Pure Florid and Pleomorphic Lobular Carcinoma in Situ of the Breast: Towards an Increasingly Uniform Management

Study Overview
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Brief Summary
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The goal of this retrospective multicenter observational study is to understand and evaluate the diagnostic and therapeutic management of pure forms of Florid Lobular Carcinoma In Situ (FLCIS) and Pleomorphic Lobular Carcinoma In Situ (PLCIS) of the breast. It addresses the significant challenges and controversies surrounding their clinical management, due to a lack of consensus or approved international guidelines. The main questions this study aims to answer are: How is the diagnostic process for pure FLCIS and PLCIS currently managed? What are the primary therapeutic approaches for these specific breast conditions? How are positive and close surgical excision margins handled? Is adjuvant treatment, such as hormone therapy and radiotherapy, necessary? What factors are associated with recurrences? What are the rates of recurrences and/or upgrade to invasive carcinoma? Participants will retrospectively collect all cases of pure FLCIS and PLCIS, reporting detailed data about their diagnostic and therapeutic management, as well as clinical and survival outcomes. Methodology: This international multicenter retrospective study will collect cases involving the pure forms of FLCIS and PLCIS of the breast. The study aims to provide insights into the current diagnostic and therapeutic approaches, along with the identification of opportunities to enhance clinical management, ultimately providing evidence-based recommendations and addressing the current lack of scientific literature regarding their treatment.

Detailed Description
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Classical lobular carcinoma in situ (CLCIS) of the breast is considered a non-obligate precursor of invasive carcinoma. Histologically, it is categorized as a lesion with uncertain malignancy potential, and clinical management often parallels that of benign neoplastic conditions. In contrast, its two variants, florid LCIS (FLCIS) and pleomorphic LCIS (PLCIS), have distinct morphological and genetic characteristics and a higher probability of being obligatory precursors to invasive carcinoma. PLCIS shows marked cellular-nuclear pleomorphism, resembling high-grade ductal carcinoma in situ (often initially misdiagnosed as such). FLCIS, on the other hand, displays a complete architectural subversion of lobular structure due to the increased rate of cell replication. Both variants may show foci of comedonecrosis, a distinctive but not specific diagnostic feature. A significant difference from CLCIS is their breast distribution; CLCIS tends to be multifocal, while the two variants typically present as unifocal. Genetically, the two variants differ from CLCIS, with higher genetic instability, and increased alterations in genes coding for tumor suppressors and proteins involved in cell growth regulation and replication. Immunohistochemically, both FLCIS and PLCIS regularly express estrogen and progesterone receptors, and they may present higher HER2 (Human Epidermal growth factor Receptor 2 - ERBB2 gene) over-expression compared to CLCIS. Many controversies persist in the clinical management of these variants, largely due to their rarity in pure, isolated forms. Often, they are associated with an invasive carcinoma, which becomes the primary therapeutic focus, according to well established treatment protocols. Dedicated studies, both prospective and retrospective, are completely lacking in the literature, especially for pure FLCIS. Consequently, there is no consensus or approved international guidelines for accurate diagnostic-therapeutic strategies. Even the histological categorization of biopsy tests still remains a subject of debate. Presently, there is unanimous consensus on the indication for surgical excision of these lesions to improve histological definition and exclude the presence of an invasive neoplastic focus. However, there is no consensus on the need of surgical margins cavity shaving and the management of resection margins when they are proved to be close or involved at the final specimen pathological report. Furthermore, there is a lack of evidence-based recommendations for adjuvant therapies like radiotherapy or endocrine therapy. Some scientific international associations, such as ESMO (European Society of Medical Oncology), suggest a similar approach to pleomorphic variants as for ductal carcinoma in situ due to their morphological similarity; yet, in the absence of robust evidence, this stance does not definitively support the benefit of adjuvant therapeutic strategies and poses a relative risk of overtreatment. To address these challenges, the investigators propose international multicenter retrospective collection of cases involving the pure forms of FLCIS and PLCIS. Our goal is to comprehensively analyze the diagnostic and therapeutic management of this specific patient group and, notably, to fill the gap in the scientific literature regarding their treatment.

Official Title
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Pure Florid and Pleomorphic Lobular Carcinoma in Situ of the Breast: Towards an Increasingly Uniform Management. A Multicenter Observational Retrospective Study.

Conditions
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Pleomorphic Lobular Breast Carcinoma in Situ, Breast Florid Lobular Carcinoma in Situ

Intervention / Treatment
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* Procedure: Surgical wide local excision
* Procedure: Cavity shaving
* Procedure: Excision margin surgical clearance
* Radiation: Adjuvant Radiotherapy
* Biological: Adjuvant Hormone Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of PLCIS and/or FLCIS of the breast on both core-biopsy and/or on final specimen histology; Aged 18 years or older. Exclusion Criteria: Histologic diagnosis of CLCIS; Histologic diagnosis of LCIS (any type) associated with invasive carcinoma

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Pleomorphic Lobular Carcinoma in Situ (PLCIS) of the breast<br>Patients with diagnosis of pure pleomorphic lobular carcinoma in situ of the breast | Procedure: Surgical wide local excision<br>* Surgical excision of breast carcinoma<br>Procedure: Cavity shaving<br>* Cavity shaving of resection margins to guarantee oncological safety<br>Procedure: Excision margin surgical clearance<br>* Surgical clearance of involved and/or closed excision margins<br>Radiation: Adjuvant Radiotherapy<br>* Adjuvant radiotherapy<br>Biological: Adjuvant Hormone Therapy<br>* Adjuvant hormone therapy<br>|
| Florid Lobular Carcinoma in Situ (FLCIS) of the breast<br>Patients with diagnosis of pure florid lobular carcinoma in situ of the breast | Procedure: Surgical wide local excision<br>* Surgical excision of breast carcinoma<br>Procedure: Cavity shaving<br>* Cavity shaving of resection margins to guarantee oncological safety<br>Procedure: Excision margin surgical clearance<br>* Surgical clearance of involved and/or closed excision margins<br>Radiation: Adjuvant Radiotherapy<br>* Adjuvant radiotherapy<br>Biological: Adjuvant Hormone Therapy<br>* Adjuvant hormone therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence rate | Recurrence rate (both invasive and LCIS, any type) | From date of surgery until the date of first documented recurrence, assessed up to 120 months | 
| Upgrade rate to invasive carcinoma | Upgrade rate from PLCIS and/or FLCIS to invasive carcinoma from diagnostic core-biopsy to final specimen histology | From date of diagnostic core biopsy until the date of final pathology report after surgery, assessed up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | From date of surgery until the date of last follow-up or date of death from any cause, whichever came first, assessed up to 120 months | 
| Disease-free survival (DFS) |  | From date of surgery until the date of first recurrence, whenever occurred, assessed up to 120 months | 
| Rate of re-operation and/or radiotherapy boost and/or clinical follow-up after close or involved resection margins being reported | Management of involved and/or closed surgical resection margins | From date of surgery until the date of surgical margins management completion (any potential clinical follow-up included), assessed up to 72 months | 
| Postoperative complications | Incidence and management of post-operative complications | From date of surgery until any post-operative complications are resolved, assessed up to 3 months | 
| Rate of adjuvant therapies utilization | Adjuvant therapies and associated side effects | From date of surgery until the date of adjuvant therapies completion, assessed up to 120 months |