Management of lobular carcinoma in-situ and atypical lobular hyperplasia of the breast-A review

Objectives

To determine the incidence of malignancy (invasive carcinoma or DCIS) in patients diagnosed with lobular neoplasia (B3) on core needle biopsy (CNB) of breast lesions by reviewing the published literature.

Methods

Medline, Embase, OVID-database and reference lists were searched to identify and review all English-language articles addressing the management of LN diagnosed on CNB. Studies on mixed breast pathologies were excluded.

Results

Of 1229 LN diagnosed on CNB, 789 (64%) underwent surgical excision. 211 (27%) of excisions contained either DCIS or invasive disease. 280 of the excision specimens were classified as ALH, 241 as LCIS, 22 as pleomorphic LCIS and 246 unspecified LN on the original CNB. After surgical excision, 19% of the ALH cases, 32% of the LCIS cases and 41% of the PLCIS cases, contained malignancy. 29% of the unspecified LNs were upgraded to malignancy. The higher incidence of malignancy within excision specimens for LCIS and PLCIS compared to ALH was significant (P < 0.04, <0.003 respectively).

Conclusion

There is a significant underestimation of malignancy in patients diagnosed with breast LN on CNB. 27% cases of CNB-diagnosed LN were found to contain malignancy following surgical excision. All patients diagnosed with LN on CNB should be considered for surgical excision biopsy.     

Increased levels of active c-Src distinguish invasive from in situ lobular lesions

Introduction  

Mounting molecular evidence suggests that invasive lobular carcinoma (ILC) is developing from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). However, little is known about the mechanisms promoting the progression of lobular breast cancer (LBC) to invasive disease. Here, we investigated whether c-Src kinase, an established inducer of invasive states, contributes to the progression from ALH/LCIS to ILC.     

A systematic review of surgical biopsy for LCIS found at core needle biopsy – Do we have the answer yet?

Background

The natural history of lobular carcinoma in-situ (LCIS) suggests that women are at increased risk of subsequent invasive breast cancer. Questions of effective management for women with this lesion have led to the need for evidence-based guidance and, in particular, guidance regarding management after LCIS is found at core needle biopsy (CNB).

Methods

A systematic review was conducted to determine the most appropriate management for women with LCIS found at CNB. A comprehensive search of the scientific literature was conducted to identify the literature pertaining to this population. Critical appraisal of the literature, data extraction and a narrative synthesis of the results were conducted. The outcome of interest was upgrade of diagnosis to invasive breast cancer or ductal carcinoma in-situ (DCIS).

Results

Sparse data, with limited generalisability and considerable uncertainty, are available for women with LCIS at CNB. Nine studies were identified that met pre-specified inclusion criteria. The reported estimates of upgrade of diagnosis from LCIS to invasive breast cancer or DCIS ranged from 2% to 25%. The body of evidence was limited by its retrospective nature, risk of selection bias and poor generalisability to all women with LCIS at CNB. Further, higher quality research is required to determine the best approach for women with LCIS at CNB with any certainty.     

Recommendations for women with lobular carcinoma in situ (LCIS)

Atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) represent a spectrum of breast disease referred to as "lobular neoplasia" (LN). Although LN occurs relatively infrequently, it is associated with an increased risk of breast cancer, ranging from a three- to four-fold increased risk with ALH up to an eight- to ten-fold increased risk with LCIS. Initially regarded as a direct precursor to invasive lobular carcinoma, LCIS used to be treated by mastectomy. Subsequent studies demonstrating that the risk of invasive disease was conferred bilaterally and that subsequent cancers were of both the ductal and lobular phenotype led to the acceptance of LCIS as a marker of increased risk rather than a true precursor. Today, a diagnosis of LCIS remains one of the greatest identifiable risk factors for the subsequent development of breast cancer. As such, patients are offered one of three options: (1) lifelong surveillance with the goal of detecting subsequent malignancy at an early stage; (2) chemoprevention; or (3) bilateral prophylactic mastectomy. Paralleling changes in the management of invasive breast cancer, trends in the management of LCIS have moved toward more conservative management. However, we have made little progress in understanding the biology of LCIS and therefore remain unable to truly optimize recommendations for individual patients.     

Synchronous lobular carcinoma in situ and invasive lobular cancer: Marker or precursor for invasive lobular carcinoma

Aim

Lobular carcinoma in situ (LCIS) is a known risk factor for invasive breast carcinoma, but there is increasing data indicating a possible precursor relationship. This study investigates the incidence of lobular carcinoma in situ that occurs with invasive lobular carcinoma (ILC).

Methods

Women diagnosed with ILC or LCIS from 2000 to 2010 were retrospectively identified and reviewed after institutional review board approval. This group was divided into two cohorts: ILC alone, and LCIS and ILC (ILC/LCIS). Patient demographics, disease characteristics, and treatment modalities were captured. p < 0.05 is considered significant.

Results

A total of 148 patients with ILC or LCIS were identified. Forty-four (54%) patients with only ILC, and 37 (46%) patients with ILC/LCIS were identified. Median age at diagnosis was 62 for ILC and 64 years for ILC/LCIS (p = 0.8). In patients with ILC, total mastectomy was the predominant treatment modality in 28 of 44 (64%) patients, while 18 of 37 (49%) patients with ILC/LCIS underwent breast conservation therapy (p = 0.3). Median largest tumor diameter was 35 mm (range 1–110) for ILC, and 15 mm (range 5–85) for ILC/LCIS (p = 0.03). Nodal status was positive in 17 of 39 (44%) ILC and 13 of 34 (38%) ILC/LCIS (p = 0.6).

Conclusions

The 46% incidence of LCIS associated with ILC in our cohort study is similar to that reported for ductal carcinoma in situ identified with invasive ductal carcinoma at ∼40%. The association of pre-invasive and invasive lobular lesions should be further studied in a large scale prospective study to assess for a precursor relationship.     

Lobular neoplasia on core needle biopsy does not require excision

BACKGROUND: Lobular neoplasia (LN), encompassing atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), is often an incidental finding on core needle biopsies (CNBs) performed in instances of radiologic densities and/or calcifications. Because LN is generally considered a risk factor for breast carcinoma, the utility of subsequent excision is controversial. METHODS: The authors' database yielded 98 cases of LCIS and/or ALH. Cases containing LN accompanied by a second lesion mandating excision (eg, radial scar, atypical ductal hyperplasia [ADH]) and those failing to meet strict diagnostic criteria for LN (eg, atypical cells, mitoses, single-cell necrosis) were excluded. Radiographic calcifications were correlated with their histologic counterparts in terms of size, number, and pattern. RESULTS: Ninety-one biopsies were performed for calcifications and 7 were performed for mass lesions. The ages of the patients ranged from 35 to 82 years. Fifty-three patients were followed radiologically without excision, 42 of whom had available clinicoradiologic information. The 45 patients who underwent excision were without disease at follow-up periods ranging from 1 to 8 years. Of these 45 patients, 42 (93%) had biopsy results demonstrating only LN. The remaining 3 patients had biopsies with the following findings: ADH in 1 biopsy, residual LCIS and a separate minute focus of infiltrating lobular carcinoma (clearly an incidental finding) in the second biopsy, and ductal carcinoma in situ admixed with LCIS in the third biopsy (a retrospective examination performed by 2 blinded breast pathologists revealed foci of atypical cells and mitoses). CONCLUSIONS: Excision of LN is unnecessary provided that: 1) careful radiographic-pathologic correlation is performed; and 2) strict histologic criteria are adhered to when making the diagnosis. Close radiologic and clinical follow-up is adequate.     

Evolving concepts in the management of lobular neoplasia

Lobular neoplasia broadly defines the spectrum of changes within the lobule, ranging from atypical lobular hyperplasia (ALH) to lobular carcinoma in situ (LCIS). This continuum of lesions is associated with an increased risk for developing subsequent invasive breast cancer, with the magnitude of that risk corresponding to the degree of proliferative change. The associated risk for developing invasive breast cancer after a diagnosis of lobular neoplasia is multicentric, bilateral, and equal in both breasts. Lobular neoplasia itself may transform into invasive carcinoma, although the frequency of this occurrence is unknown. Thus, lobular neoplasia is a risk factor for invasive breast cancer and may be a precursor lesion in unusual circumstances. The management of ALH and LCIS depends on the setting in which they are encountered. When ALH and LCIS are diagnosed after core needle breast biopsy, wire localization for surgical excision is required for definitive diagnosis because rates of histologic underestimation approach those of atypical ductal hyperplasia (ADH). When diagnosed on surgical biopsy, ALH and LCIS generally do not require further intervention, even when present at a surgical margin. However, bilateral breast cancer risk must be considered, especially when patients have a family history of breast cancer. In selected situations, bilateral prophylactic mastectomy with or without reconstruction may be considered when atypical hyperplasia or LCIS is diagnosed. Although this reduces risk for developing subsequent breast carcinoma by 90%, patients selected for prophylactic mastectomy represent a small subgroup of lobular neoplasia patients and generally have other risk factors, such as strong family history or evidence of genetic predisposition.     

Impact of concurrent proliferative high-risk lesions on the risk of ipsilateral breast carcinoma recurrence and contralateral breast carcinoma development in patients with ductal carcinoma in situ treated with breast-conserving therapy

BACKGROUND: The purpose of the study was to determine the risk of ipsilateral breast carcinoma recurrence (IBCR) and contralateral breast carcinoma (CBC) development in patients with a concurrent diagnosis of ductal carcinoma in situ (DCIS) with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in situ (LCIS). METHODS: Records of all 307 patients with DCIS treated with breast-conserving treatment (BCT) from 1968 to 1998 were analyzed. Initial pathology reports and all slides available were re-reviewed for evidence of ADH, ALH, or LCIS. Actuarial local recurrence rates were calculated. RESULTS: Fifty-five cases of DCIS were associated with ADH, 11 with ALH or LCIS, and 14 with both ADH and ALH or LCIS. Overall, IBCR occurred in 14% and no significant difference in the IBCR rate was identified for patients with proliferative lesions compared with patients without these lesions (P = 0.38). Development of CBC in patients with concurrent DCIS and ADH was 4.4 times (95% confidence interval [CI], 1.44-13.63) that in patients with DCIS alone (P < 0.01). The 15-year cumulative rate of CBC development was 22.7% in patients with ALH or LCIS compared with 6.5% in patients without these lesions (P = 0.30) and 19% in patients with ADH compared with 4.1% in patients with DCIS alone (P < 0.01). CONCLUSION: The risk of CBC development is higher with concurrent ADH than in patients with DCIS alone, and these patients may therefore be appropriate candidates for additional chemoprevention strategies. Concurrent ADH, ALH, or LCIS with DCIS is not a contraindication to BCT.     

Late age at first full term birth is strongly associated with lobular breast cancer

BACKGROUND:

Late age at first full‐term birth and nulliparity are known to increase breast cancer risk. The frequency of these risk factors has increased in recent decades.

METHODS:

The purpose of this population‐based case‐control study was to examine associations between parity, age at first birth (AFB), and specific histological subtypes of breast cancer. Women with breast cancer were identified from cancer registries in Wisconsin, Massachusetts, and New Hampshire. Control subjects were randomly selected from population lists. Interviews collected information on reproductive histories and other risk factors. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of ductal, lobular, and mixed ductal‐lobular breast cancer diagnosis in association with AFB and nulliparity.

RESULTS:

AFB ≥30 years was associated with a 2.4‐fold increase in risk of lobular breast cancer compared with AFB <20 years (OR, 2.4; 95% CI, 1.9‐2.9). The association was less pronounced for ductal breast cancer (OR, 1.3; 95% CI, 1.2‐1.4). Nulliparity was associated with increased risk for all breast cancer subtypes, compared with women with AFB <20 years, but the association was stronger for lobular (OR, 1.7; 95% CI, 1.3‐2.2) than for ductal (OR, 1.2; 95% CI, 1.1‐1.3) subtypes (P = .004). The adverse effects of later AFB was stronger with obesity (P = .03) in lobular, but not ductal, breast cancer.

CONCLUSIONS:

Stronger associations observed for late AFB and nulliparity suggest that these factors preferentially stimulate growth of lobular breast carcinomas. Recent temporal changes in reproductive patterns and rates of obesity may impact the histological presentation of breast cancer. Cancer 2011. © 2010 American Cancer Society.     

The diagnosis and management of pre-invasive breast disease: pathology of atypical lobular hyperplasia and lobular carcinoma in situ

The term lobular neoplasia refers to a spectrum of lesions featuring atypical lobular hyperplasia and lobular carcinoma in situ (LCIS). The histopathological characteristics of these lesions are well documented. What is less well understood is the management implications of a patient diagnosed with LCIS; treatment regimes vary and are somewhat controversial. LCIS is now considered a risk factor and a non-obligate precursor for the subsequent development of invasive cancer.     

Amplification of the prolactin receptor gene in mammary lobular neoplasia

The identification of lobular carcinoma in situ (LCIS) in a patient’s specimen confers an appreciable increased risk of development of future invasive mammary carcinoma. However, the study of LCIS presents a challenge as it is usually only recognized in fixed specimens. Recent advances in high throughput genomics have made possible comprehensive copy number analysis of lesions such as this. Using array comparative genomic hybridization (aCGH), we characterized eight cases of lobular carcinoma (four invasive and four non-invasive) from microdissected samples of archival specimens and validated our results by quantitative real-time PCR (qRT-PCR). Immunohistochemistry (IHC) was performed on an independent set of 80 in situ ductal (DCIS) and lobular breast lesions to confirm our results. Amplification of the prolactin receptor gene (PRLr) was identified in 4/4 cases of LCIS by aCGH. We confirmed this amplification by qRT-PCR and demonstrated PRLr expression in 29/40 (73%) cases of lobular neoplasia by IHC. Amplification of PRLr was neither detected in 10 cases of DCIS nor in 5 areas of normal breast tissue by qRT-PCR and only 14/40 (35%) cases of DCIS showed PRLr expression by IHC (P = 0.0008). Our study suggests the prolactin receptor gene is a molecular target that may be important in the pathogenesis and progression of lobular neoplasia. Investigation of the status of this gene in cases of DCIS has indicated that it may not be as important in the progression of this type of breast cancer, supporting the view that lobular and ductal carcinomas may evolve along separate pathways.     

How Do We Approach Benign Proliferative Lesions?

Purpose of Review

The aim of this review is to summarize recently published literature addressing atypical ductal hyperplasia (ADH), lobular neoplasia (atypical lobular hyperplasia [ALH] and classic lobular carcinoma in situ [C-LCIS]), non-classic lobular carcinoma in situ (NC-LCIS), papillary lesions, and flat epithelial atypia (FEA).

Recent Findings

While ADH, ALN, and C-LCIS are well-established markers of an increased risk of future breast cancers, the risk implications are less clear for papillary lesions and FEA. NC-LCIS is the least well-characterized lesion, with scant published literature on its natural history and surgical management when encountered on needle biopsy.

Summary

Recent data suggest that lobular neoplasia on core biopsy of a BI-RADS ≤?4 concordant lesion does not require an excision, while ADH, atypical papillomas, and NC-LCIS should be excised. Evidence on FEA and papillomas without atypia suggests a low risk of upgrade on excision, and prospective studies on the upgrade of these lesions are ongoing.

     

Histologic extension of lobular carcinoma--study of a case of infiltrating lobular carcinoma accompanied by various patterns of lobular proliferation

Histologic examination using serial sections of a mastectomy specimen from an ILC patient with LCIS and unusual lobular proliferation showed the following: 1) Cancer cells and their infiltration patterns varied and were not typical of ILC, so that this case was categorized as ILC partially possessing some histologic features of IDC. 2) Unusual lesions of proliferation, which were initially regarded as ALH, consisted of both pure ALH and ILC invading the ALH and normal lobules. For the correct diagnosis of ALH in biopsy specimens, therefore, we must bear in mind the (possible) concomitant presence of ILC. 3) The histologic criteria for ALH and ILC must be defined more clearly.     

Concurrent lobular neoplasia increases the risk of ipsilateral breast cancer recurrence in patients with ductal carcinoma in situ treated with breast‐conserving therapy

BACKGROUND:

Multiple clinicopathologic factors have been analyzed for their association with an increased risk of ipsilateral breast tumor recurrence (IBTR) after women receive breast‐conserving treatment (BCT) for ductal carcinoma in situ (DCIS). The reported incidence of proliferative lesions, such as atypical ductal hyperplasia (ADH), columnar cell changes (CCC), and lobular neoplasia associated with breast cancer, has been as high as 23%; however, the relevance of these lesions on the natural history of DCIS and the risk of IBTR remains unknown.

METHODS:

Two hundred ninety‐four patients with DCIS who received BCT between 1991 and 1995 were identified from the authors' institutional database. Slides were reviewed by a dedicated breast pathologist with particular attention to the presence of lobular neoplasia, ADH, and CCC. The actuarial 5‐, 10‐, and 15‐year IBTR rates were calculated using the Kaplan‐Meier method and were compared using the log‐rank test.

RESULTS:

Concurrent lobular neoplasia was present in 41 of 294 patients (14%), ADH was present in 37 of 294 patients (13%), and CCC was present in 71 of 294 patients (24%). The median follow‐up was 11 years. IBTR occurred in 40 of 227 patients without lobular neoplasia (18%) versus 15 of 41 patients with lobular neoplasia (37%; P=.005; hazard ratio [HR], 2.49). The 5‐, 10‐, and 15‐year cumulative incidence rates of IBTR were twice as high in women who had DCIS and lobular neoplasia compared with women who had DCIS alone (P=.002). Concomitant ADH (HR, 1.53) and CCC (HR, 1.24) were not associated significantly with IBTR (P=.20 and P=.44, respectively).

CONCLUSIONS:

Concurrent lobular neoplasia is associated with a significantly higher risk of IBTR in women with DCIS who received BCT. Women with coexisting DCIS and lobular neoplasia who receive BCT should consider using additional risk‐reducing strategies. Cancer 2009. © 2009 American Cancer Society.     

Accuracy of screening mammography in women with a history of lobular carcinoma in situ or atypical hyperplasia of the breast

Women with lobular carcinoma in situ (LCIS), atypical lobular hyperplasia (ALH), atypical ductal hyperplasia (ADH), or atypical hyperplasia (AH) are at increased breast cancer (BC) risk. We investigated the accuracy and outcomes of mammography screening in women with histology-proven LCIS, ALH, ADH, or AH history who had screening through Breast Cancer Surveillance Consortium-affiliated mammography facilities. Screens from two cohorts, defined by LCIS/ALH or ADH/AH history, were compared to two cohorts without such history mammogram-matched for age-group, breast density, family history, screen-year, and mammography registry. Overall 359 BCs (277 invasive BC) occurred within 1 year from screening among 52,380 screens. In the LCIS/ALH cohort [versus comparator screens] cancer incidence rates, cancer detection rates (CDR), and interval cancer rates (ICR) were significantly higher (all P < 0.001); although ICR was 4.4/1,000 screens [versus 0.9/1,000; P < 0.001] the proportion that were interval cancers did not differ between compared cohorts (P = 0.43); screening sensitivity was 76.1 % [versus 82.3 %; P = 0.43], however, specificity was significantly lower at 85.1 % [versus 90.7 %; P < 0.0001]. In the ADH/AH cohort [versus comparator] cancer rates and CDR were significantly higher (P < 0.001); although ICR was 2.6/1,000 screens [versus 0.9/1,000; P = 0.002] the proportion that were interval cancers did not differ between cohorts (P = 0.74); screening sensitivity was 81.0 % [versus 82.6 %; P = 0.74] and specificity was lower at 86.2 % [versus 90.2 %; P < 0.0001]. Mammography screening sensitivity in LCIS/ALH and ADH/AH cohorts did not significantly differ from that of matched screens, however, specificity was lower, and ICRs were higher (reflecting underlying cancer rates). Adjunct screening may be of value in these women if it reduces ICR without substantially reducing specificity.     

Histology after lumpectomy in women with epithelial atypia on stereotactic vacuum-assisted breast biopsy

Background

Large-core needle biopsy of the breast (LCNB) and vacuum-assisted breast biopsy (VABB) are widely used as alternatives to open surgical biopsy (OSB) for initial diagnosis of mammographic abnormalities. Between 18% and 80% of cases in which such specimens show atypical lobular hyperplasia (ALH) or atypical ductal hyperplasia (ADH) are found to be malignant at surgery.

Design

From 1999 to 2005, 68 women with mammographic abnormalities were sampled by stereotactic VABB and presented atypical epithelial hyperplasia. Immunohistochemical staining with anti-cytokeratin 5/6 and anti-E-cadherin antibodies was performed. All women underwent a lumpectomy. Clinical, radiological or histological factors predictive of the risk of finding malignancy at surgery were sought.

Results

VABB initially showed 28 cases of ADH, 32 cases of ALH, one case of flat epithelial atypia, five cases of mixed atypia, and two cases of Lobular Carcinoma In Situ (LCIS). After slide review with immunohistochemical staining, two cases of ADH were reclassified as simple hyperplasia and two cases of ALH were reclassified as mixed atypia. Seven lesions (10.3%) that appeared to be benign on VABB were found to be malignant on OSB (Ductal Carcinoma In Situ (DCIS) in six cases and invasive ductal carcinoma in one case). ADH was the only predictive factor of malignancy on OSB (p = 0.04 versus ALH).

Conclusion

ADH diagnosed by vacuum-assisted breast biopsy frequently corresponds to cancer on open surgical biopsy. Surgical excision of all breast lesions containing atypical hyperplasia on percutaneous biopsy can be recommended.     

伴多发性乳头状瘤的乳腺病变的临床病理分析

目的探讨乳腺病变中多发性头状瘤(MPS)与乳腺癌之间的关系.方法对20例伴有MPS的病变进行回顾性临床病理分析.所有的病例均有纤维囊性乳腺病、不典型性导管增生(ADH)、不典型性小叶增生(ALH)、小叶原位癌(LCIS)及不典型性乳头结构,与伴有MPS的导管原位癌(DCIS,8例)及导管侵袭癌(INS,12例)比较.结果乳腺MPS病变的特征性是在形成多发性肿块的导管内充满乳头,相邻的组织纤维化,伴有不同程度的增生性纤维囊性病.特别是在不典型性乳头状瘤病例(8例中5例,占62.5%)中,不典型增生常见(20例中9例,占44.1%).结论乳腺MPS往往与ADH、ALH、LCIS的恶性病变相关,而双侧乳腺MP提示乳腺癌发生的危险明显增加.     

Age-specific incidence rates of in situ breast carcinomas by histologic type, 1980 to 2001.

Incidence rates of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) have increased rapidly over the past several decades largely due to the increased use of mammography. However, recent data from 1987 to 1999 indicate that invasive ductal carcinoma incidence rates have remained essentially constant, whereas rates of invasive lobular carcinoma have increased 65%, with greater increases observed among postmenopausal women. Data on recent trends in DCIS and LCIS incidence rates, particularly age-specific trends, are lacking. We evaluated trends in the incidence rates of DCIS overall, noncomedo DCIS, comedo DCIS, and LCIS using data from nine Surveillance, Epidemiology, and End Results cancer registries. DCIS incidence rates increased 7.2-fold [95% confidence interval (95% CI), 6.8-7.7] from 1980 to 2001, 1.8-fold (95% CI, 1.7-1.9) over the past 10 years (1992-2001), and 1.1-fold (95% CI, 1.0-1.2) over the past 5 years (1997-2001). The magnitudes of these increases were highest among women ages > or = 50 years. Furthermore, over the past 10- and 5-year periods, rates of noncomedo DCIS have generally increased across all age groups, whereas rates of comedo DCIS held constant or decreased. LCIS incidence rates increased 2.6-fold (95% CI, 2.3-2.9) from 1980 to 2001, 1.3-fold (95% CI, 1.2-1.5) over the past 10 years, and 1.1-fold (95% CI, 1.0-1.3) over the past 5 years. Similar to invasive lobular carcinoma, but unlike invasive ductal carcinoma, incidence rates of both DCIS and LCIS continue to increase in the United States primarily among older women. These trends present important public health and clinical challenges.