The newly proposed International Endocervical Adenocarcinoma Criteria and Classification and its relevance to cervical cytology screening assessed in a prospective 2-year study of 118 cases.

BACKGROUND: It is generally acknowledged that interobserver variability for the histological diagnosis of endocervical adenocarcinoma (EA) subtypes is suboptimal. The recently proposed International Endocervical Adenocarcinoma Criteria and Classification (IECC) system is based on the presence of associated human papilloma virus (HPV) infection. It recognises HPV-associated EAs and non-HPV-associated EAs. METHODS: This prospective cytology-histology and molecular genetics-based study investigated the potential effect of IECC being applied to Papanicolaou (Pap) test with regard to the diagnostic accuracy of severe glandular lesions reported at least as adenocarcinoma in situ (AIS). RESULTS: Out of 118 liquid-based cytology Pap tests with AIS+ lesion, complete information on follow-up biopsy and HPV status was available in 51 cases. AIS and EA category correlated with histologically confirmed AIS/EA in 88.5% (23/26) and 70.5% (12/17) of cases, respectively. Interestingly, 93% (40/43) of cases diagnosed as AIS/EA were HPV positive and 7% (3/43) were HPV negative (originating in the cervix, endometrium and adnexa). CONCLUSIONS: Our findings suggest that this approach could possibly divide Pap tests containing severe glandular lesion into two groups: (a) robust diagnosis of HPV-associated EA and (b) non-HPV associated glandular lesions of heterogeneous origin, requiring further clinical preoperative diagnostic workup.

The detection of DNA methylation of tumour suppressor genes in cervical high-grade squamous intraepithelial lesion: A prospective cytological-histological correlation study of 70 cases.

BACKGROUND: DNA methylation has been suggested as one of the epigenetic changes promoting carcinogenesis. The aim of this study was to prospectively evaluate the methylation status of CADM 1, MAL and hsa-miR-124 genes in high-grade squamous intraepithelial lesion (HSIL) liquid-based cytology (LBC) samples with a histological correlation. METHODS: Seventy histologically confirmed cases of HSIL paired with prior screening LBC diagnosis of HSIL within a 3-month interval were selected. Histologically, the lesions were reviewed and assessed including: (a) number of blocks harbouring dysplastic squamous epithelium; (b) number of blocks containing glandular extension of dysplastic epithelium; and (c) the depth of glandular extension (which was assessed semi-quantitatively as graded 1-3). Human papillomavirus (HPV) subtyping was performed from residual LBC materials using the LINEAR ARRAY HPV Genotyping Test and in-house polymerase chain reaction targeting the HPV E1 gene. The detection of methylation silencing of tumour suppressor genes CADM1, MAL and hsa-miR-124 was performed by multiplex methylation-specific real-time polymerase chain reaction. RESULTS: A positive methylation status was detected in 41 cases (58.6%). The number of blocks with HSIL varied from one to 13. Glandular extension was seen in 44 cases with the number of blocks involved ranging from one to 10. The depth of HSIL glandular extension varied. CONCLUSION: The DNA methylation test allows HSIL lesions to be divided into two distinct groups of methylated HSIL in significantly older patients and unmethylated HSIL in younger patients. This study was not able to prove that methylation status in cervical HSIL correlates with the size of the lesion (measured by the number of blocks involved) or with HSIL propensity for endocervical glandular extension, nor with HPV type or multi-infection.

Biphasic alveolosquamoid renal carcinoma: a histomorphological, immunohistochemical, molecular genetic, and ultrastructural study of a distinctive morphologic variant of renal cell carcinoma.

Only a few cases of sarcomatoid renal cell carcinomas (RCCs) with squamous differentiation have been published. We present 2 RCCs exhibiting a hitherto not reported biphasic neoplastic cell population exhibiting a predominantly alveolar architecture where squamoid differentiation was identified in one of the neoplastic cell populations. None of the tumors showed chromophobe features or any evidence of sarcomatoid transformation. The tumors arose in 2 adult patients and were characterized by routine histology, immunohistochemistry, ultrastructure, array comparative genomic hybridization, confirmatory fluorescent in situ hybridization, and loss of heterozygosity analysis. Tumors measured 3 and 4 cm and were located within the renal parenchyma and had no pelvicalyceal connection. Both tumors were composed of a distinctly dual-cell population. The larger tumor cells displayed squamoid features and formed round well-demarcated solid alveolated islands that, in large parts, were surrounded by a smaller neoplastic cell component. The squamoid cells were immunoreactive for cytokeratins (CKs) (AE1-AE3, Cam 5.2, CK5/6, CK7, and CK20), epithelial membrane antigen, racemase/AMACR, and carboanhydrase IX (in 1 case focally). The small cell population was positive for CK7, epithelial membrane antigen, and racemase/AMACR, whereas CK20, AE1-3, and carboanhydrase IX were negative. CD10 was focally positive in the large squamoid cells in 1 case. Cathepsin K, E-cadherin, and CD117 displayed focal positivity in 1 case. Vimentin, RCC marker, parvalbumin, S100 protein, S100 A1, p63, p53, CDX2, uroplakin III, HMB45, TFE3, WT1, synaptophysin, chromogranin A, thyroglobulin, and TTF1 were negative. The proliferative activity (Ki-67) was low (1%) in the small cell component in both cases, whereas the large neoplastic tumor cells displayed a significantly higher proliferation (20%-35%). Ultrastructurally, desmosomes and tonofilaments were identified in the large tumor cells, confirming squamoid differentiation in a subset of tumor cells. Array comparative genomic hybridization of 1 analyzable case (confirmed with fluorescent in situ hybridization and loss of heterozygosity analysis) revealed partial or complete losses of chromosomes 2, 5, 6, 9, 12, 15, 16, 17, 18 and 22, (including biallelic loss of CDKN2A locus) and partial gains of chromosomes 1, 5, 11, 12 and 13. Follow-up at 6 years showed no recurrence or metastasis in 1 patient. The other (male) patients had a subcutaneous metastasis at presentation, but during a 1-year follow-up no evidence of recurrence or further metastatic events have been documented. Our data indicate that biphasic alveolosquamoid renal carcinoma is a unique and distinctive tumor. The large squamoid and small tumor cells have overlapping but still distinctive immunohistochemical patterns of protein expression. Multiple chromosomal aberrations were identified, some of them located in regions with known tumor suppressor genes and oncogenes.