Genetic characterisation of molecular targets in carcinoma of unknown primary.

BACKGROUND: Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions. METHODS: Carcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations. RESULTS: Variants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1). CONCLUSION: Taken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP.

Mucocoele-like lesions: is surgical excision still necessary?

AIM: To assess the rate of upgrade in our screening population to determine whether open excision biopsy of mucocoele-like lesions (MLL) is still required. MATERIALS AND METHODS: A retrospective review of the breast screening database from 1999-2014 was performed. RESULTS: MLL were identified on core biopsy in 113 women (0.6% of those recalled for a core biopsy). The majority (n=100, 88%) had a localised cluster of calcification prompting screening recall. Eighty-seven percent (n=99) underwent an excision biopsy; there was a 5% upgrade rate to malignancy (all low/intermediate ductal carcinoma in situ [DCIS]) and 15 women (15%) were found to have an additional "B3" lesion. Fourteen women did not undergo excision biopsy; none of these women had a subsequent cancer at an average of 5-years follow-up. Within the follow-up period, five additional cancers were identified, one of these was in the ipsilateral breast and location, albeit 9-years later. CONCLUSION: This is the largest study of MLL in the literature to date. The present findings show a 5% upgrade rate to DCIS. As long as the current management of low-risk DCIS remains surgical excision, the present results support continued excision of MLLs, either surgically or by vacuum-assisted biopsy.

Validation of mitosis counting by automated phosphohistone H3 (PHH3) digital image analysis in a breast carcinoma tissue microarray.

Mitosis counting in H&E stained sections is the most informative constituent of the Nottingham histological grade in breast carcinoma prognosis. Phosphohistone H3 (PHH3) immunohistochemistry (IHC) is a highly specific marker of mitoses, with practical application in identifying mitoses in poorly fixed or distorted tissue and is of prognostic significance in breast carcinoma. Our aim was to assess methods of PHH3 IHC mitosis counting in a tissue microarray (TMA) of 2 mm cores from 36 resected breast carcinomas. Mitoses in H&E and PHH3 stained slides were manually scored by pathologist consensus and expressed as counts/2 mm. PHH3 stained cores were also evaluated by automated digital image analysis (DIA). Results were compared using Spearman correlation. A strong and significant correlation was observed between manual PHH3 and manual H&E mitotic counts (correlation = 0.81; p < 0.0001) and between automated PHH3 DIA and manual H&E mitotic counts (correlation = 0.79; p < 0.0001). More mitoses were identified with PHH3 IHC than with H&E. Manual and DIA PHH3 counts were strongly and significantly correlated (correlation = 0.83; p < 0.0001) and of similar absolute values. PHH3 DIA is a valid alternative to manual counting with potential application in breast cancer reporting and prognostication.

CD117 and CD43 are useful adjuncts in the distinction of adenoid cystic carcinoma from adenoid basal cell carcinoma.

Distinction of cutaneous adenoid cystic carcinoma (ACC) from adenoid basal cell carcinoma (BCC) is an occasional diagnostic dilemma in dermatopathology.We examined the immunohistochemical staining patterns with CD117 and CD43 in ACCs and BCCs, including BCCs with an adenoid growth pattern, to determine whether a combination of these markers can assist in the differential diagnosis.Fifteen cases each of ACC and BCC, including seven BCCs with a partial or entirely adenoid growth pattern were immunohistochemically stained for CD117 and CD43. The stains were interpreted semi-quantitatively.Staining for CD43 and CD117 was significantly more common in ACC than in BCC. Forty percent of ACCs showed staining for CD43, while no cases of BCC were positive. CD117 was positive in all cases of ACC, with 93% showing moderate or strong staining. BCC were less frequently positive, with only 20% of cases showing labelling of weak or moderate intensity.Immunohistochemical positivity for CD117 and CD43 are likely to be helpful adjuncts in the separation of cutaneous ACC from adenoid BCC.

Handling of radioactive seed localisation breast specimens in the histopathology laboratory: the Western Australian experience.

Radio-guided occult lesion localisation using iodine-125 seeds (ROLLIS) is a novel method of localisation for impalpable in situ and invasive carcinomas that has been the subject of a recent pilot study and pilot study extension in Western Australia. Robust protocols for radiation safety, specimen labelling, specimen tracking, seed retrieval and seed disposal were developed at two Western Australian laboratories to minimise the risk of seed loss. The processes are safe and effective with no significant radiation exposure to pathologists and with acquisition of all seeds intact and undamaged. The success can be attributed to developing specific seed retrieval techniques, suited to local preferences at each institution, with input from surgeons, radiologists and medical physics personnel. These techniques are now routine and will continue in the randomised control phase of the ROLLIS study.

Squamous metaplasia of lactiferous ducts (SMOLD).

The aim of this review is to illustrate the mammographic and sonographic appearances of squamous metaplasia of the lactiferous ducts (SMOLD) and to discuss the disease processes of this uncommon breast disease, which shows a strong correlation with smoking. The most common mammographic appearance is of a retro-areolar asymmetrical density. Ultrasonography of the symptomatic breast typically shows a retro-areolar, predominately medial, ill-defined, hypoechoic lesion with either abscess or sinus/fistula formation. Duct dilatation and continuity with lactiferous ducts is commonly seen. Increased vascularity is occasionally seen on colour Doppler ultrasound. Pathology tissue confirmation is always required and this can be by histology of a core biopsy or excision specimen, or fine-needle aspiration (FNA) cytology. Occasionally smears of an associated abundant nipple or sinus discharge may be of value.