Grade Invasive Ductal Carcinoma Research Articles

Sonographic evaluation of solid breast nodules

Because of the heterogeneity of breast cancer from nodule to nodule, single findings cannot achieve the sensitivity or the negative predictive value necessary to identify a low-risk group that can be offered the option of follow-up (ACR Breast Imaging Reporting and Data System [BIRADS] 3 group). However, by using multiple findings in a strict algorithm, such a group can be identified. It is also important to keep in mind that breast cancer can be heterogeneous within an individual nodule. Part of the nodule may have circumscribed features that simulate a benign lesion, while another part may be spiculated and obviously malignant. Only by scanning the whole surface and substance of the nodule in two orthogonal planes (radial and anti-radial) can the presence of suspicious findings be excluded, and if there is a mixture of benign and suspicious findings, the benign findings should be ignored. These studies show that sonography is useful in the characterization of solid breast masses. Characterizing solid breast nodules into BIRADS categories defines carcinomas that might have been missed clinically or mammographically. It identifies a BIRADS 3 group that has far less than 2% risk of being malignant and can offer the patient the option of follow-up rather than biopsy. Currently, approximately 80% of patients with BIRADS 3 solid nodules are electing to be followed rather than to undergo biopsy. It improves the accuracy of the diagnosis of malignant breast lesions. Importantly, it also accurately defines a population of benign solid breast lesions that do not require biopsy when strict sonographic criteria of benignity are present. To achieve the desired sensitivity and negative predictive values of 98% or greater the algorithm must be strictly adhered to. When the patient elects to be followed rather than undergo biopsy, follow-up should be performed in 6 months, not 1 year. The malignant lesions at most risk to be mischaracterized as BIRADS 3 are higher grade invasive ductal carcinomas that grow rapidly enough for change to be readily detected at 6 months. Table 1 Current study: characterization of solid breast nodules Table 2 Prospective characterization of 1211 solid nodules into BIRADS categories (all 1211 nodules have undergone biopsy)

Expression of PC-cell-derived growth factor in benign and malignant human breast epithelium

PC-cell-derived growth factor (PCDGF, progranulin) is a novel autocrine growth factor that is overexpressed in human breast cancer cell lines. We have examined immunohistochemical PCDGF expression in 206 paraffin-embedded human breast lesions and investigated its association with clinicopathological variables. PCDGF staining was observed in breast carcinoma, whereas it was almost always negative in benign breast epithelium. PCDGF expression was more common in invasive ductal carcinoma (80% cases positive) than in invasive lobular carcinoma (53% positive). PCDGF staining was almost never observed in lobular carcinoma in situ. Ductal carcinoma in situ expressed PCDGF in 66% of the cases, and this expression correlated strongly with nuclear grade. Similar correlation was observed between PCDGF expression and histologic grade of invasive ductal carcinoma. Average Ki-67 index of PCDGF-negative/weakly positive invasive carcinomas (30.3) was significantly lower than that of strongly PCDGF-positive tumors (48.8, P = 0.01). A larger percentage of tumors that expressed PCDGF with a staining intensity of 2+ or 3+ were p53 positive (44%) than were PCDGF-negative tumors (25%), P = 0.02. PCDGF expression was independent of c-erbB-2 overexpression and of ER and PR status. Our study provides the first evidence of high incidence of PCDGF expression in human breast cancer in which it correlates with clinicopathological variables such as tumor grade, proliferation index, and p53 expression. These characteristics, as well as the virtual absence of expression in benign breast tissue, suggest an important role of PCDGF in breast cancer pathogenesis and make it a potential novel target for the treatment of breast cancer.

Nonpalpable breast cancer: mammographic appearance as predictor of histologic type.

To investigate the association between mammographic appearance and histologic diagnosis of nonpalpable breast cancers. Mammographic characteristics of 317 consecutive clinically nonpalpable breast cancers in patients treated with breast-conserving surgery were reviewed. Malignant lesions were categorized as spiculated masses, other lesions, calcifications, and combined findings. Calcifications were characterized as amorphous, pleomorphic, or fine linear and branching. Logistic regression was used for the evaluation. Odds ratios (ORs) represent the magnitude of the association between a histologic diagnosis and a mammographic finding. Spiculated mass without calcifications (n = 150) and calcifications alone (n = 79) accounted for three of four cancers. A spiculated mass without calcifications was strongly associated with invasive cancers (OR = 12). Calcifications alone were strongly associated with ductal carcinoma in situ (DCIS) (OR = 19). In a decreasing order, the following invasive cancers were each associated with spiculated lesions without calcifications: ductal carcinoma grade 1 (OR = 28), ductal carcinoma grade 2 (OR = 17), lobular carcinoma (OR = 11), and ductal carcinoma grade 3 (OR = 4.6). Fine linear and branching calcifications alone were associated with not only DCIS nuclear grades 3 (OR = 17) and 2 (OR = 9.7) but also with invasive ductal carcinoma grade 3 (OR = 13). Mammographic appearance can be a predictor of histologic diagnosis in three of four nonpalpable breast cancers.

A study of breast cancers detected in the incident round of the UK NHS Breast Screening Programme: the importance of early detection and treatment of ductal carcinoma in situ

One hundred and seventy eight cancers detected on incident round screening in the UK National Health Service Breast Screening Programme were reviewed. Critical review of the immediately preceding screening films (from 3 years previously) found abnormalities at the site of the subsequently detected cancer in 93 cases (52%). Forty-eight of these (27% of the total) had microcalcification as the sole abnormality. All of these 48 women had invasive ductal carcinoma and/or ductal carcinoma in situ (DCIS) (including four cases in which DCIS was associated with another type of primary invasive breast cancer). The finding of microcalcification on the previous mammograms at the site of a subsequently detected cancer was a strong predictor for the presence of DCIS (with or without associated invasive disease) (P<0.0001). Of the women with invasive ductal carcinoma, those with microcalcification on previous films were significantly more likely to have intermediate or high grade (grade 2 or 3) tumours than those women without microcalcification on previous films (P=0.0015).Previous films were also read blind by two independent experienced breast radiologists. Cancers were correctly identified by one or both readers in 39 cases. However, 35 of the remaining 139 cases showed microcalcification which was not detected or considered significant by the readers. If only these 139 ‘true negative’ screens are analysed, similar associations are seen between microcalcification on previous films and subsequent finding of DCIS (P=0.03) and between microcalcification on previous films and high grade invasive ductal carcinomas (P=0.015).These findings provide support for the hypothesis that microcalcification seen on previous screening films at the site of a subsequently detected invasive ductal carcinoma represents ductal carcinoma in situ. In this series, 19 of 82 women (23%) with invasive ductal carcinoma in the ‘true negative’ screen group had microcalcification suggestive of DCIS on mammograms taken, on average, 3 years previously. Significant microcalcification is often overlooked using current detection criteria. Early detection and treatment of DCIS is essential in order to prevent the development of aggressive invasive disease. Revision of the NHSBSP targets for DCIS detection is recommended.

Progression of Heterogeneous Breast Tumors

Two possible pathways of breast tumor progression were investigated by searching for values of transition rates that could reproduce the clinically observed co-occurrence frequencies of grades of ductal carcinoma in situ and grades of invasive ductal carcinoma in heterogeneous tumors. Two different pathways were analysed, a linear pathway with seven parameters, and a nonlinear pathway with three parameters. In each pathway ductal carcinoma in situ (DCIS) is a progenitor of invasive carcinoma (IDC). In the linear pathway breast tumor progression is along increasing grades: DCIS 1–DCIS 2–DCIS 3–IDC 1–IDC 2–IDC 3. In the nonlinear pathway progression of DCIS and progression of IDC can proceed in parallel steps, and in addition, with transitions from each grade of DCIS to a corresponding grade of IDC. The biological pathways were interpreted mathematically as compartment models with transition rates between stages in an explicit series of coupled differential equations. Two methods were used to search for transition rates that could reproduce the obseverd co-occurrence frequences, a limited empirical search and an extensive genetic algorithmic search. Neither search method, with either pathway, could find a combination of transition rates that would reproduce the set of observed co-occurrence frequencies. We conclude that neither the linear pathway, nor the nonlinear pathway considered here, is an adequate description of progression in heterogeneous breast tumors. This quantitative investigation lends support to previous evidence from histopathology and molecular biology that the grades of DCIS and IDC seen together in heterogeneous breast tumors may not be obligate steps in tumor progression.

Bax protein expression in DCIS of the breast in relation to invasive ductal carcinoma and other molecular markers.

This study describes the incidence of Bax protein expression in a series of 106 cases of breast cancer including 56 cases of ductal carcinoma in situ (DCIS) and 50 cases of invasive ductal carcinoma (IDC). Relationships of Bax expression to the histological grades of DCIS & IDC, and to the expression of Ki67, ER, p53, cerbB2 & Bcl2 are described. The expression of Bax, Ki67, ER, p53, cerbB2 and Bcl2 proteins is determined immunohistochemically. Cases were regarded positive for Bax, Bcl2 and cerbB2 when they showed either moderate or strong staining for these markers. The nuclear stains (Ki67, ER, and p53) were quantified in terms of percentage positive cells and cases for ER and p53 were considered positive when more than 10% cells were labelled. DCIS were graded histologically as well (n=18), intermediately (n=18), and poorly differentiated (n=20) Invasive ductal carcinoma was graded as grade I (well-differentiated) n=7, grade II (intermediate) n=24 and grade III (poorly differentiated) n=19. 65/106 cases (61%) were Bax positive including 37/56 (66%) of DCIS and 28/50 (56%) of IDC. Bax expression did not correlate to increasing histological grades of either DCIS or IDC. It did not correlate to Ki67, ER, p53 or cerbB2 but positive correlation was seen with Bcl2 (p=0.003). Bcl2 immunostaining displayed a negative correlation with increasing histological grades both of DCIS and IDC (p=0.026), (p=0.041) respectively. There was a trend of negative correlation of Bcl2 with Ki67 (p=0.062). It correlated positively with Bax (p=0.003) and ER (p<0.0001). Results suggest that the regulation of apoptosis is important in ductal carcinoma in situ of the breast as well as invasive ductal carcinomas. Bcl2 is associated with good prognostic markers in both DCIS and IDC, whereas the regulation of Bax is complex and does not necessarily correlate with mutant p53.

Does routine grading of invasive lobular cancer of the breast have the same prognostic significance as for ductal cancers?

Aim The routine tumour grading of invasive ductal carcinoma of the breast has been shown to be a robust determinant of outcome but pathologists have been reluctant to grade lobular cancers. The aim of this study was to determine the prognostic significance of the routine reporting of lobular grade. Methods All patients with invasive lobular carcinoma (ILC) treated between 1981 and 1996 were reviewed. Patients with ILC which had been graded were included in the study. These cases were matched with two control patients with invasive ductal carcinoma (IDC) who were operated on in the same year and were closest to the patients in age. Recurrence-free survival was compared with grade for ILC cases and IDC controls using life-table analysis. Similar comparisons were made with the Nottingham Prognostic Index (NPI) between the different prognostic groups. Results Of 139 cases with ILC, 33 were excluded from the study because 24 were ungraded, five had advanced disease and four had mixed tumours. The mean length of follow-up for ILC cases was 75 months vs 70 months for IDC controls. Recurrence rates for grade I were 10% ILC vs 24% IDC, for grade II 32%vs 32% and for grade III 33%vs 49%. The reported grades for ILC and IDC both showed the expected trend for an increased recurrence rate with more severe tumour grade, but this was only significant for IDC grade II vs grade III (P<0.02) on life-table analysis; only 6% of lobular cancers were reported as grade III. However, there was significant separation of the survival curves when NPI was compared for both lobular and ductal cancers. Conclusion The routine reporting of tumour grade for ILC did not show significant difference in outcome between grade I and grade II, and very few tumours were rated grade III. The validity of grading lobular cancer of the breast requires further evaluation.

Prognostic value of prominent DCIS component in the breast-conserving therapy of stage I and II invasive ductal breast cancer

<h2>Abstract</h2> The aim of this study was to determine the presence and histological grade of prominent ductal carcinoma in situ (DCIS) and the relationship between the histological grade of DCIS and the grade of invasive ductal carcinoma of the breast to local recurrence and survival. We have analysed 175 patients with stage I and II invasive ductal breast carcinoma who underwent breast-conserving therapy in the period 1987–1994. Patients were divided into those with carcinomas showing prominent DCIS (74 patients), and those with tumours without a DCIS component (101 patients). Ten patients developed recurrences and were treated by hormonal and/or chemotherapy. Local recurrence was observed in 2 (2%) patients without, and in 8 (10.8%) patients with prominent DCIS (<i>χ</i>₂=12.954, <i>P</i><0.005). There was a highly significant correlation between DCIS type and the histological grade of the infiltrating carcinoma (<i>χ</i>₂=73.77, <i>P</i><0.001). Our results suggest that the patients with poorly differentiated DCIS are significantly more likely to develop recurrence than patients with intermediately or well-differentiated DCIS.

Histological precision of stereotactic core biopsy in diagnosis of malignant and premalignant breast lesions

The reliability of stereotactic core biopsy in the diagnosis of malignant and premalignant breast lesions was assessed in comparison to excision biopsy in patients with non-palpable suspicious breast lesions detected in a mammography breast screening programme. Fifty-two cases of malignancy and nine of atypical ductal hyperplasia were diagnosed on the programme during the two year period July 1993 to June 1995; two patients did not have excision biopsy. Stereotactic core biopsies and representative sections from 59 excision specimens from the same patients were assessed "blind' by one pathologist. All 51 cancers diagnosed on stereotactic core biopsy were confirmed to be malignant on excision biopsy. There was 96% concordance between stereotactic core biopsy and excision biopsy for the diagnosis of invasive or in situ cancer, and 78% concordance for the type of cancer. The stereotactic core biopsy and excision biopsy diagnoses were: invasive ductal carcinomas (39 on stereotactic core biopsy vs. 33 on excision biopsy), mucinous carcinomas (1 vs. 2), invasive lobular carcinomas (3 vs, 8), and in situ carcinomas (8 vs. 8), two of which had invasive cancer present only in the stereotactic core biopsy. Of the nine cases of atypical ductal hyperplasia diagnosed on stereotactic core biopsy, eight had an excision biopsy, six showed low nuclear grade in situ or invasive cancer, one had a 3 mm focus of high grade invasive ductal cancer and one was atypical ductal hyperplasia. In the invasive ductal carcinoma group stereotactic core biopsy underestimated tumour grade: In nine cases (31%) the cancer at excision was of a higher grade. Stereotactic core biopsy is a reliable alternative to excision biopsy in the diagnosis of breast cancer, however, stereotactic core biopsy may underestimate tumour grade in invasive ductal carcinoma and may not differentiate between invasive ductal carcinoma and lobular carcinoma. It is recommended that the diagnosis of atypical ductal hyperplasia on stereotactic core biopsy be followed by excision biopsy, as stereotactic core biopsy underestimates the presence of cancer in this group.

Tumour development, histology and grade of breast cancers: Prognosis and progression

Using 1,973 breast tumours from women aged 40-69 participating in the Swedish two-county trial of mammographic screening for breast cancer, we examined the effect of histological type on prognosis and sojourn time (the duration of the preclinical screen-detectable phase) by age. The hypothesis of dedifferentiation, according to which a cancer of mixed malignancy grade drifts towards grade 3 as the more poorly differentiated part of the tumour grows faster than the well-differentiated part, was also assessed. Ductal carcinoma in situ, invasive ductal carcinoma of grade 1, mucinous carcinoma and tubular carcinoma were all associated with good survival. Ductal carcinoma of grade 3 was associated with poor survival. Ductal carcinoma of grade 2, lobular and medullary carcinoma were associated with intermediate survival. These patterns were much the same in women aged 40-49 as in women aged 50-69. In women aged 40-49, sojourn time was estimated at about 2 years regardless of histological type. For women aged 50-69, there was a marked association of sojourn time with histological type, the shortest sojourn time being observed for lobular (2 years) and medullary (1.2 years) carcinoma, and the longest for ductal carcinoma grade 1 (7.7 years) and tubular carcinoma (7.1 years). There was strong evidence of a potential to dedifferentiation. A mover-stayer mixture of Markov chain models estimated that, in women aged 40-54, 91% of ductal tumours have the potential to dedifferentiate and, in women aged 55-69, 38% of ductal tumours have such a potential.

Carcinomas of the breast with endocrine differentiation: a review.

The occurrence of endocrine differentiation in some mammary carcinomas seems well-established, but pathologists continue to debate its significance. Contemporary thinking suggests that endocrine tumours of the breast do not constitute a single clinicopathological entity with a consistent histogenesis but rather that endocrine differentiation represents a pathway of neoplastic development available to a range of breast cancers. This pattern of differentiation occurs in tumours with vastly different morphological appearances, such as: ductal carcinoma in situ, mucinous carcinoma, a variant of lobular carcinoma, and low grade invasive ductal carcinoma. Although such tumours share some characteristics with intestinal endocrine neoplasms, the typical pattern of intestinal carcinoid virtually never occurs in mammary lesions. Conventional microscopy permits the diagnosis in most cases. Specialized techniques (histochemistry, immunohistochemistry, and electron microscopy) can serve as the basis for diagnosis in the absence of the appropriate morphological features. Although the system of nomenclature proposed by the World Health Organization for use with endocrine tumours in other organs can be used for endocrine tumours of the breast, only a minority of lesions will fit the established criteria. Most lesions are classifiable in the conventional categories of mammary carcinomas. No special prognostic significance is attached to these tumours at the present time.

Proliferative responses of epithelial cells to 8‐bromo‐cyclic AMP and to a phorbol ester change during breast Pathogenesis

We have explored the relationship of changes in proliferative responses of human mammary epithelial cells to a phorbol ester (TPA) and to 8-Br-cAMP, which modulate the activities of protein kinases A and C (PKA and PKC), with breast tumour progression. Treatment with TPA had no effect on nontumorigenic cell lines established from human fibrocystic biopsies and apparently normal tissue around a tumour. In contrast, TPA strongly inhibited the proliferation of numerous human tumorigenic breast cell lines. Treatment with 8-Br-cAMP decreased the proliferation of all studied nontumorigenic and tumorigenic cell lines. We have also studied the effect of TPA and 8-Br-cAMP on growth of epithelial cells in short-term culture obtained from surgical human mammary biopsies with different states of breast disease. Both drugs enhanced growth of normal breast cells but had no significant effects on cells from biopsies with benign breast disease. In contrast, all examined cultures from breast cancer biopsies were strongly inhibited by 8-Br-cAMP. Otherwise, TPA had an inhibitory effect only in the case of invasive ductal carcinoma of grade III. Malignant Ha-ras-transformation of nontumorigenic TPA-insensitive breast HBL-100 cells induced an inhibitory effect of TPA. In addition, a TPA-insensitive MCF7 clone was much less tumorigenic in athymic mice than the parental strain shown to be inhibited by TPA. These data suggest that the two intracellular transduction pathways change at different stages of breast pathogenesis. Alterations in the PKA pathway are early events and are probably important to cell immortalization but do not necessarily lead to malignant development. In contrast, changes in PKC pathway are rather later events associated with advanced malignant transformation.

Nm23 Protein Expression in Ductal In Situ and Invasive Human Breast Carcinoma

Mortality associated with human breast carcinoma is almost entirely due to subsequent metastatic disease, but the molecular basis of this metastasis is not understood. Elucidation of the genetic control of metastatic propensity of a tumor is important in determining prognosis and choice of therapy. Expression of nm23, a putative metastasis suppressor gene, has been detected in human breast cancers, but studies have not consistently shown high levels of the Nm23 messenger RNA or protein to be associated with better histological differentiation. This inconsistency suggests that Nm23 protein may act independently as a metastasis suppressor. The purpose of this retrospective study was to investigate the relationship of Nm23 protein expression with 1) histology in ductal breast carcinoma in situ and 2) the variables considered to be the major prognostic indicators in invasive breast carcinoma. We obtained formalin-fixed biopsy specimens of breast tissue excised from 128 patients with breast lesions detected by mammography. Of these patients, 35 had been diagnosed with benign breast disease, 26 with ductal carcinoma in situ (DCIS), and 67 with invasive carcinoma. Tissue sections were embedded in paraffin blocks, and immunohistochemical staining was used to determine Nm23 expression. Specimens were rated positive if all lesional epithelium was stained and negative if any lesional epithelium was unstained. Statistical analysis was performed by multiple regression analysis because of nonorthogonality of the data. All 35 examples of benign breast disease showed uniform epithelial cell staining. The seven cases of comedo DCIS were negative for Nm23 protein; all 18 noncomedo types were positive. Nm23 negativity was significantly associated with worsening invasive ductal carcinoma grade and advancing lymph node stage but not with tumor diameter or vascular invasion. Despite the putative antimetastatic role of the nm23 gene, no statistically significant association was found between Nm23 protein expression and vascular invasion. The precise role of the nm23 gene remains to be established, but our simplified immunohistochemical rating system shows an association between Nm23 protein expression and the two most significant prognostic factors relating to histologic grade and stage. Nm23 negativity distinguished comedo ductal carcinoma in situ from the other histological types, a finding consistent with the fact that comedo histology is known to have a higher likelihood of becoming invasive and of having higher cell proliferation rates and higher expression of growth factor (c-erb B2) receptor.