Category Archives: Breast Surgery

St Gallen

Guest blog: Invasive lobular cancer of the breast remains a surgical challenge

U Narbe, P -O Bendahl, M Fernö, C Ingvar, L Dihge, L Rydén

Invasive lobular breast cancer is the second most common histological subtype and constitutes around 10-15% of all breast cancer. It is recognized by a peculiar diffuse growth pattern and disseminated spread of cancer cells contributing to diagnostic delay and difficulties in detecting the primary tumors by mammography and nodal metastasis by axillary ultrasound. Consequently, although invasive lobular breast cancer mainly displays a favorable luminal A molecular subtype, it is often diagnosed at a higher stage than invasive cancer of no special type. Despite these characteristics, histopathological subtype is not accounted for in Clinical Guidelines, in contrast to the molecular subtypes. In the BJS publication “The St. Gallen 2019 Guidelines understage the Axilla in Lobular Breast Cancer: a Population-Based Study” by Ulrik Narbe and co-authors, we have elaborated on the consequences for patients with invasive lobular cancers if completion axillary clearance would be omitted in patients with 1-2 nodal metastases.

For the breast surgeon, lobular cancer poses a challenge to surgery of the breast and to the axilla. Large tumor size and diffuse infiltrating margins are associated with an increased risk of positive margins after breast conserving surgery and in breast centers where MRI is available, complementary imaging is recommended ahead of primary surgery. Still a larger proportion of patients (66%) with lobular cancer undergo a mastectomy compared to other histological subtypes (43%) according to our registry study, supporting previous publications. So the dogma of de-escalating breast surgery from mastectomy to partial mastectomy in lobular cancer is challenging, keeping in mind that positive resection margins is a mandatory quality criteria in most centers pushing the choice of initial surgery towards upfront mastectomy.

Axillary surgery is moving towards de-escalation of surgical interventions for patients with 1-2 sentinel node metastases after the results of the Z0011 trial have been implemented worldwide and clearly supports that omission of completion axillary dissection is non-inferior provided the inclusion criteria for the trial is fulfilled. The Z0011 criteria for omission of completion axillary dissection is restricted to patients undergoing breast-conserving surgery, and is thus not applicable for lobular cancers operated by mastectomy. The St. Gallen 2019 guidelines extended the indication for abstaining completion axillary dissection to all patients of any tumor size irrespective of type of breast surgery. In addition, the guidelines recommended that the decision on adjuvant chemotherapy for luminal A-like tumors should include nodal staging and patients with 4 or more nodal metastasis (nodal stage II) were recommended adjuvant chemotherapy. For these patients there is hitherto no data on the role of genomic tests for risk stratification until the results of OPTIMA trial are presented. In this paper, we present data from the National Swedish Quality Registry with prospectively collected data retrieved from the period when a completion axillary clearance for patients with sentinel node metastases was recommended. We found a strong association between invasive lobular breast cancer and nodal stage II disease independent of other determinants such as tumour size.

Moreover, we validated the predominance of luminal A-like subtype in lobular cancer and among those the risk of nodal stage II disease was higher than for the corresponding group of invasive cancers of no specific type (19% compared with 3%). Importantly, patients with lobular cancer retained a predominance (60%) for luminal A-like subtype in the nodal stage II subgroup. In contrast, patients with nodal stage II disease and non-lobular cancers had a lower fraction of luminal A-like tumors (23%) compared with patients with a lower nodal status implicating that for most patients with nodal stage II and non-lobular cancers, the molecular subtype would guide adjuvant treatment decisions rather than nodal stage.

The biological mechanism behind the prevalence of a higher nodal burden in lobular cancer is today speculative. Hormone responsive tumors (ER positive) of all histological subtypes are characterized by a slightly increased risk of nodal metastasis, probably linked to a lower immunologic reaction in the primary tumor facilitating lymphatic spread. Moreover, the cornerstone of lobular cancers – loss of E-cadherin – facilitates detachment of cancer cells which might be of importance for metastatic spread. In the present study, we clearly present data on the independent association of lobular cancer with nodal spread underscoring that this association is not solely explained by a hormone responsive phenotype or a larger tumor size. 

This study highlights that lobular cancer is associated with a higher nodal burden than non-lobular cancer and omission of completion axillary clearance in sentinel node positive patients could thus understage the axilla. The consequence of this is that some 19% of all patients with invasive lobular cancer and luminal A-like subtype would be dismissed from recommendation of adjuvant chemotherapy. Today, the updated St. Gallen 2021 guidelines states that completion axillary clearance is recommended for patients where staging is necessary for adjuvant treatment recommendations and would largely correspond to lobular cancers with a luminal A-like molecular subtype. The challenge of de-escalating axillary surgery in lobular cancer is thus unresolved.

The consequence of understaging of the axilla in lobular cancer in terms of clinical outcome is, however, unclear while the responsiveness of chemotherapy in lobular cancer is considered poorer than the corresponding effect in non-lobular cancer. Despite the findings from neoadjuvant trials, lobular cancer is included in general recommendations on adjuvant chemo-endocrine therapy due to the lack of data specific for lobular cancer. The ongoing randomized trial SENOMAC holds some promise to shed light on the outcome for lobular cancers in the experimental arm in which adjuvant recommendations are not based on complete axillary staging. A strong recommendation for the future is to always include data on histological subtype in clinical trials to be able to stratify the cohort in future analysis. The small but aggressive molecular subtypes, triple-negative and HER2-positive, represent subgroups as small as the lobular histological subtype and today clin.trials.gov is overloaded by adjuvant and neoadjuvant treatment protocols specific for these molecular subtypes. So isn´t it time to reconsider protocols on invasive lobular breast cancer with luminal A-like subtypes? The phenotype indicates cancers at low-risk of distant spread which is balanced by a higher stage at diagnosis associated with a substantial risk of recurrence and death after long-term follow-up. The role of neoadjuvant endocrine therapy in this subgroup is far from settled and might open up for de-escalating surgery of the breast and axilla and shed light on the fascinating biology of lobular breast cancer.

Increased level of fluorescence intensity of breast cancer and normal mammary gland tissue a Haematoxylin and eosin-stained sections of normal and cancer tissue. The area outlined in green indicates the breast cancer. b Top images are fluorescence intensity images of γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) (green) at each time point overlaid on white light images. The fluorescence increase (FI) was obtained by subtracting the baseline fluorescence from the fluorescence at each time point. FIs are represented by the pseudocolour scale on the right side of the image.

Guest blog: a novel fluorescence technique for detecting breast cancer

Author: Hiroki Ueo, Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Ueo Breast Cancer Hospital, Oita, Japan

Breast cancer is the most common cancer in women, and its incidence continues to increase worldwide. From the patient’s perspective, breast conserving surgery (BCS) with radiation achieves a balance between a satisfactory cosmetic result and a low recurrence rate. Although it has been established as a routine surgery, surgeons need to be careful about positive surgical margins. Remnant cancer cells in the preserved tissue increase the risk of recurrence. Therefore, a positive margin on postoperative pathology warrants additional surgery. In these cases, the additional treatment harbours unexpected outcomes, including physical, mental, cosmetic, and economic burden on the patients. 

To avoid the additional operation, pathological evaluation using an intraoperative frozen section is conducted. It is the most reliable method to prevent misdiagnosis and to achieve clear surgical margins. However, this conventional method is time consuming and costly. Moreover, it is dependent on the skill and experience of the pathologists and personnel, and it requires space for preparation of the frozen sections. Therefore, only a limited number of samples are examined to save time and resources. An alternative, rapid, and reliable technique to detect cancer in surgical margins enables simultaneous testing, leading to a reduced false negative rate of local recurrence incidence. In addition, pathologists can focus on the definitive diagnosis using permanent paraffin sections because it is difficult to make a diagnosis based on intraoperative frozen sections without pathological architecture. Pathologists only need to make an intraoperative diagnosis when the specimen cannot be evaluated via the fluorescence procedure. Thus, it is important to enhance the rapid fluorescent detection of breast cancer during surgery. To address these diagnostic issues, Prof. Urano invented chemical reagents (gamma-glutamyl hydroxymethyl rhodamine green [gGlu-HMRG]) that quickly fluoresce by reacting with an enzyme (gamma-glutamyl transferase [GGT]), overexpressed in cancerous tissues. It exhibits strong fluorescence a few minutes after reacting with GGT in vitro. A gGlu-HMRG solution is applied to the surgical margins to recognize cancer cells as green fluorescence intraoperatively. A previous study in 2015 documented the ability of this reagent to mark cancerous tissues in surgical breast tissues. Furthermore, this reagent did not interfere with the pathological examination, while the frozen section analysis tissues were difficult to reuse as formalin-fixed and paraffin-embedded permanent pathological specimens. 

The clinical utility of this technique was examined. The results were published in the British Journal of Surgery. Since the initial report in 2015, a more feasible and reproducible sample preparation protocol has been developed. Then, a dedicated apparatus, including a built-in camera, software program, and multiple sample wells, was developed. This system automatically measured and analyzed the increase in fluorescence of multiple samples simultaneously. Then, the increase in fluorescence of gGlu-HMRG, applied to breast tissues, was measured in four different institutes. The sample tissues were examined by four pathologists independently. These pathologists diagnosed the samples without knowing the background information of the patients. The clinical utility of the current fluorescent procedure was evaluated by comparing the fluorescence data and the pathological diagnosis. 

A clear threshold to distinguish between cancerous and non-cancerous tissues was not determined due to the heterogeneity of breast cancer tissues. Instead, the negative threshold to achieve a false negative rate <2% and the positive threshold to achieve a false positive rate <2% were established. Samples in which the increase in fluorescence was below the negative threshold value were considered cancer-free margins with a false negative rate <2%. The false negative samples in our study were tissues containing non-invasive cancer. This suggested that the samples below the negative threshold can be considered free of invasive cancer. Samples in which the increase in fluorescence was above the positive threshold value were considered cancerous tissue with a false positive rate <2%.

The disease prevalence determines the performance of a diagnostic tool. The percentage of positive and negative test results among those with or without the disease are the positive and negative predictive values, respectively. These positive and negative predictive values depended on the prevalence. Therefore, to estimate the performance of this technique, the prevalence and margin positive rate in this case should be considered. The margin positive rate was expectedly lower than that of our clinical study. In our protocol, three pieces of tissue were sampled: the central portion, where the breast cancer is located; its periphery, which contains non-invasive cancer; and the distal portion, which ideally contains normal mammary tissue. Cancer was detected in 46% of the samples. Based on the actual margin assessment, the prevalence was lower than that of our study. Assuming a prevalence <30%, the negative predictive value, the ratio of true negative samples among fluorescent negative samples, was larger than 98%. This indicated that this method was useful for detecting negative margins. 

According to this multicenter study, the fluorescent diagnosis was applicable to any breast cancer subtype, regardless of its pathological findings and subtype. Moreover, the similar accuracy among several institutes confirmed that the fluorescent diagnosis was applicable to any institute, following the protocol. Compared to the intraoperative frozen section analysis, the fluorescent diagnosis was a more rapid and accessible method with a low cost. It was not dependent on the skills of pathologists, and it did not require a large amount of space.           

In conclusion, this method can facilitate the rapid assessment of negative surgical margins during BCS while reducing the testing time, cost of diagnosis, and tasks of the pathologists and staff. 

worried woman in mask looking out of the window

Guest post: Mental health and BRCA

Exploring psychological consequences for BRCA+ women in the post-Covid era

by Grace Brough1, Douglas Macmillan2, Kristjan Asgeirsson2, and Emma Wilson1
1Division of Epidemiology and Public Health, University of Nottingham
2Nottingham Breast Institute, Nottingham University Hospitals NHS Trust

Whilst the global female population has a 12.5% overall lifetime risk of developing breast cancer and a 1.3% risk of ovarian cancer (Howlader et al), the risk for those with a pathogenic BRCA1 or BRCA2 mutation is 60-70% and 10-20% respectively (van Egdom et al). BRCA1 mutation carriers have a particularly high incidence of triple-negative breast cancer (TNBC) (Greenup et al) for which treatment options are more limited and always include chemotherapy (Bianchini et alCollignon et al). 

In the NHS, asymptomatic women with at least a 10% estimated chance of having a BRCA mutation are offered testing (NICE).  Knowing you are at high risk of breast cancer and the increased likelihood of TNBC is a well-documented  cause of anxiety (Wenzel et al) and many women describe having a BRCA gene mutation as living with a ‘ticking time bomb’. Bilateral mastectomy with or without reconstruction is the only proven method of drastically decreasing risk and can improve quality of life (McCarthy et al) and decrease anxiety (Rebbeck et al) for correctly selected cases, despite its potential negative outcomes (Gahm et al). 

The strongest predictor for choosing to undergo risk reducing mastectomy is having a first or second degree relative die from breast cancer (Singh et al), a factor associated with fear, anxiety and vulnerability to this disease.  Most women choosing it have clear and long-considered reasoning and have been prepared for it through well-established pathways guided by genetic counsellors, specialised surgeons and nurses.  It is however, classified as elective surgery. As such, waiting lists for risk reducing mastectomies are impacted by other healthcare challenges and needs. 

Being on NHS waiting lists causes anxiety across all specialities (Carr et al). With an estimated 10 million people on NHS waiting lists in the post-COVID era, levels of health-related anxiety within the population are anticipated to significantly increase. For BRCA mutation carriers, the prevailing fear is that they will develop breast cancer whilst on the waiting list.  This reality is related to the length of time on the waiting list and represents potential conversion of a risk reducing scenario to one of chemotherapy and cancer surgery, often with other treatments, and all the life changing and life threatening implications of cancer diagnosis.   

In pre-COVID times, there was a 18 week target time from referral to treatment for risk reducing mastectomy (UK GOV). Due to COVID, the majority of elective surgery has been put on hold and Breast Units now anticipate at least a 2-year waiting list for non-cancer surgery, such as risk reducing mastectomies, delayed reconstructions, and revisional surgery. Prioritisation is a difficult necessity.

In addition, breast screening services ceased or were significantly curtailed as a result of COVID related restrictions, and this adds to an already complex situation for BRCA mutation carriers.  Not only may they now get breast cancer whilst on the waiting list, but they are denied the reassurance afforded by negative screening, or potentially a diagnosis may be delayed (Maringe et al). 

Combining pre-existing anxieties of being a BRCA mutation carrier, new waiting list anxieties, and wider COVID general health anxieties, the post-COVID era has the potential to see significant levels of psychological burden in this population, which could negatively impact mental health and quality of life. Providing additional psychological support is likely to be the short-term solution, though this is also resource limited. In reality the collateral impact of pandemic related consequences for healthcare in this particular group may not be realised for some time.