From this month’s Histopathology

Mutation profi ling of adenoid cystic from multiple CCCTTG GGG CCC anatomical sites T Case 46 “Adenoid cystic carcinomas from different sites show similar patterns of genomic alterations. HRAS Q61K

Here, we characterized the mutation status of known genes in a large series of breast CCCTTGG CCC GG AdCCs, and selected cancer genes in a large series of AdCCs from various anatomical sites. Our results demonstrate that mutations affecting the RAS pathway are found in a subset of AdCCs. In Case 51 HRAS wt addition, our results show that KIT mutations are either absent or vanishingly rare in AdCCs, suggesting that they are unlikely to constitute clinically useful therapeutic targets for this disease.” HRAS Q61K mutation in adenoid cystic Adenoid cystic carcinomas are malignant tumours most commonly found in salivary (Wetterskog et al. p. 543) glands but these can also occur in a variety of other organs and tissues. They tend to show an indolent growth pattern but can recur locally and may metastasise. Recent studies have demonstrated that some adenoid cystic carcinomas are characterised by the presence of a fusion transcript involving MYB and NFIB. In the study by Wetterskog et al. (p. 543) a detailed mutational analysis of microdissected from a variety of sites using Sanger sequencing demonstrated that mutations in genes relating to the canonical Ras pathway are present in a minority of these tumours but contrary to previous studies KIT mutations were not identifi ed. These fi ndings are of importance in attempts to identify potential therapeutic targets for this .

DNA ploidy abnormalities and increased Mcm2 expression Peak D.I. CV I.O.D # Cells % Cells AN1-G1 CTRL 1.00 5.06 3.25 54 11.87 AN1.G1 1.63 1.76 5.30 64 14.07 may predict malignant change in oral proliferative verrucous 50

leukoplakia 40

“The current findings corroborate the already described clinicopathological profile of 30 PVL; Mcm2 expression showed a positive relationship with microscopic progression and CTRL epithelial changes in PVL, and could be used to predict areas of malignant transformation. 20

In addition, abnormal DNA content was observed in PVL, even in early indolent Number of cells 10 leukoplakia, in contrast to other premalignant conditions, which show a pattern of 0 progressive ploidy abnormality in conjunction with epithelial abnormality.” 3.00 6.00 9

Proliferative verrucous leukoplakia is regarded as a precursor lesion for oral Moderate aneuploidy in proliferative . Its aetiology is uncertain but it is not associated with verrucous leukoplakia (Gouvêa et al. alcohol and tobacco use. Gouvêa et al. (p. 551) demonstrated that there is a p. 551). correlation between Mcm2 expression and high grade dysplasia. Areas of high grade epithelial alterations were also shown to have marked aneuploidy. They suggest that these may represent useful biomarkers for the prediction of malignant transformation. The pattern of immunoreactivity for Mcm2 and geminin was also suggested as supporting the distinct nature of this entity.

Underexpression of hepatocyte nuclear factor 1-beta (HNF1β) in chromophobe “In conclusion, among renal tumours, HNF1β underexpression is specifi cally observed in ChRCCs. Combined with CK7, HNF1β can serve as a good IHC marker for the differential diagnosis of ChRCC versus renal or CCRCC. The specifi c underexpression of HNF1β also suggests possible mechanisms for the pathogenesis of ChRCC.” Renal cell carcinomas of chromophobe type are relatively uncommon tumours and these are associated in most cases with a good long term survival. Previous molecular studies have indicated that in some patients with this type of malignancy there is inactivation of the HNF1β gene. Wang et al. (p. 589) have demonstrated that underexpression can be detected in the majority of such tumours by immunohistochemistry. By contrast HNF1β expression is preserved in the majority of other forms of renal cell carcinoma. In Loss of expression of HNF1β in combination with profi ling, this may be of diagnostic value. chromophobe renal cell carcinoma (Wang et al. p. 589)

hhis_62_4_prepicture.inddis_62_4_prepicture.indd 1 22/14/2013/14/2013 11:09:1811:09:18 AMAM Telomere shortening distinguishes inverted urothelial “Our findings of significant telomere shortening in inverted urothelial carcinoma as compared with inverted , and the lack of a significant difference between and benign, reactive processes, are in keeping with the belief that the two entities are unrelated, and bolster the hypothesis that inverted papilloma is a benign neoplasm. Assessment of telomere length by FISH may have utility in resolving the differential diagnosis of challenging cases.” Telomere shortening is thought to be an important early event in the development of a number of carcinomas. Williamson et al. (p. 595) have demonstrated that there is significant telomere shortening in urothelial carcinomas but this was not seen in inverted or cystitis glandularis. This reinforces the concept that inverted Telomeric FISH in inverted papilloma papillomas do not represent malignant neoplasms and are biologically distinct from (Williamson et al. p. 595) urothelial carcinomas. Telomeric FISH analysis may therefore be of help as a biomarker in the distinction between inverted papillomas and urothelial with inverted growth patterns.

Adipophilin/perilipin-2 as lipid droplet-specifi c marker for metabolically active cells and diseases associated with metabolic dysregulation “Adipophilin is found highly specifically at the surfaces of minuscule to large LDs in normal tissues (except for mature adipocytes, where perilipin takes its place) and in disease, irrespective of the cause. Owing to its ubiquitous expression, adipophilin may be of only limited use as a marker for cell type or tumour recognition, but may rather reflect the severity of disease, e.g. in microvesicular hepatocyte steatosis, cardiomyopathies, diseases, and hypoxia, and at the border zone of organ infarcts. Several of the key metabolic disorders with a high morbidity and mortality are characterised by abnormal lipid droplet accumulation, for example in atheromatous Adipophilin staining in microvesicular blood vessels and in steatotic livers. Assessment of the degree of lipid droplet steatosis (Straub et al. p. 617) accumulation is not always reliable in routinely processed tissue sections. Straub et al. (p. 617) in their paper have used antibodies to amphiphilic proteins of the PAT/ perilipid family. These are proteins that stabilise the interface between lipid droplets and the cytoplasm of cells. They have shown that this approach reliably demonstrates small lipid droplet accumulation under physiological and diseased conditions that are not visible by traditional light microscopy. The utility of this in diagnostic practice is yet to be confirmed but this approach appears promising in the study of metabolic disorders.

Cathepsin K expression in perivascular epithelioid cell neoplasms PEComas “In this study, we showed that cathepsin K was expressed in a wide spectrum of PEComas in various anatomical sites including lung, vertex subcutaneous tissue, uterus, abdominal wall, liver, and renal. The tumors displayed a higher percentage of cells with stronger positive reactions for cathepsin K (mean, 91%; range, 80–100%) than for HMB45, Melan-A, and SMA. Except for moderate immunoreactivity for cathepsin K in one breast carcinoma and one lung , none of the various other neoplasms used as controls was positive for cathepsin K. Therefore, based upon the above, cathepsin K, can be more useful in diagnosing a wide spectrum of PEComas than HMB45, Melan-A, and SMA, which are also very specific but often display just focal or patchy immunoreactivity. Cathepsin K immunoreactivity in broad In addition, our results also suggest that cathepsin K can be used as a relatively specific ligament PEComa (Rao et al. p. 642) marker to distinguish PEComas from the majority of human cancers.” PEComas are mesenchymal tumours composed of histologically and immunohisto- chemically distinctive perivascular epithelioid cells. They include , clear cell sugar tumour of lung, lymphangiomas and a variety of other neoplasms that can arise in soft tissues, visceral organs, the skeletal system and skin. Cathepsin K has recently been demonstrated to be a useful marker in identifying renal PEComas. The present study extended this to examine expression of this protein in extra-renal PEComas. Moderate to strong immunoreactivity was seen in the vast majority of cases and more consistenty than expression of HMB45 melanin A and SMA. Alastair D. Burt Editor

hhis_62_4_prepicture.inddis_62_4_prepicture.indd 2 22/14/2013/14/2013 11:09:2011:09:20 AMAM