Histopathology

Over the last 20 years it has become clear that colorectal cancer (CRC) evolves through multiple pathways. These pathways may be defined on the basis of two molecular features: (i) DNA microsatellite instability (MSI) status stratified as MSI‐high (MSI‐H), MSI‐low (MSI‐L) and MS stable (MSS), and (ii) CpG island methylator phenotype (CIMP) stratified as CIMP‐high, CIMP‐low and CIMP‐negative (CIMP‐neg). In this review the morphological correlates of five molecular subtypes are outlined: Type 1 (CIMP‐high/MSI‐H/BRAF mutation), Type 2 (CIMP‐high/MSI‐L or MSS/BRAF mutation), Type 3 (CIMP‐low/MSS or MSI‐L/KRAS mutation), Type 4 (CIMP‐neg/MSS) and Type 5 or Lynch syndrome (CIMP‐neg/MSI‐H). The molecular pathways are determined at an early evolutionary stage and are fully established within precancerous lesions. Serrated polyps are the precursors of Types 1 and 2 CRC, whereas Types 4 and 5 evolve through the adenoma–carcinoma sequence. Type 3 CRC may arise within either type of polyp. Types 1 and 4 are conceived as having few, if any, molecular overlaps with each other, whereas Types 2, 3 and 5 combine the molecular features of Types 1 and 4 in different ways. This approach to the classification of CRC should accelerate understanding of causation and will impact on clinical management in the areas of both prevention and treatment.

Breast cancer is a heterogeneous disease that encompasses several distinct entities with remarkably different biological characteristics and clinical behaviour. Currently, breast cancer patients are managed according to algorithms based on a constellation of clinical and histopathological parameters in conjunction with assessment of hormone receptor (oestrogen and progesterone receptor) status and HER2 overexpression/gene amplification. Although effective tailored therapies have been developed for patients with hormone receptor‐positive or HER2+ disease, chemotherapy is the only modality of systemic therapy for patients with breast cancers lacking the expression of these markers (triple‐negative cancers). Recent microarray expression profiling analyses have demonstrated that breast cancers can be systematically characterized into biologically and clinically meaningful groups. These studies have led to the re‐discovery of basal‐like breast cancers, which preferentially show a triple‐negative phenotype. Both triple‐negative and basal‐like cancers preferentially affect young and African‐American women, are of high histological grade and have more aggressive clinical behaviour. Furthermore, a significant overlap between the biological and clinical characteristics of sporadic triple‐negative and basal‐like cancers and breast carcinomas arising in BRCA1 mutation carriers has been repeatedly demonstrated. In this review, we critically address the characteristics of basal‐like and triple‐negative cancers, their similarities and differences, their response to chemotherapy as well as strategies for the development of novel therapeutic targets for these aggressive types of breast cancer. In addition, the possible mechanisms are discussed leading to BRCA1 pathway dysfunction in sporadic triple‐negative and basal‐like cancers and animal models for these tumour types.

Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases

Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin‐embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with `malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC‐derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer–Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin‐embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.

Aims : To standardize the histopathological assessment of synovial membrane specimens in order to contribute to the diagnostics of rheumatic and non‐rheumatic joint diseases.

Methods and results : Three features of chronic synovitis (enlargement of lining cell layer, cellular density of synovial stroma, leukocytic infiltrate) were semiquantitatively evaluated (from 0, absent to 3, strong) and each feature was graded separately. The sum provided the synovitis score, which was interpreted as follows: 0–1, no synovitis; 2–4, low‐grade synovitis; 5–9, high‐grade synovitis. Five hundred and fifty‐nine synovectomy specimens were graded by two independent observers. Clinical diagnoses were osteoarthrosis (n = 212), post‐traumatic arthritis (n = 21), rheumatoid arthritis (n = 246), psoriatic arthritis (n = 22), reactive arthritis (n = 9), as well as controls (n = 49) from autopsies of patients without joint damage. Median synovitis scores when correlated with clinical diagnoses were: controls 1.0, osteoarthritis 2.0, post‐traumatic arthritis 2.0, psoriatic arthritis 3.5, reactive arthritis 5.0 and rheumatoid arthritis 5.0. The scores differed significantly between most disease groups, especially between degenerative and rheumatic diseases. A high‐grade synovitis was strongly associated with rheumatic joint diseases (P < 0.001, sensitivity 61.7%, specificity 96.1%). The correlation between the two observers was high (r = 0.941).

Conclusion : The proposed synovitis score is based on well‐defined, reproducible histopathological criteria and may contribute to diagnosis in rheumatic and non‐rheumatic joint diseases.

Ki67 protein: the immaculate deception?

This article updates our previous review of Ki67 published in Histopathology 10 years ago. In this period the numbers of papers published featuring this antibody has increased 10‐fold from 338 to 3489 indicating the considerable enthusiasm with which this antibody has been studied. This review attempts to provide an update on the characterization of the Ki67 protein, its function and its use as a prognostic or diagnostic tool.

The histological tumour type determined by current criteria has been investigated in a consecutive series of 1621 women with primary operable breast carcinoma, presenting between 1973 and 1987. All women underwent definitive surgery with node biopsy and none received adjuvant systemic therapy. Special types, tubular, invasive cribriform and mucinous, with a very favourable prognosis can be identified. A common type of tumour recognized by our group and designated tubular mixed carcinoma is shown to be prognostically distinct from carcinomas of no special type; it has a characteristic histological appearance and is the third most common type in this series. Analysis of subtypes of lobular carcinoma confirms differing prognoses. The classical, tubulo‐lobular and lobular mixed types are associated with a better prognosis than carcinomas of no special type; this is not so for the solid variant. Tubulo‐lobular carcinoma in particular has an extremely good prognosis similar to tumours included in the ‘special type’ category above. Neither medullary carcinoma nor atypical medullary carcinoma are found to carry a survival advantage over carcinomas of no special type. The results confirm that histological typing of human breast carcinoma can provide useful prognostic information.