Three-tier systems (well/moderate/poor differentiation or Grade 1/2/3, bladder carcinoma WHO I/II/III) have traditionally been used based on subjective assessment of similarity to the ancestral tissue of origin (e.g. kera-tinization and intercellular bridges in squamous carcinoma and tumour gland formation in adenocarcinoma), cellular pleomorphism,1 mitoses2 and

1Cellular pleomorphism: this largely relates to nuclear alterations in size, shape, polarity, chromasia, crowding and nucleolar prominence. Cytoplasmic differentiation may also be taken into account (e.g. breast carcinoma—tubule formation). 2Mitoses: The assessment of mitotic activity either as a stand-alone mitotic activity index or as part of a grading system is a strong prognostic factor as in breast carcinoma. However, care must be taken: (a) delayed fixation may significantly alter numbers of mitoses but also makes them more difficult to identify; (b) hyperchro-matic, pyknotic, apoptotic bodies should be ignored and only clearly defined mitotic figures counted. Strict criteria should be used such as absence of the nuclear membrane and clear hairy extension of nuclear material ± increased basophilia of the cell cytoplasm; (c) counts should be related to a fixed field area against which various high-power microscope objectives can be calibrated. In general a x40 objective is used.

necrosis.3 This is strengthened when the individual criteria are formally evaluated and assimilated into a score that gives strong prognostic information (breast carcinoma, sarcoma). However, a subjective three-tier system is not advantageous when the majority of lesions fall into one category (e.g. colorectal carcinoma is predominantly moderately differentiated) and there is a lack of prognostic stratification. It is also compounded by poor reproducibility and tumour heterogeneity. This has resulted in emergence of two-tier systems to identify prognostically adverse cancers (poorly differentiated vs. others in colorectal carcinoma; low-grade/high-grade in non-Hodgkin's lymphoma and soft tissue sarcoma). In addition, specific grading systems exist, e.g. Fuhrman nuclear grade in renal cell carcinoma, the Bloom and Richardson grade in breast carcinoma and glandular/non-squamous morular components in uterine adenocarcinoma. Poor differentiation (G3) overlaps with and is sometimes combined with the undifferentiated (G4) category. Mixed differentiation with regard to tumour subtype and grade is relatively common. Carcinosarcoma/ spindle cell carcinoma/sarcomatoid carcinoma represent carcinoma with spindle cell change and variable monophasic/biphasic/homologous/ heterologous mesenchymal differentiation arising from malignant pluripotential stem cells.

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