Zsolt Hodi

Prognostic Significance of Nottingham Histologic Grade in Invasive Breast Carcinoma

PURPOSE The three strongest prognostic determinants in operable breast cancer used in routine clinical practice are lymph node (LN) stage, primary tumor size, and histologic grade. However, grade is not included in the recent revision of the TNM staging system of breast cancer as its value is questioned in certain settings. MATERIALS AND METHODS This study is based on a large and well-characterized consecutive series of operable breast cancer (2,219 cases), treated according to standard protocols in a single institution, with a long-term follow-up (median, 111 months) to assess the prognostic value of routine assessment of histologic grade using Nottingham histologic grading system. RESULTS Histologic grade is strongly associated with both breast cancer-specific survival (BCSS) and disease-free survival (DFS) in the whole series as well as in different subgroups based on tumor size (pT1a, pT1b, pT1c, and pT2) and LN stages (pN0 and pN1 and pN2). Differences in survival were also noted between different individual grades (1, 2, and 3). Multivariate analyses showed that histologic grade is an independent predictor of both BCSS and DFS in operable breast cancer as a whole as well as in all studied subgroups. CONCLUSION Histologic grade, as assessed by the Nottingham grading system, provides a strong predictor of outcome in patients with invasive breast cancer and should be incorporated in breast cancer staging systems.

High frequency of coexistence of columnar cell lesions, lobular neoplasia, and low grade ductal carcinoma in situ with invasive tubular carcinoma and invasive lobular carcinoma

This study was undertaken to determine the morphologic features and frequency of putative precursor lesions involved in the development of some pure forms of special types and low grade breast carcinoma. We reviewed 147 successive tumor cases, comprising tubular carcinoma (TC); pure type (n=56) and mixed type (n=20), invasive lobular carcinoma (ILC); classic type (n=57), and tubulolobular carcinoma (TLC; n=14). The presence of preinvasive lesions including columnar cell lesions (CCLs), usual epithelial hyperplasia, ductal carcinoma in situ (DCIS), and lobular neoplasia (LN) was determined. Estrogen receptor and E-cadherin immunohistochemistry was performed. Ninety-five percent (95%) of pure TCs had associated CCLs with the majority showing flat epithelial atypia. Atypical ductal hyperplasia (ADH)/DCIS was present in 89% patients. Colocalization of CCL, ADH/DCIS, and TC was seen in 85% patients, all displaying the same cytologic-nuclear morphology in most cases. LN was seen in 16%. In ILC, 91% cases showed LN. CCL and ADH/DCIS were seen in 60% and 42% cases, respectively. E-cadherin was positive in TLC but reduced in TC and completely absent in ILC. In conclusion, our findings support the hypothesis that CCLs are associated with pure and mixed forms of TC, and that LN is involved in ILC development. Our observations suggest that these lesions represent family members of low grade precursor, in situ and invasive neoplastic lesions of the breast. Molecular studies are being performed to substantiate the hypothesis that tubular and lobular carcinomas have direct evolutionary links to CCLs and flat epithelial atypia.

Morphologic and molecular evolutionary pathways of low nuclear grade invasive breast cancers and their putative precursor lesions: Further evidence to support the concept of low nuclear grade breast neoplasia family

We have previously provided evidence showing an association between some precursor lesions with low nuclear grade breast carcinomas (LNGBCs). In this study, further immunophenotypic support to our proposed route of pathogenesis of LNGBC and their precursor lesions was provided. Precursor lesions including columnar cell lesions, atypical ductal hyperplasia, ductal carcinoma in situ, usual epithelial hyperplasia, and lobular neoplasia were compared with matching “morphologically normal” terminal lobular duct units and matching invasive carcinoma. The epithelial cells in the putative precursor flat epithelial atypia, atypical ductal hyperplasia, lobular neoplasia, ductal carcinoma in situ lesions, and their coexisting LNGBC were negative for basal and myoepithelial markers, but positive for CK19/18/8, estrogen receptor (ER)-α, Bcl-2, and cyclin D1. The ER-α/ER-β expression ratio increased during carcinogenesis, as did expression of cyclin D1 and Bcl-2. p53 immunopositivity was found 3% in LNGBC versus 43% in high nuclear grade breast carcinoma (HNGBC), whereas ataxia telangiectasia mutated expression was absent or reduced in 22% of LNGBC versus 53% of HNGBC cases. In summary, our findings support the concept that flat epithelial atypia is the earliest morphologically identifiable nonobligate precursor lesion of LNGBC. These may represent a family of precursor, in situ and invasive neoplastic lesions belonging to the luminal “A” subclass of breast cancer. The balance between ER-α and ER-β expression may be important in driving cyclin D-1 and Bcl-2 expression. Ataxia telangiectasia mutated may be one of the alternative regulatory mechanisms to TP53 mutation or dysfunction in low-grade and high-grade breast carcinoma. Our findings support the concept that progression of LNGBC to HNGBC (basal-like or HER2+) phenotype is an unlikely biologic phenomenon.

Is acinic cell carcinoma a variant of secretory carcinoma? A FISH study using ETV6'split apart' probes.

Aims:  Acinic cell carcinomas (ACCs) and secretory carcinomas (SCs) of the breast are rare, low‐grade malignancies that preferentially affect young female patients. Owing to the morphological and immunohistochemical similarities between these lesions, they have been proposed to be two morphological variants of the same entity. It has been demonstrated that SCs of the breast consistently harbour the t(12;15)ETV6‐NTRK3 translocation. The aim was to determine whether ACCs also harbour ETV6 gene rearrangements and are thus variants of SCs.

Tubular Carcinoma of the Breast: Further Evidence to Support Its Excellent Prognosis

PURPOSE Although tubular carcinoma (TC) is known to have a favorable prognosis, it is still unknown whether this subtype represents a distinct type of breast carcinoma or whether it behaves like other low-grade luminal A-type breast carcinomas. METHODS In this study, we performed a retrospective analysis of a large well-characterized series of breast cancers (2,608 carcinomas) to assess the clinicopathologic and molecular features and prognostic value of TC compared with grade 1 ductal carcinomas of the breast. Results When compared with grade 1 ductal carcinoma (n = 212), TC (n = 102) was more likely to be detected on mammographic screening, had smaller median size, and less frequently showed lymphovascular invasion. Compared with grade 1 ductal carcinoma, TC was associated with longer disease-free survival (chi(2) = 13.25, P < .001) and breast cancer-specific survival (chi(2) = 8.8, P = .003). In this study, none of the patients with TC developed distant metastasis or died from the disease without an intervening recurrence as invasive carcinoma of different histologic type. CONCLUSION We conclude that the biologic behavior of TC is excellent and is more favorable than that of grade 1 ductal carcinoma. Patients with TC may be at risk of developing second primary carcinomas in the contralateral breast, which may be of higher grade and poorer potential prognostic outcome. In addition, patients with TC seem to have a close to normal life expectancy, and as a consequence, adjuvant systemic therapy may not be justified in their routine management.

The prognostic significance of lymphovascular invasion in invasive breast carcinoma.

Although lymphovascular invasion (LVI) has been associated with a poor outcome in patients with breast cancer, it is not included in most internationally recognized staging systems, including the American Joint Committee on Cancer tumor, lymph node, metastasis (TNM) classification. This is mainly because it remains unclear whether the presence of LVI is an independent, high‐risk criterion in clinically relevant staging subgroups.

Histological features useful in the distinction of phyllodes tumour and fibroadenoma on needle core biopsy of the breast

Aim:  To identify features useful in distinguishing phyllodes tumours from fibroadenomas on core biopsy.

The reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breast

Aim: To assess the reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breast. Previous studies have mostly been small, with a range of agreement from 62% to 100%. Methods: Retrospective audit of 338 tumours surgically excised within 60 days of core biopsy, that had had oestrogen receptor assessed on both the core biopsy and tumour specimens. Surgical specimens were incised when fresh to ensure good fixation. External controls including a weakly positive tumour were included in each immunohistochemistry run. Results: Oestrogen receptor expression was bimodal, with H score in both specimens of either 0 or >50 in 96% of tumours. Using H score cut-off of 10 for positivity, there was an agreement between core and excision in 334 of 338 tumours (98.8%). All discrepancies were between weakly positive and negative tumours. Intratumoral heterogeneity could explain the one tumour that was negative on core and positive on excision. H score tended to be slightly higher on core than excision (means 146 and 136). Better fixation on the core is the most likely explanation for this and for the three tumours that were positive on core and negative on excision. Repeat staining on tumours with discrepant results gave similar results in all except one case. An internal control was present in 97% of excisions and 55% of cores of oestrogen receptor-negative tumours; the internal control stained positively in all except two sections. Conclusion: Oestrogen receptor can be assessed reliably on needle core biopsies of invasive carcinomas of the breast.

Vacuum-assisted excision of breast lesions of uncertain malignant potential (B3) - an alternative to surgery in selected cases

To assess whether vacuum-assisted excision (VAE) is a safe alternative to surgery in the treatment of breast lesions of uncertain malignant potential (B3) in which no atypia is present on needle core biopsy (NCB). Forty two VAE procedures were performed for B3 lesions. Twenty four (57%) were papillary lesions. Eighteen (43%) were radial scars. Two patients (4.7%) were upgraded to carcinoma at VAE. Two patients with papillary lesions went on to develop cancer in the same breast (at 24 and 41 months post VAE). No cancer developed in the radial scar group. Eight patients (19%) had surgery - four for carcinoma, two for radial scars missed at VAE excision and two for symptomatic papillomatosis. Follow-up mammography after VAE of radial scars often showed residual distortion. VAE can be a safe alternative to surgery in the treatment of B3 lesions without atypia, providing thorough multidisciplinary discussion has taken place.

Concordance of HER2 status assessed on needle core biopsy and surgical specimens of invasive carcinoma of the breast

Lee A H S, Key H P, Bell J A, Hodi Z & Ellis I O 
(2012) Histopathology 60, 880–884