borderline IPMT) and correlated with p53 mutations (one at exon 8 and the other at exon 5) in two carcinomas. p53 abnormalities were unrelated to K-ras mutation. c-erbB-2 overexpression was observed in 65% of IPMT, with various grades of dysplasia. Twenty-two of 24 patients are alive and well after a mean post-operative follow-up of 41 months. Only two patients, both with invasive cancer at the time of surgery, died of tumour disease. It is concluded that pancreatic IPMT encompass neoplasms which, in general, have a favorable prognosis, but are heterogeneous in regard to grade of dysplasia and marker expression. Adenoma, borderline tumour, intraductal carcinoma and invasive carcinoma can be differentiated. p53 changes but not K-ras mutation or c-erbB-2 overexpression are related to the grade of malignancy. Most IPMT differ in histological structure, marker expression and behaviour from ductal adenocarcinoma.

PEComas: the past, the present and the future

The perivascular epithelioid cell (PEC) is a cell type constantly present in a group of tumors called PEComas. PEC expresses myogenic and melanocytic markers, such as HMB45 and actin. Recently, recurrent chromosomal alterations have been demonstrated in PEC. At present, PEComa is a widely accepted entity. In the past 10 years, the use of this term has allowed to report and describe numerous cases permitting to start highlighting the biology of this group of lesions. PEComas are related to the genetic alterations of tuberous sclerosis complex (TSC), an autosomal dominant genetic disease due to losses of TSC1 (9q34) or TSC2 (16p13.3) genes which seem to have a role in the regulation of the Rheb/mTOR/p70S6K pathway. There are some open questions about PEComas regarding its histogenesis, the definition of epithelioid angiomyolipoma and the identification of the histological criteria of malignancy. An innovative therapeutic trial using rapamycin is under way for tumors occurring in TSC such as renal angiomyolipoma and lymphangioleiomyomatosis. Its success could provide the rationale for the use of the same drug in other lesions composed of PECs, especially in the malignant ones.

Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients.

Objective:Mucinous cystic neoplasms (MCNs) of the pancreas have often been confused with intraductal papillary mucinous neoplasms. We evaluated the clinicopathologic characteristics, prevalence of cancer, and prognosis of a large series of well-characterized MCNs in 2 tertiary centers. Methods:Analysis of 163 patients with resected MCNs, defined by the presence of ovarian stroma and lack of communication with the main pancreatic duct. Results:MCNs were seen mostly in women (95%) and in the distal pancreas (97%); 25% were incidentally discovered. Symptomatic patients typically had mild abdominal pain, but 9% presented with acute pancreatitis. One hundred eighteen patients (72%) had adenoma, 17 (10.5%) borderline tumors, 9 (5.5%) in situ carcinoma, and 19 (12%) invasive carcinoma. Patients with invasive carcinoma were significantly older than those with noninvasive neoplasms (55 vs. 44 years, P = 0.01). Findings associated with malignancy were presence of nodules (P = 0.0001) and diameter ≥60 mm (P = 0.0001). All neoplasms with cancer were either ≥40 mm in size or had nodules. There was no operative mortality and postoperative morbidity was 49%. Median follow-up was 57 months (range, 4–233); only patients with invasive carcinoma had recurrence. The 5-year disease-specific survival for noninvasive MCNs was 100%, and for those with invasive cancer, 57%. Conclusions:This series, the largest with MCNs defined by ovarian stroma, shows a prevalence of cancer of only 17.5%. Patients with invasive carcinoma are older, suggesting progression from adenoma to carcinoma. Although resection should be considered for all cases, in low-risk MCNs (≤4 cm/no nodules), nonradical resections are appropriate.

Clear cell (“sugar”) tumor of the lung is a lesion strictly related to angiomyolipoma— The concept of a family of lesions characterized by the presence of the perivascular epithelioid cells (PEC)*

&NA; We report a comparative study of 3 clear cell tumors of the lung (CCTL) and 3 angiomyolipomas (AML) of the kidney. Morphological analysis shows that the cells of CCTL are identical to the perivascular epithelioid component of AML. Phenotypically they both consistently expressed melanoma-associated antigens recognized by Moabs HMB45 and HMSA-1, while they were negative for HMSA-5. A minority of cells also expressed S-100 protein, vimentin and actin. In addition, one case of CCTL showed mature adipose tissue entrapped in the proliferation, thus suggesting an intermediate form between CCTL and AML. Based on morphological and phenotypical similarities, it is suggested that CCTL and AML belong to the same family of lesions, characterized by the presence of a peculiar muscle cell, expressing different melanoma-associated antigens.

The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma

Intraductal papillary-mucinous neoplasms of the pancreas seem to comprise various types, whose relationship to ductal adenocarcinoma and mucinous noncystic carcinoma is unclear. We analyzed the mucin immunophenotype and the DPC4/SMAD4 expression in intraductal papillary-mucinous neoplasms, ductal carcinomas, and mucinous noncystic carcinomas to define features that may help to distinguish between different types of intraductal papillary-mucinous neoplasms and to establish their relationship to other neoplasms of the exocrine pancreas. A series of 51 intraductal papillary-mucinous neoplasms, three mucinous noncystic carcinomas (two with an intraductal component), and 35 ductal adenocarcinomas were screened immunohistochemically for their expression of MUC1, MUC2, MUC5, and DPC4/SMAD4. All intraductal papillary-mucinous neoplasms and mucinous noncystic carcinomas were positive for MUC5. Thirty-two intraductal papillary-mucinous neoplasms and three mucinous noncystic carcinomas abundantly expressed MUC2 but no (or only little) MUC1. The remaining intraductal papillary-mucinous neoplasms showed either mainly MUC1 expression or focal MUC1 and MUC2 expression. All ductal carcinomas but one were MUC2 negative and MUC1 and MUC5 positive. DPC4 was not expressed in two intraductal papillary-mucinous neoplasms that showed a tubular invasion pattern. Twelve of 23 ductal adenocarcinomas were DPC4 positive. Intraductal papillary-mucinous neoplasms can be divided into at least three different mucin immunophenotypes. The first and largest group of intraductal papillary-mucinous neoplasms and mucinous noncystic carcinomas is MUC1 negative and MUC2 positive and probably forms one tumor entity. The second group seems to be related to ductal carcinoma because of its MUC1 positivity in the absence or very weak MUC2 staining. The third group shows focal MUC1/MUC2 expression and is characterized by oncocytic histology.

European experts consensus statement on cystic tumours of the pancreas.

Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.