Variants and new entities of bladder cancer

Pathological evaluation of bladder cancer typically reveals great tumour heterogeneity, and therefore the common observation of urothelial carcinoma exhibiting a wide variety of histopathological patterns is not surprising. Some of these patterns are so distinctive that they have been recognised as specific variants of urothelial carcinoma. Classifications have recently been revised in the 2016 World Health Organisation (WHO) classification of tumours of the urinary system and male genital organs. The current WHO classifications clarify terminological issues and provide better definition criteria, but also incorporate some new entities. Many of these variants have important prognostic or therapeutic implications worth knowing by the urologist and oncologist, but also represent diagnostic challenges in daily pathology practice. This review will discuss the features of variants of urothelial carcinoma in the context of our current clinical practice. Histological variations and new entities of bladder cancer not included in the current WHO classification of urothelial tumours will be briefly discussed.     

sLex expression in invasive micropapillary breast carcinoma is associated with poor prognosis and can be combined with MUC1/EMA as a supplementary diagnostic indicator

Objective:Mucin 1 (MUC1/EMA) and sialyl Lewis X (sLe^x) indicate polarity reversal in invasive micropapillary carcinoma (IMPC). The purpose of this study was to evaluate the expression of MUC1/EMA and sLe^x and to assess their diagnostic and prognostic value in patients with IMPC.Methods:The expression of sLe^x and MUC1/EMA in 100 patients with IMPC and a control group of 89 patients with invasive ductal carcinoma not otherwise specified (IDC-NOS) were analyzed with IHC. Fresh tumor tissues were collected from patients with IMPC or IDC-NOS for primary culture and immunofluorescence analysis.Results:The rate of nodal metastasis was higher in patients with IMPC than those with IDC-NOS, and IMPC cells tended to express more sLe^x and MUC1/EMA in the cytomembranes (the stroma-facing surfaces of the micropapillary clusters) than IDC-NOS cells. In IMPC, high cytomembrane expression of sLe^x, but not MUC1/EMA, indicated poor prognosis. In addition, among the 100 patients with IMPC, 10 patients had sLe^x+/EMA– expression patterns, and 8 patients had sLe^x–/EMA+ expression patterns. The primary IMPC cells were suspended, non-adherent tumor cell clusters, whereas the primary IDC cells were adherent tumor cells. Immunofluorescence analysis showed that MUC1/EMA and sLe^x were co-expressed on the cytomembranes in IMPC cell clusters and in the cytoplasm in IDC-NOS cells.Conclusions:sLe^x can be used as a prognostic indicator and can be combined with MUC1/EMA as a complementary diagnostic indicator to avoid missed IMPC diagnosis.     

The nonsmokers’ and smokers’ pathways in lung adenocarcinoma: Histological progression and molecular bases

There could be two carcinogenetic pathways for lung adenocarcinoma (LADC): the nonsmokers’ pathway and the smokers’ pathway. This review article describes the two pathways with special reference to potential relationships between histological subtypes, malignant grades, and driver mutations. The lung is composed of two different tissue units, the terminal respiratory unit (TRU) and the central airway compartment (CAC). In the nonsmokers’ pathway, LADCs develop from the TRU, and their histological appearances change from lepidic to micropapillary during the progression process. In the smokers’ pathway, LADCs develop from either the TRU or the CAC, and their histological appearances vary among cases in the middle of the progression process, but they are likely converged to acinar/solid at the end. On a molecular genetic level, the nonsmokers’ pathway is mostly driven by EGFR mutations, whereas in the smokers’ pathway, approximately one-quarter of LADCs have KRAS mutations, but the other three-quarters have no known driver mutations. p53 mutations are an important factor triggering the progression of both pathways, with unique molecular alterations associated with each, such as MUC21 expression and chromosome 12p13-21 amplification in the nonsmokers’ pathway, and HNF4α expression and TTF1 mutations in the smokers’ pathway. However, investigation into the relationship between histological progression and genetic alterations is in its infancy. Tight cooperation between traditional histopathological examinations and recent molecular genetics can provide valuable insight to better understand the nature of LADCs.     

Villin is a biomarker for reverse polarity in colorectal micropapillary carcinoma

Colorectal cancer (CRC) is a common malignant tumor of digestive system. CRC with micropapillary pattern (MPP) is an aggressive variant of colorectal adenocarcinoma. The aim of the present study was to clarify the clinicopathological significance and the prognostic role of an immunohistochemical marker, MPP, in CRC. The association between MPP and clinicopathological characteristics and prognosis in 286 cases of CRC (286/453 cases had follow-up information) were analysed. Then, 81 tissues without MPP and 90 tissues with MPP were analysed by immunohistochemistry using antibodies against villin, E-cadherin and epithelial membrane antigen (EMA). Bioinformatics was used to evaluate the expression of these three indicators in CRC. The proportion of micropapillary carcinoma in the overall tumour was ≥5%, and was observed in 90/453 cases (19.8%). The present data showed that CRC with MPP displayed higher rates of vascular and lymphatic invasion, a higher metastatic lymph node ratio and a higher pathological tumour and metastasis stage compared with CRC without MPP. The positive expression rates of EMA, E-cadherin and villin were 50.3, 93.4 and 96.5%, respectively. In 90 CRC cases with MPP, EMA inside-out pattern (I/OP) staining was observed in 26 cases (28.9%), and it was often focal and partial, while 37 cases (41.1%) had E-cadherin focal and partial staining compatible with reverse polarity. Villin I/OP staining was observed in 77 cases (85.6%), and circumferential staining predominated over partial staining. Overall, the data suggested that the presence of MPP is significantly associated with aggressive tumour behaviour and worse overall survival rate in CRC. Visualization and distinction of reverse polarity of colorectal micropapillary carcinomas is improved villin compared with EMA or E-cadherin.     

Clinical and therapeutic significance of aberrant differentiation patterns in bladder cancer

Pure urothelial carcinoma makes up 90–95% of all bladder cancer. The remaining 5–10% represent urothelial carcinoma with aberrant differentiation patterns and nonurothelial carcinoma. Reviews on this topic often focus on the pathological features of these histologic subtypes. In this review we have summarized the clinical significance of each major histologic pattern and analyzed the response of each to standard treatment modalities. The main limitation to optimizing management is the inability to perform clinical trials owing to the rarity of these tumors. This can be circumvented to some degree by extrapolating knowledge acquired from more common similar tumors in other organ sites. Ultimately, however, multicenter clinical trials will need to be organized to address some key management issues.