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Clinical validation on role of cancer diagnostic probe in detecting the involved cavity margins missed in permanent pathology of tumor side in breast cancer surgery

Diagnostic Pathology volume 19, Article number: 148 (2024) Cite this article

Abstract

Cancer diagnostic probe (CDP) as a newly entered tool in real-time breast cavity margin evaluation showed great improvement in smart margin shaving intra-operatively. This system increased the rate of involved margin detection to 30% with respect to frozen section. In this study for the first time we showed the independent role of CDP in finding the involved cavity side margins which were not diagnosed by permananet pathology of their tumor side interface. Among 147 detected margins by CDP, 23 lesions with invasive component and ductal carcinoma in-situ/ductal cancerization weren’t reported as involved margins in permanent pathology of tumor side. Our gold standard was the histology of cavity margin specimen had been scored as involved lesion by CDP. It seems that even when the permanent pathology of surgical margins is used for final declaration, role of CDP is irreplaceable. This distinguished achievement has been obtained intra-operatively in real-time by CDP while involved report in permanent pathology of tumor margins induce re-surgery for the patient.

Introduction

Breast cancer (BC) is the most prevalent malignant solid tumor among women worldwide, and Breast Conserving Surgery (BCS) has been proven as the best surgery method for early-stage BC patients in clinical studies [1, 2]. Remained positive margins is still a moot point with drastic impact on risk of cancer recurrence. Residue of tumor cells in cavity side may induce dangerous challenge as they are in interaction with accumulated cytokines (in surgical bed fluid). Most of these cytokines such as TGF, TNF, IL6 and IL1 are cancer supportive agents [3]. Therefore, it is imperative to develop effective strategies to minimize involved margins and ensure optimal results for patients [4, 5]. A recent meta-analysis study demonstrated a correlation between local recurrence before 5 years and mortality at 15 years [6]. Following the excision of breast cancer mass, positive margins are associated with an increase of 2-fold in the likelihood of ipsilateral breast tumor regional recurrence (IBTR), which neither radiotherapy nor systemic chemotherapy and endocrine therapy can eliminate this risk [7, 8].

Frozen section, as the most common method, have been applied intra-operatively to address margin involvement in tumor side [9, 10]. up to 30% of the margins may be remained positive despite utilizing conventional intra-operative methods [8, 11,12,13]. In addition, frozen section is a time-consuming and costly process, which has 20–70% false negative due to the technical limitations such as incomplete fixation of pathology samples [14]. On the other hand the main weakness of frozen section is evaluation of neoadjuvant cases [15]. post chemo/radiotherapeutic tissue shrinkage and fibrosis are the main limitations to investigate the pathological diagnosis of the margins by frozen section [16, 17]. Another concern which has been raised from 2010, was the results of many trials which showed between 20–60% discripancies between permanent pathological states of tumor side and cavity side margins in breast cancer patients [18]. Satellite lesions escape from the primary tumor (with non homogenous shape) may be the main hidden factor behind such descripancies [19]. Blind cavity side margins shaving has been rolled out because of adverse effects on cosmetic outcome due to extensive resection of normal tissues [20]. Hence, smart cavity side shaving has become a main concern for the scientists in recent years.

Bioelectronic science has emerged as a novel strategy in the cancer research field, and analysis of characteristic and bioelectronic functions of cancerous and non-cancerous cells and tissues, which lead to numerous achievements in cavity side smart shaving and developing a new broad field, namely Electrotechnical Onco-surgery [21,22,23]. Regarding this, several novel technologies have been reported such as Margin Probe (radio frequency spectroscopy), MassPen (protein spectroscopy of cavity side margin), confocal laser endomicroscopy (CLE) and etc. to enhance the efficacy of BCS outcomes and restrict the recurrence of breast tumors due to the remaining the tumoral cells residue in cavity margins [24,25,26,27]. Despite their promising potential, these systems are still in the development phase and require extensive clinical trials to validate their effectiveness.

A recently developed technique, the Cancer diagnostic probe (CDP) [28], has been known as another complementary electrical method, which shed new lights in real-time diagnosing the presence of pre-cancerous and cancerous cells in cavity margins of breast tumors via the assistance of electrical probing on biochemical metabolism of the live cells in the margins. CDP determines the released ROS molecules, through glycolysis metabolism and reverse Warburg effect pathways in cancer cells [22, 29,30,31]. A recent clinical trial (On 188 BC patients, candidate for BCS), illustrated that CDP could enhance the accuracy of diagnosis of margins involvement from 88 to 97% [28]. Moreover, in another recent study, it has been assessed that the CDP sensitivity in patients who underwent neoadjuvant chemotherapy, is 91% [32]. it seems that CDP can cover the limitations of post therapeutic tissue distortion and shrinkage, which could potentially affect the quality of frozen sections during evaluation [33, 34]. This highlights the imapct of CDP as an innovative intraoperative techniques to effectively evaluate cavity side margins.

In this new research, we aimed to evaluate the accuracy of CDP scoring in detecting the cavity side positive margins in comparison with permanent pathological results of the tumor side based on histopathology of resected cavity side specimen as gold standard, in 91 adjuvant and neoadjuvant BCS cases. Results of this study better highlights the role of CDP in smart cavity side shaving and covering the inavoidable missed margins without any trace in permanent pathology of reciplocal tumor side.

Methods

Study design and participants

All patients diagnosed with breast cancer, which were candidates for breast conserving surgery between 5 May 2022 to 15 May 2023 registered in the study. In patients with various histologic subtypes of breast tumors, who underwent first-line BCS, the cavity side margin would be checked by CDP (A clinically approved surgical tool during breast cancer surgery in Iran (IMED No: 23212882) with granted USA patents [21, 22, 28, 32, 35,36,37,38].

The patient’s gender, age and surgical history, and adjuvant or neoadjuvant chemotherapy were not effective parameters for the patient’s recruitment. Regarding CDP, as an approved complementary tool for breast conserving surgery, we designed this study to evaluate the accuracy rate of CDP in detecting the involved margins during BCS by comparing the positive CDP scores with the permanent pathology of cavity margins. From a total of 237 patients who had appropriate presurgical radiological and pathological evaluation results for using CDP, 146 patients who had clear margins during surgery based on CDP scores, were excluded. This device is clinically approved in Iran; we don’t have permission to excise CDP negative score margins for pathological evaluations.

All the patients were informed about the process and signed the consent before the surgery. The trial designation was part of a registered trial in IRCT (registration ID:IRCT20190904044697N1, IRCT20190904044697N3) with Ethical Certificate No: IR.TUMS.VCR.REC.1397.355. The patient’s information confidentiality was upheld.

The CDP device and its disposable sensor were designed and manufactured by the Funder Company Nano Hesgar Sazan Salamat Arya under the scientific guidance of the Cancer Electronics Research Center at the University of Tehran. The Khatamolanbia and Shohada Tajrish hospitals, in addition, the breast cancer clinics of Motamed Cancer Institute were the locations of the surgeries. Pathological assessments were also done by the pathology labs of the mentioned centers as well as the Sepas pathobiology laboratory, all of them located in Tehran, Iran.

CDP operating procedure in the study

In this study, the internal margins (IMs) of the tumor cavity including medial, lateral, inferior and superior. would be checked by CDP, in which each of the margins utilized one specific disposable sensor. Just positively scored lesions must be removed, labeled, and sent for assessment by permanent section pathology to examine the validity of CDP scores. Furthermore, the pathology results of CDP samples were compared with the permanent diagnosis of cavity side margins and also tumor side margins.

The samples with a positive score of CDP were categorized into 4 groups; carcinoma lesions such as invasive ductal carcinoma (IDC), ductal carcinoma in situ/ductal cancerization (DCIS/DC), and invasive lobular carcinoma (ILC), high-risk lesions such as lobular carcinoma in situ (LCIS), atypical ductal hyperplasia (ADH) and atypical papillary lesion, low-risk lesions such as atypical lobular hyperplasia (ALH), atypical apocrine metaplasia, intraductal papilloma and other lesions such as sclerosing adenosis, flat epithelial atypia (FEA), and lymph vascular invasion focus, and the last group was benign lesions and labeled as No-risk lesions which were regarded as the false positive of CDP such as fibrocystic cell change (FCC), apocrine metaplasia, columnar cell change (CCC) and columnar cell hyperplasia (CCH).

We assessed a total of 147 lesions in IMs from 91 cases by CDP. The number of samples from each margin did not have any limitation and completely depended on the surgeon’s decision. Our gold standard was permanent pathology for cavity side margins.

Statistical analysis

The results of the study were analyzed by the SPSS software (ver.26). In addition, the positive-predictable value of the study was calculated with SPSS. A p-value lower than 0.05 was considered statistically significant.

Results

To commence with, all cases with positively scored CDP in at least one of their margins were followed-up by doing H&E on the specimen and comparing the result with permanent pathological score of the same margin tumor side. In this regard, the tumor side and cavity side margins were taken into account to compare the tissue.

In this study, 147 CDP positive score margins were excised from 91 patients to evaluate the accuracy of CDP scoring. 28 IDC lesions were detected in the cavity side by CDP intraoperatively, while only 17 of them were detected in the permanent pathology of the same tumor side. In fact, 11 IDC legions would be remained inside the patient’s body, which was not detected even by the permanent pathology of the tumor side margins. This diagnosis is completely independent of frozen pathology; because of the free margin declartion of permanent pathology, even the patient does not have the chance to be re-operated and the role of CDP has not any alternative option here. It is noteworthy that 21 DCISs were detected by CDP in cavity side, while permanent pathology of tumor side pathology had detected only 9 of these 21 involved margins.

Out of 10 ILCs detected by CDP, 6 of them have been declared in permanent tumor-side pathology. In fact, 24 out of 147 margins were re-surgry required cavity side positive lesions (confirmed by H&E) which just were detected by CDP and not by permanent pathology of tumor side margins. To the best of our knowledge the surgeon must perform a re-surgery for the remaining IDC, ILC and DCIS.

A complete list of tumor side margin permanent pathology missed involved margin were provided in Table 1. 32 high-risk lesion included ADH & LCIS were detected by CDP intra operatively which only 2 (9.5%) and 1 (9.1%) of those lesions were detected by permanent pathology of tumor side margin, respectively. In the case of low-risk lesions, 18 ALH and 12 AAM were detected by CDP. Permanent pathology of tumor side declared 1/30 of these lesions. 7 Intraductal papilloma with vascular core, 1 FEA and 1 lymphovascular invasion histologies were just detected by CDP as additive supports of this system for better margin clearance (Table 2).

Table 1 Patient’s carcinoma lesion missed in tumor side permenant pathology and detected by CDP
Full size table
Table 2 Margin detection accuracy by CDP & permenant pathology
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It depicted that 54% of re-surgery required lesions were just detected by CDP in cavity side without any trace in tumor side margins (Fig. 1).

Fig. 1
figure 1

Schematic of the cancer diagnosis probe (CDP) in BCS

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In Fig. 2, it has been elucidated three patients with negative tumor side margin & positive cavity side margin. It depicted that with attention to the lumpectomy margin (LM) histology, the residual tumor cells were camouflaged from the pathologist sight. Instead, cavity margin (CM) histology has confirmed the residual tumor existence which smartly categorized as positive by CDP. About 402 margins were scored as negative by both CDP and permanent pathology of tumor side.

Fig. 2
figure 2

H&E histology image of tumor side margins of patients reported that the lumpectomy margins were free of tumor. The permanent pathology of the excised cavity side margins due to CDP-positive scoring confirmed the CDP diagnosis

Full size image

Categorization of the result according to the age, showed that about 74% of patients under 50 years old depicted as negative samples by tumor side margin histology, while these patients categorized as positive patients by cavity side CDP confirmed by histology. This shows the impact of CDP in surviving younger patients (Table 3).

Table 3 CDP positive result confirmed by tumor margin pathology
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Table 4 summarizes the results of Spearman’s correlation between some selected variables. It is seen, the correlation coefficient between tumor size and Ki-67 with permanent tumor pathology is equal to 0.171 and 0.238, respectively, and both of them are significant with P-values equal to 0.027, 0.003. But none of the variables have significant association to permanent cavity side pathology.

Table 4 Spearman’s Correlation Matrix of selected variables
Full size table

Discussion

Involvement of the surgical margin is the most significant factor in delineating the risk of local breast tumor recurrence [39,40,41]. Recently, cavity shaving sampling was employed to examine residual cancer in the remnant cavity or tumor bed by pathological assessment [42, 43].

Given past researches, it has been determined that the 5-year risk of local recurrence in patients with final negative margins is 2–7%; however, the risk is up to 22% in patients with positive margins [44]. Lumpectomy margin (LM) and cavity margin (CM) are two primary approaches that are applied for surgical margin assessment. In a previous study in 2005, Cao et al. reported that 42.9% and 81.8% of patients were defined as CM and LM positive, respectively, which demonstrated that regarding cavity margin as a golden standard, many positive LMs are false-positive, which depicts discrepancy between CM and LM sampling [45]. It is uncertain whether the increased resection of LMs may have substantial survival benefits. These discrepancies better highlight the requirement for independent cavity side margin evaluation tools and technologies that can score the CM before excision and send it for pathological evaluation [45,46,47].

Based on the importance of the cavity margins, in this clinical research, we have assessed the impact rate of CDP in comparison with permanent pathology of tumor side, as a novel device, in reducing the probability of re-surgery after BCS due to the involved margins and also the recurrence of the tumor because of residual cancerous cells in cavity margins.

This study showed that CDP plays a unique role in detecting positive cavity side margins with no trace of tumor residues in tumor side margin even in permanent pathological results. Our results showed (131/147 = 89%) PPV of CDP detection of cavity side margins involvement during BCS of breast cancer cases, which was approved the reputable role of CDP in smart cavity shaving. In this study, about 54% of involved margins by re-surgery reuired carcinoma lesions from 24 patients were diagnosed in cavity side with the assistance of CDP while they weren’t found in similar tumor side margins due to declaration of permanent pathology. this shows the use of CDP has surviving role in prevention from the rate of recurrence independent from conventional permanent pathology procedure of BCS cases. In other fact among 59 CDP scored involved cavity side margins by invasive carcinoma, in-situ ductal carcinoma/ductal cancerization and invasive lobular carcinoma, permanent pathology of tumor side margin just declared about half of them as involved margins (Table 2).

Neoadjuvant chemotherapy (NAC) treatment also might bring shrinkage in a mosaic or honeycomb histological pattern which makes the diagnosis of invasive component more hard for the pathologist [48]. As a result, NAC led to more residual carcinoma in the cavity than resection in non-NAC-treated patients. According to Chen et al. study, it has shown that the cavity margin status was significantly correlated with locoregional recurrence in NAC-treated patients. Our promising results, lend credence to this idea that CDP could enhance the rate of involved margin detection in both adjuvant and neoadjuvant patients.

Taking in to consideration of worst prognosis of patients with DCIS margin involvement in comparison with IDC ones [49], and multifocal distribution of DCIS in many IDC cases, it is vital to detect the DCIS involved margins during the lumpectomy [50]. More than two folds increase in the rate of detected DCIS by the assistance of CDP (Table 2), indicated the requirement to new technologies for supporting BCS with lowest recurrence.

Another additive supports of CDP is real-time detection of high-risk margins. these margins (such as LCIS and ADH) may not need to be re-excised in margins after permanent pathology declaration but are very supportive in favor of recurrence prevention if could be found intra-operatively. for example the risk of ADH to be turned to cancer lesions is 3 times higher than UDH [51, 52]. Moreover, if we found ADH in biopsy sample of a patient with solid mass westrongly are recommended to do mass resection for the case [53]. Surgical resection or close follow up by MRI and mammography are the recommendation for LCIS depend on the case [54]. On the other hand, some other types of reports indiated that, Proliferative diseases with atypia, such as ADH and ALH, are characterized by excessive growth of atypical cells in the ducts and lobules of the breast and significantly enhance the risk of breast cancer by 4–5 times; also, LCIS increases the risk of invasive cancer of both mammary glands by 8–10 times [55]. As the result, intraoperative excision of Atypia and LCIS is recommended. The role of CDP in real-time detecting of these lesions is unrivaled. Important proliferative diseases without atypia, including sclerosing adenosis and intraductal papilloma with vascular core can increase the risk of breast cancer by 1.5–2 times [56, 57]. CDP also helped the surgeon in detecting these abnormalities (Table 2).

In this study, 16 out of 153 positively scored lesions by CDP were not included any histological abnormalities (assumed as false positive lesions). This must be considered in future to elaborate hidden factors which resulted in such false scores. However, 147 true positive among 153 positive scores, while 24 of these lesions were re-surgry required and wre not diagnosed in permanent pathology of the reciplocal tumor side, revealed the promising presence of CDP during BC surgery. All in all, smart cavity shaving by CDP, has been proven to significantly decrease the likelihood of requiring a second surgery and minimize the risk of local recurrences. While it may have some impact on the cosmetic outcome and operation duration, the benefits of this technique far outweigh any potential drawbacks.

Conclusion

In summary, by evaluating more than 500 margins from 91 patients, CDP showed the role of an independent tool during BCS which not only facilitates the probability of smart cavity margin shaving but also reduces the rate of involved margins which may be even missed in permanent pathology of tumor side. This may make a considerable improvement in perfect tumor resection and minimize the recurrence rate. So, the potentials of impressive effects on local recurrence rate reduction of breast carcinoma, enhancing the overall survival of breast cancer patients through smart cavity side shaving and also assisting the surgeon in the cosmetic aspect of breast surgery by reducing the mass dissection from margins could be assumed for CDP. limitations such as reason of false positives, long term follow-up of the cases checked by CDP and further case samples must be investigated in future investigations.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The research has been done under the funding of NANO HESGARSAZAN SALAMAT ARYA Company. Some granted and published USA Patents have relations to this work which all are under the ownership of the Company (US 11,179,076 B2, US 10,786,188 B1, US 11,179,077 B2, US 11,181,499 B2).

Author information

Author notes

  1. Fereshteh Abbasvandi and Zohreh Sadat Miripour contributed equally to this work.

Authors and Affiliations

  1. Nano Bioelectronics Devices Lab, Cancer Electronics Research Group, School of Electrical and Computer Engineering, Faculty of Engineering, University of Tehran, 4563-11155, Tehran, Iran

    Fereshteh Abbasvandi, Zohreh Sadat Miripour, Mahdis Bayat, Seyed Mohamad Sadegh Mousavi-Kiasary, Fatemeh Shojaeian, Faeze Aghaei, Fahimeh Jahanbakhshi, Niloofar Abbasvandi, Mohammad Hadizadeh, Parisa Hosseinpoor & Mohammad Abdolahad

  2. ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, 1517964311, Tehran, Iran

    Fereshteh Abbasvandi, Niloofar Abbasvandi, Parisa Hosseinpoor, Mohammad Parniani & Zeinab Nourinjad

  3. Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fereshteh Abbasvandi, Mahdis Bayat, Samira Shayanfar, Fatemeh Shojaeian, Maryam Omranihashemi, Atieh Akbari, Morteza Yousefi, Naiemeh Shahrabi Farahani & Mohammad Esmaeil Akbari

  4. SEPAS Pathology Laboratory, Tehran, Iran

    Parisa Hosseinpoor

  5. Cancer Institute, Imam-Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Abdolahad

Authors
  1. Fereshteh Abbasvandi
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  2. Zohreh Sadat Miripour
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  3. Mahdis Bayat
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  4. Seyed Mohamad Sadegh Mousavi-Kiasary
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  5. Samira Shayanfar
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  6. Fatemeh Shojaeian
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  7. Faeze Aghaei
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  8. Fahimeh Jahanbakhshi
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  9. Niloofar Abbasvandi
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  10. Maryam Omranihashemi
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  11. Atieh Akbari
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  12. Morteza Yousefi
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  13. Mohammad Hadizadeh
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  14. Naiemeh Shahrabi Farahani
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  15. Parisa Hosseinpoor
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  16. Mohammad Parniani
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  17. Zeinab Nourinjad
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  18. Mohammad Abdolahad
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  19. Mohammad Esmaeil Akbari
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Contributions

Fereshteh Abbasvandi and do most of the surgeries in the manner as was designed for the research by Mohammad Abdolahad and Mohammad Esmaeil Akbari. Fereshteh Abbasvandi also helped in performing the experiments. Zohreh Sadat Miripour manufactured the needle sensors for clinical studies, performed the experiments, sorting the results and edited the manuscript. Parisa Hoseinpour and Mohammad Parniani did the pathological experiments and declared diagnostics. Fayezeh Aghaee assisted in the experiments. Mohammad Esmaeil Akbari supervised the surgical procedure, managed the clinical samples and helped in designation of the research. Mohammad Abdolahad designed and coordinated the research, supervised the use of CDP and designed its guideline for margin evaluations during the surgeries, analyzed the data and wrote the manuscript. Seyed Mohamad Sadegh Mousavi-Kiasari and Mahdis Bayat wrote and edit the manuscript, analyzed the data. All authors and participants reviewed the paper and approved the final manuscript.

Corresponding author

Correspondence to Mohammad Abdolahad.

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The authors declare no competing interests.

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Abbasvandi, F., Miripour, Z.S., Bayat, M. et al. Clinical validation on role of cancer diagnostic probe in detecting the involved cavity margins missed in permanent pathology of tumor side in breast cancer surgery. Diagn Pathol 19, 148 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13000-024-01574-2

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13000-024-01574-2

Diagnostic Pathology

ISSN: 1746-1596

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