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Invasive lobular cancer (ILC) represents 10% to 15% of invasive breast cancers and is defined by noncohesive tumor cells arising from lobular units, most commonly driven by CDH1 mutations causing E-cadherin loss. This course reviews the unique tumor biology of ILC, which leads to subtle clinical and radiologic findings and contributes to delayed diagnosis, larger tumor size, multifocality, and atypical metastatic patterns involving the gastrointestinal tract, peritoneum, and ovaries. Participants will also gain an understanding of ILC's immunoprofiles, predominantly hormone receptor–positive with low proliferative activity, diagnostic challenges, requiring careful integration of imaging modalities and histopathology, and multimodal management approach guided by stage and biology. This activity for healthcare professionals is designed to enhance the learner's competence in identifying ILC’s distinct presentation, diagnostic strategies, applying evidence-based treatment principles, and implementing an appropriate interprofessional approach when managing this condition to support timely, patient-centered care. Objectives: Differentiate invasive lobular carcinoma from invasive ductal carcinoma using characteristic diagnostic features to guide management. Interpret imaging and histopathologic findings to accurately distinguish invasive lobular cancer from other breast cancer subtypes. Apply evidence-based treatment principles for invasive lobular cancer based on tumor staging. Collaborate with interprofessional team members to improve coordinated care and outcomes for patients diagnosed with invasive lobular cancer. Access free multiple choice questions on this topic.

Invasive lobular cancer (ILC) represents the second most common type of invasive breast cancer, accounting for 10% to 15% of cases. This malignancy arises from the lobular units and exhibits a characteristic histologic pattern of small, noncohesive cells arranged in single-file strands or dispersed within the fibrous stroma. A defining molecular feature involves mutation of the CDH1 gene in more than 90% of cases, leading to loss of E-cadherin, a protein essential for cell-to-cell adhesion.[1][2] ILC exhibits a predominantly hormone receptor (HR)-positive profile and commonly aligns with the luminal A subtype, characterized by HR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and a low mitotic index. This biologic profile correlates with reduced sensitivity to chemotherapy and a low pathologic complete response (pCR), while supporting favorable responsiveness to endocrine therapy.[3] Diffuse growth patterns contribute to subtle and less distinct clinical and radiologic findings, often delaying diagnosis. Patients frequently present at an older age with larger tumors, greater nodal involvement, and higher rates of multifocality, multicentricity, and bilaterality.[3][4] Unique tumor biology also drives metastasis to atypical sites, including the gastrointestinal tract, peritoneum, retroperitoneum, ovaries, meninges, and orbits, distinguishing ILC from invasive ductal carcinoma (IDC).[5] Despite these distinctions, core principles of breast cancer management remain consistent across histologic subtypes. Current National Comprehensive Cancer Network (NCCN) guidelines recommend similar treatment strategies for ILC and IDC, emphasizing a multimodal approach incorporating surgery, endocrine therapy, chemotherapy, and radiation.

ILC arises from milk lobules, defined by a proliferation of small noncohesive cells within the terminal duct lobular unit (TDLU). The precursor lesions, atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), are classified based on the extent of TDLU involvement, with less than 50% involvement classified as ALH and greater than 50% as LCIS.[5][6] Once cells proliferate past the lobule and invade into the surrounding breast stroma, lesions are classified as ILC. The presence of ALH confers a 4- to 5-fold increased risk of ILC, while LCIS confers an 8- to 10-fold increased risk. ILC is associated with several genetic alterations. The predominant genetic mutation is in CDH1, located on chromosome 16q22.1, resulting in loss of E-cadherin and commonly abnormal expression of β-catenin and p120-catenin.[7] ILC is the second most common neoplasia seen in CDH1 mutations after hereditary diffuse gastric cancer, with a lifetime risk of breast cancer of 39% to 52%.[8] ILC can also be associated with mutations in genes PIK3CA, FOXA1, PTEN, AKT1, and GATA3. More than 50% harbor mutations in ERBB2, ESR1, FGF, or NF1, conferring endocrine therapy resistance. Interestingly, BRCA1 mutations are less frequent in ILC than in IDC, with similar frequencies of BRCA2, TP53, and CHEK2.[1][5]

Breast cancer remains the most common cancer in women worldwide, with 1 in 8 women developing breast cancer in their lifetime.[9][WCRF. Breast Cancer Statistics. 2026] The incidence of ILC increased in the 1990s from 9.6% in 1987 to 15.6% in 1999, attributed to the widespread use of hormone replacement therapy (HRT) during this time. Interestingly, despite the reduction in HRT use in subsequent years, no significant corresponding downtrend in ILC incidence was noted.[10] According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, an estimated 316,950 new diagnoses of female breast cancer were reported in the United States in 2025, with approximately 47,500 (~15%) new cases of invasive lobular carcinoma specifically.[NIH. Cancer Stat Facts: Invasive Lobular Carcinoma. 2025] ILC more commonly presents at an older age; for example, 68% of all ILC diagnoses from 2018 to 2022 in the United States were in women older than 60, and the mean age at diagnosis is 64, versus 60 in IDC.[11][NIH. Cancer Stat Facts: Invasive Lobular Carcinoma. 2025] ILC is also more frequent in the Western world, with lower incidence in the Middle East, Africa, and Asia (~5%).[3] In the United States, White women have the highest incidence of ILC; despite this, Black women have the highest reported mortality and worst survival outcomes.[10] Most risk factors for ILC are related to increased hormone exposure, including early menarche, late menopause, number of pregnancies and live births, late age at first birth, use of hormone replacement therapy, and oral contraceptive use.[12] Other lifestyle factors include alcohol intake, with some studies citing a 10% increased risk per 10 g of ethanol consumed every day. The Western diet, characterized by a high intake of red or processed meats and refined grains and sugar, with a low intake of fruits and vegetables, is associated with a 45% higher risk of ILC compared to the Mediterranean diet (high intake of fruits, vegetables, and whole grains; low fat).[6] Obesity is associated with an increased breast cancer risk in postmenopausal women but a decreased risk in premenopausal women, with similar risks when comparing ILC to IDC.[11][12]

Most risk factors for ILC are related to increased hormone exposure, including early menarche, late menopause, number of pregnancies and live births, late age at first birth, use of hormone replacement therapy, and oral contraceptive use.[12] Other lifestyle factors include alcohol intake, with some studies citing a 10% increased risk per 10 g of ethanol consumed every day. The Western diet, characterized by a high intake of red or processed meats and refined grains and sugar, with a low intake of fruits and vegetables, is associated with a 45% higher risk of ILC compared to the Mediterranean diet (high intake of fruits, vegetables, and whole grains; low fat).[6] Obesity is associated with an increased breast cancer risk in postmenopausal women but a decreased risk in premenopausal women, with similar risks when comparing ILC to IDC.[11][12] Lobular carcinoma is thought to be more often bilateral, with some studies demonstrating bilateral cancers to be more frequently lobular on histology.[13] Older studies have shown an association of ILC with contralateral breast cancer, while newer studies show no difference in the risk of a contralateral breast cancer between IDC and ILC.[14][15] Genetic predisposition also plays a large role in ILC development, with germline mutations commonly found in CDH1 and FOXA1. Other affected genes include RUNX1, TBX3, PIK3CA, PTEN, AKT1, PALB2, ATM and ERBB2 among others.[3]

Macroscopic Findings Invasive lobular carcinomas frequently present as irregular, poorly delineated tumors that can be difficult to define macroscopically due to the diffuse growth pattern of the cellular infiltrate. The size of the ILC is also difficult to determine, although it has been reported to be slightly larger than that of IDC in some series.[8] Microscopic Findings ILC is histologically characterized by a proliferation of small cells that lack cohesion and are often dispersed individually within fibrous connective tissue or organized into single-file linear cords that invade the stroma. The infiltrating cords often present a concentric pattern around normal ducts. Usually, little host reaction to the background architecture is present. The neoplastic cells have round or notched ovoid nuclei and a thin rim of cytoplasm with an occasional intracytoplasmic lumen, often harboring a central mucoid inclusion. Additionally, little to no nuclear atypia and low proliferation activity are present, defined as low mitotic activity and low Ki67.[1] Histological Variants Several ILC variants have been described that share either the cytological or growth pattern of classic ILC, but all lack cell-to-cell cohesion, including: Solid type Pleomorphic lobular carcinoma Tubulo-lobular variant Alveolar variant Mixed type Notably, pleomorphic and solid variants are generally more aggressive than classic ILC, with higher grade and worse features at diagnosis. For instance, pleomorphic ILC often has a higher mitotic rate/Ki-67, higher nuclear grade with luminal B features, lower HR expression, and higher HER2 expression.[10] The tubulo-lobular variant may have the best prognosis of all subtypes (even more so than classic ILC) due to its low grade and generally node-negative status.[3] In addition to the variants described, several distinct morphologies, including histiocytoid and signet ring cells, were identified on pathologic evaluation.[2] Immunoprofile One of the most consistent molecular alterations in ILC and its variants is the loss of expression of the cell-cell adhesion molecule E-cadherin, which contributes to the characteristic discohesive nature of lobular cells.[16] E-cadherin loss is commonly accompanied by abnormal expression of other parts of the cadherin-catenin complex, eg, membranous B-catenin and cytoplasmic p120-catenin.[7]

One of the most consistent molecular alterations in ILC and its variants is the loss of expression of the cell-cell adhesion molecule E-cadherin, which contributes to the characteristic discohesive nature of lobular cells.[16] E-cadherin loss is commonly accompanied by abnormal expression of other parts of the cadherin-catenin complex, eg, membranous B-catenin and cytoplasmic p120-catenin.[7] Although the literature suggests that 80% to 95% of ILC’s exhibit estrogen receptor positivity, in current practice, classic invasive lobular carcinomas are almost invariably estrogen receptor-positive. In comparison, 70% to 80% of IDC’s are estrogen receptor-positive. Progesterone receptor positivity is found in 60% to 70% of both tumor types.[17] HER2 overexpression and amplification are rare in invasive lobular carcinoma, although they are evident in some pleomorphic or solid variant lobular carcinomas and in metastatic ILCs. The proliferation rate, measured by MIB1/Ki67 labeling, is generally low in invasive lobular carcinoma, although it can be higher in some variants.[18] ILC was typically considered “immune-cold” due to low numbers of tumor-infiltrating lymphocytes (TILs). However, a subset of ILC has been identified as having high TILs, which correlate with adverse pathologic features, including HER2 amplification, multinucleation, and prominent nucleoli.[5] The expression of p53, basal markers (keratin 14, keratin 5/6, EGFR) and myoepithelial markers (smooth muscle actin, and p63), is rare in ILC.[19] Histological Grading ILC is still routinely evaluated using the standard Nottingham grading system, which assesses tubule formation, nuclear pleomorphism, and mitotic activity, and assigns a grade of 1 (well-differentiated), 2 (moderately differentiated), or 3 (poorly differentiated). Low histologic grade is associated with a good prognosis and improved survival.[20] Classic ILC is typically assigned a low grade, connoting a good prognosis. However, this may not fully account for other factors, including estrogen receptor, progesterone receptor, HER2 status, tumor size, nodal involvement, and other genetic and molecular alterations.[1]

Clinical History Similar to invasive ductal carcinoma, a complete history should be obtained when evaluating for invasive lobular cancer, to include an assessment of symptomatology, risk factors, personal and family history of cancer, and genetic syndromes. Breast-specific symptoms include breast or axilla masses, nipple retraction or drainage, and, less commonly, breast pain. Features of more advanced disease include generalized malaise, weight loss, and bone pain. Of note, given the unique metastatic spread of ILC and association with diffuse gastric cancer in patients with a CDH1 mutation, the clinician should consider non-breast-related complaints, in particular, concurrent abdominal symptoms. Testing criteria for high-penetrance breast cancer susceptibility genes CDH1, BRCA 1, BRCA 2, PALB2, PTEN, STK11 and TP53 include personal history of breast cancer younger than 50 or patients with breast cancer of any age to aid in systemic and adjuvant treatment decisions, triple negative breast cancer, multiple primary breast cancers, lobular breast cancer with personal or family history of diffuse gastric cancer, male breast cancer or Ashkenazi Jewish ancestry. Additionally, a family history of a first or second-degree blood relative with breast cancer at age younger than 50, male breast cancer, ovarian cancer, pancreatic cancer, metastatic or high-risk prostate cancer, or lastly 3 diagnoses of breast or prostate cancer on the same side of the family, including the patient with breast cancer.[21] Physical Examination A thorough physical exam should also be performed, focusing on the breasts and lymph nodes. A bilateral breast exam should be performed with the patient in upright and supine positions, evaluating for breast masses, asymmetry, nipple retraction or discharge, and overlying skin changes. The bilateral axillae, cervical region, and supra- and infraclavicular regions should be evaluated for lymphadenopathy.

A thorough physical exam should also be performed, focusing on the breasts and lymph nodes. A bilateral breast exam should be performed with the patient in upright and supine positions, evaluating for breast masses, asymmetry, nipple retraction or discharge, and overlying skin changes. The bilateral axillae, cervical region, and supra- and infraclavicular regions should be evaluated for lymphadenopathy. Notably, ILC can be difficult to detect on physical exam due to its growth pattern. ILC is less likely to form a palpable mass than IDC and may present with vague findings, eg, skin thickening or induration. This presents a diagnostic challenge, especially in women with dense breast tissue or fibrocystic changes.[4] Furthermore, many women with ILC present with no overt physical exam findings; therefore, annual screening mammograms, along with breast magnetic resonance imaging in patients with high-risk or dense breasts, are strongly recommended.[NCCN. Breast Cancer. 2026]

Diagnostic Imaging The abnormal growth pattern of invasive lobular carcinoma also poses challenges in radiologic detection. The similar density of pathologic tissue in ILC to that of the surrounding breast parenchyma, along with the lack of a desmoplastic reaction and minimal disruption of normal breast architecture, makes it difficult to identify malignancies.[22] Mammography imaging Mammography is the current gold standard for the detection of invasive breast cancer. However, mammography has been noted to have a much lower sensitivity for ILC, ranging between 57% to 81%, and even as low as 30% in women with dense breast tissue.[23] This is because ILC is usually poorly spiculated with ill-defined lesions and less commonly presents with microcalcifications or a well-defined mass.[24] A portion of invasive lobular carcinoma is only visible on 1 view, usually craniocaudal, with a high false negative rate between 19% to 43%.[25][3] Mammography is also less sensitive in determining tumor extent and identifying multifocality or multicentricity, which are more common in ILC.[6] Ultrasound imaging Ultrasound may be used as an adjunct to mammography, with increased sensitivity in younger women (<45 years old) and those with dense breast tissue.[26]The addition of ultrasound to mammography may also increase detection of ILC, with sonographic features including irregular, hypoechoic masses, ill-defined margins, posterior shadowing, and changes in breast tissue without a defined mass.[3][27] Unfortunately, a percentage of ILC is also not visible on ultrasound, with a reported rate of 10%.[6] Magnetic resonance imaging The most recent NCCN guidelines on invasive breast cancer recommend MRI to help diagnose ILC, citing that these lesions are more often clinically occult on physical exam and poorly defined on other imaging modalities, eg, mammography and ultrasound.[NCCN. Breast Cancer. 2026] MRI sensitivity for ILC is high (many series >90%), though reported ranges vary; MRI may overestimate tumor extent and has lower specificity than mammography.[11] In the case of ILC, this may be related to limitations of MRI imaging in differentiating between classic LCIS and ILC.

The most recent NCCN guidelines on invasive breast cancer recommend MRI to help diagnose ILC, citing that these lesions are more often clinically occult on physical exam and poorly defined on other imaging modalities, eg, mammography and ultrasound.[NCCN. Breast Cancer. 2026] MRI sensitivity for ILC is high (many series >90%), though reported ranges vary; MRI may overestimate tumor extent and has lower specificity than mammography.[11] In the case of ILC, this may be related to limitations of MRI imaging in differentiating between classic LCIS and ILC. Studies on the utility of preoperative MRI show that while this modality can overestimate tumor size, resulting in tumor downstaging after final pathology, MRI may also identify additional mammographically occult disease, multicentricity/multifocality, and contralateral cancers, particularly in women with dense breast tissue.[14][28] The role of MRI in lymph node assessment is controversial, with some recommending its use for routine axillary imaging in ILC patients, and others stating that MRI does not help identify occult lymph node disease and thus does not confer any additional benefit.[14][29] Overall, MRI should be used in combination with mammography and ultrasound in the assessment of ILC. Newer contrast-enhanced mammography may help detect ILC, with preliminary studies demonstrating its noninferiority to MRI.[30][31] Histologic Diagnosis A core needle biopsy of suspicious lesions provides tissue for histologic diagnosis of breast cancer. Classically, hematoxylin-eosin morphology is used to diagnose ILC. However, some IDCs may appear similar to ILC, leading to misclassification. Thus, combining hematoxylin-eosin morphology with immunohistochemical identification of E-cadherin loss may be advisable. The estrogen receptor, progesterone receptor, and HER2 status will also be evaluated during histopathologic diagnosis.[11][32]

After a histologic diagnosis of ILC, treatment is interprofessional, involving medical oncology, surgery, and radiation oncology. Due to its insidious pattern of growth and consequent challenges with clinical and radiologic detection, ILC tends to present at an older age with larger tumors and increased lymph node involvement, and is more commonly multifocal and multicentric. Even so, current NCCN guidelines for invasive breast cancer treatment do not differentiate between IDC and ILC. NCCN instead treats invasive breast cancer by stage and biology rather than histologic subtype. Systemic Treatment Systemic treatment in ILC may include endocrine therapy, chemotherapy, and sometimes immunotherapy in neoadjuvant and adjuvant settings, depending on tumor biology and clinical staging. Given ILC’s higher estrogen receptor/progesterone receptor-positive status and low mitotic activity, lesions are generally more sensitive to endocrine therapy and less sensitive to chemotherapy, with a lower pathologic complete response rate.[10] Genomic testing may also be used, as indicated, to help determine systemic therapy options similar to those for IDC. Although ILC is less frequently HER2-positive, this subset of patients is treated similarly to IDC with chemotherapy and HER2-targeted therapy, including trastuzumab and pertuzumab.[6] Immunotherapy is still evolving, but it seeks to target gene mutations common in ILC or immune pathways affected by tumor progression. Surgical Treatment Surgery is an integral part of the treatment of invasive lobular carcinoma, involving either breast-conserving surgery (BCS) or mastectomy. In either case, axillary staging is done through sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). Oncoplastic reconstruction may be considered at the time of the index operation or after the completion of systemic therapy and radiation. Oncoplastic techniques during primary surgery have been found to have lower rates of positive margins (6%-12%) compared with BCS alone (18%-40%) and lower reexcision rates (as low as 4%), thought to be due to more extensive tissue resection.[33][34]

Surgery is an integral part of the treatment of invasive lobular carcinoma, involving either breast-conserving surgery (BCS) or mastectomy. In either case, axillary staging is done through sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). Oncoplastic reconstruction may be considered at the time of the index operation or after the completion of systemic therapy and radiation. Oncoplastic techniques during primary surgery have been found to have lower rates of positive margins (6%-12%) compared with BCS alone (18%-40%) and lower reexcision rates (as low as 4%), thought to be due to more extensive tissue resection.[33][34] Higher rates of mastectomy and positive margins after BCS have been found in ILC, with up to 65% of patients requiring a second surgery.[7][11][7] Even so, studies show similar survival and local recurrence rates between ILC patients undergoing BCS versus mastectomy, and when compared to IDC.[6][10] Therefore, BCS remains a viable option for the appropriate patient diagnosed with ILC. Radiation Therapy Radiation typically follows BCS, with most patients receiving whole breast irradiation. Some patients may receive radiation after a mastectomy, depending on the final pathology. Most studies have found no difference in local recurrence rates after BCS with postoperative radiation between ILC and IDC. However, as ILC commonly presents with larger, multifocal and multicentric tumors contributing to higher mastectomy rates, postmastectomy radiation is more common, again with similar recurrence and survival rates as IDC.[6][11][NCCN. Breast Cancer. 2026] Posttreatment Surveillance NCCN and American Society of Clinical Oncology (ASCO) guidelines for posttreatment surveillance recommend that patients follow up with their physicians for history and physical exams 1 to 4 times per year for 5 years, then annually, as clinically appropriate. Patients who have been treated with BCS are recommended to obtain yearly mammograms. Shorter interval imaging is not indicated unless suspicious findings are present on physical exam.

NCCN and American Society of Clinical Oncology (ASCO) guidelines for posttreatment surveillance recommend that patients follow up with their physicians for history and physical exams 1 to 4 times per year for 5 years, then annually, as clinically appropriate. Patients who have been treated with BCS are recommended to obtain yearly mammograms. Shorter interval imaging is not indicated unless suspicious findings are present on physical exam. Additional routine imaging, eg, a positron emission tomography (PET), CT, or bone scan, and laboratory studies are not indicated if no signs or symptoms of recurrent disease are noted.[NCCN. Breast Cancer. 2026][35][36] Women who underwent mastectomies do not need mammograms of the treated side, but still need yearly physical exams and mammograms of the contralateral breast.[37] MRI may be utilized in patients with a history of breast cancer who were diagnosed at age 50 or younger and have dense breasts. MRIs may still be recommended if the patient has silicone breast implant reconstruction to assess the integrity of the breast implant; current FDA guidelines suggest ultrasound or MRI 5 to 6 years postoperatively, then every 2 to 3 years thereafter.[FDA. Breast Implants: Certain Labeling Recommendations to Improve Patient Communication Guidance for Industry and Food and Drug Administration Staff Preface Public Comment. 2020]

The differential diagnoses for ILC include: IDC with lobular features Metastases from gastric or other primary signet-ring carcinomas Leukemia Lymphoma Sclerosing epithelioid fibrosarcoma Mucosa-associated lymphoid tissue lymphoma Myeloid sarcoma Plasma cell neoplasms (eg, multiple myeloma, which may mimic ILC morphologically), though rare [38]

Surgical intervention consists of breast-conserving surgery or mastectomy with axillary staging. Breast-Conserving Surgery Patients undergoing BCS will receive a lumpectomy or partial mastectomy, sometimes with concurrent oncoplastic tissue rearrangement or reconstruction. Patients with ILC are evaluated similarly to those with IDC to determine candidacy for BCS. Factors to consider include tumor size, multicentricity or multifocality, extent of lymph node involvement, estimated volume of remaining breast tissue after excision, and resulting cosmesis. Surgical planning may include a preoperative MRI to evaluate tumor extent and lymph node burden, as well as localization of the lesion with implantation of a localization device, eg, a wire, radioactive seed, or radiofrequency identification chip.[28] Preoperative localization of the lesion is particularly important for ILC, given its tendency to form ill-defined lesions without an isolated, palpable mass. In the operating room, the surgeon may use the localization device to guide excision, ensuring negative margins. Guidelines for invasive breast cancer, with or without ductal carcinoma in situ (DCIS), define negative margins as “no ink on tumor.” [39][ASBrS. Consensus Guideline on Breast Cancer Lumpectomy Margins. 2024] After specimen excision, the surgeon will confirm the presence of the targeted lesion or intact localization device via specimen radiograph in radiology or intraoperative imaging device. Of note, intraoperative margin evaluation is limited in ILC due to the frequent lack of a lesion with well-defined borders. If the tumor margins appear close, additional shave biopsies of the concerning margins are recommended. Clips should then be placed to mark the borders of the lumpectomy cavity for radiation planning.

In the operating room, the surgeon may use the localization device to guide excision, ensuring negative margins. Guidelines for invasive breast cancer, with or without ductal carcinoma in situ (DCIS), define negative margins as “no ink on tumor.” [39][ASBrS. Consensus Guideline on Breast Cancer Lumpectomy Margins. 2024] After specimen excision, the surgeon will confirm the presence of the targeted lesion or intact localization device via specimen radiograph in radiology or intraoperative imaging device. Of note, intraoperative margin evaluation is limited in ILC due to the frequent lack of a lesion with well-defined borders. If the tumor margins appear close, additional shave biopsies of the concerning margins are recommended. Clips should then be placed to mark the borders of the lumpectomy cavity for radiation planning. If final pathology reveals positive margins postoperatively, reexcision of the positive margins in the operating room is recommended to reduce the risk of local recurrence. The surgeon may decide not to reexcise a positive margin if no residual breast tissue remains at that margin (eg, pectoralis muscle or skin without involvement). Per the most recent American Society of Breast Surgeons (ASBrS) guidelines, the presence of ALH or classic LCIS at or close to a margin should not guide the decision to reexcise and, in and of itself, does not mandate reexcision.[ASBrS. Consensus Guideline on Breast Cancer Lumpectomy Margins. 2024] Pleomorphic and florid variant LCIS is more controversial, given the lack of consensus guidelines, and reexcision may be more case dependent.[Human Pathology Reports. Lobular Carcinoma In Situ: A Pragmatic Approach to the Controversies. 2022][40] Mastectomy Although studies demonstrate breast-conserving surgery is an acceptable option in the appropriate patient with ILC, there is still a higher mastectomy rate, likely due to its larger tumor size at diagnosis and increased multifocality/multicentricity. Indications for mastectomy include a large tumor-to-breast-size ratio, inadequate response to neoadjuvant systemic treatment, persistent positive excision margins, early pregnancy, extensive/indeterminate microcalcifications, recurrence after BCS, contraindications to radiation, and patient preference.[ASBrS. Mastectomy. 2018]

Although studies demonstrate breast-conserving surgery is an acceptable option in the appropriate patient with ILC, there is still a higher mastectomy rate, likely due to its larger tumor size at diagnosis and increased multifocality/multicentricity. Indications for mastectomy include a large tumor-to-breast-size ratio, inadequate response to neoadjuvant systemic treatment, persistent positive excision margins, early pregnancy, extensive/indeterminate microcalcifications, recurrence after BCS, contraindications to radiation, and patient preference.[ASBrS. Mastectomy. 2018] Preoperative localization of the lesion is not indicated in the case of mastectomy due to the excision of the entire breast. Patients may still benefit from a preoperative MRI for surgical planning, which would involve consideration of the incision type, ability to perform a skin-sparing or nipple sparing incision, and immediate versus delayed reconstruction. Regardless of the incision type, all breast tissue should be removed from the clavicle superiorly, sternal border medially, inframammary fold/rectus sheath inferiorly, anterior border of the latissimus dorsi muscle laterally, and dissected off the pectoralis major muscle posteriorly.[ASBrS. Mastectomy. 2018] Reconstructive procedures, including implant-based or autologous reconstruction, may be performed during the index operation or after the completion of adjuvant therapy, depending on preoperative discussions and recommendations by the plastic surgeon. Surgical Axillary Staging Surgical axillary staging is indicated in most patients undergoing both breast-conserving surgery and mastectomy. Sentinel lymph node biopsy is the standard of care for T1 to T2 invasive breast cancer with clinically negative nodes, regardless of histology or surgery type. Other indications for SLNB include DCIS treated with mastectomy or clinically node-negative patients following neoadjuvant chemotherapy.[ASBrS. Sentinel Lymph Node Biopsy in Breast Cancer Patients. 2018] A subset of the population who may omit SLNB per Choosing Wisely guidelines are clinically node-negative women ≥ 70 years old with early stage T1 to T2, HR-positive, HER2-negative breast cancers.[41]

Surgical axillary staging is indicated in most patients undergoing both breast-conserving surgery and mastectomy. Sentinel lymph node biopsy is the standard of care for T1 to T2 invasive breast cancer with clinically negative nodes, regardless of histology or surgery type. Other indications for SLNB include DCIS treated with mastectomy or clinically node-negative patients following neoadjuvant chemotherapy.[ASBrS. Sentinel Lymph Node Biopsy in Breast Cancer Patients. 2018] A subset of the population who may omit SLNB per Choosing Wisely guidelines are clinically node-negative women ≥ 70 years old with early stage T1 to T2, HR-positive, HER2-negative breast cancers.[41] Preoperatively, patients are injected with a radioisotope the day before or the morning of surgery and with a blue dye (isosulfan or methylene blue) at the start of surgery to aid in lymphatic mapping. SLNB involves identifying the first nodes in the axillary lymphatic basin that receive drainage from the breast to assess for metastatic spread. Any radioactive “hot”, blue, or palpable nodes will be excised, typically 1 to 3 sentinel lymph nodes, ensuring the background isotope count is less than 10% of the most radioactive node.[ASBrS. Sentinel Lymph Node Biopsy in Breast Cancer Patients. 2018] According to the ACOSOG Z0011 trial, women with T1 to T2 invasive breast cancer undergoing BCS who are clinically node negative with 1 to 2 sentinel lymph nodes positive for metastases on SLNB do not need a completion axillary dissection as their 10-year survival outcomes are comparable.[42]

Preoperatively, patients are injected with a radioisotope the day before or the morning of surgery and with a blue dye (isosulfan or methylene blue) at the start of surgery to aid in lymphatic mapping. SLNB involves identifying the first nodes in the axillary lymphatic basin that receive drainage from the breast to assess for metastatic spread. Any radioactive “hot”, blue, or palpable nodes will be excised, typically 1 to 3 sentinel lymph nodes, ensuring the background isotope count is less than 10% of the most radioactive node.[ASBrS. Sentinel Lymph Node Biopsy in Breast Cancer Patients. 2018] According to the ACOSOG Z0011 trial, women with T1 to T2 invasive breast cancer undergoing BCS who are clinically node negative with 1 to 2 sentinel lymph nodes positive for metastases on SLNB do not need a completion axillary dissection as their 10-year survival outcomes are comparable.[42] Women with 3 or more nodes positive for metastatic involvement after SLNB, clinically node-positive patients confirmed by FNA or core biopsy, who will not receive neoadjuvant systemic therapy, or those with persistent positive nodes after neoadjuvant chemotherapy, may require an axillary lymph node dissection. Some clinically node-negative patients with biopsy-proven lymph node metastasis with limited nodal burden may still be candidates for sentinel lymph node biopsy based on ACOSOG Z0011. Technically, ALND involves excision of level I and II nodes bounded by the axillary vein superiorly, serratus muscle medially, latissimus dorsi muscle laterally, axillary tail of the breast inferiorly, subscapularis posteriorly, and the lateral edge of the pectoralis major anteriorly. The long thoracic, thoracodorsal, and medial pectoral nerves should be identified and protected.[ASBrS. Sentinel Lymph Node Biopsy in Breast Cancer Patients. 2018] A higher incidence of nodal involvement at the time of diagnosis and surgery in ILC has been reported, consequently leading to a higher ALND rate. Nodal architecture is largely preserved in ILC, making preoperative assessment for metastasis more difficult and pathologic upstaging more frequent. This raises a concern that the Choosing Wisely guidelines recommending omission of axillary staging in certain patients should be carefully considered for patients diagnosed with ILC.[6][29]

After BCS, most patients are treated with whole breast irradiation, usually after completion of systemic therapy. A subset of patients may consider omitting breast irradiation if adjuvant endocrine therapy is planned and they are 70 years and older with less than 2 cm HR-positive, HER2-negative, node-negative breast cancers. After mastectomy, patients do not need radiation therapy if nodes are negative for metastases, the tumor is less than 5 cm, and negative margins are obtained. Partial breast radiation is also an option for select patients. Radiation should be strongly considered if they have 4 or more positive nodes, a large tumor size greater than 5 cm, high-risk features, or positive margins are present despite excision of all breast tissue. Radiation therapy should be individualized for each patient, with 3D CTs obtained for treatment planning and setup. Radiation dose and treatment duration are tailored to the patient. High-risk patients may also receive radiation boosts to the tumor bed or regional nodal irradiation.[NCCN. Breast Cancer. 2026] Radiation therapy approaches and local recurrence rates remain comparable between ILC and IDC following both breast-conserving surgery and mastectomy.[6] Higher rates of multifocality and multicentricity in ILC have led to frequent exclusion from clinical trials evaluating partial breast irradiation, although future inclusion may evolve as evidence expands.[11] Contraindications to radiation therapy, and consequently to BCS, include early pregnancy, prior radiation exposure, and specific connective tissue or collagen vascular disorders, eg, scleroderma or systemic lupus erythematosus. Careful interprofessional evaluation, including preoperative consultation with radiation oncology, supports the selection of the most appropriate surgical approach in these clinical scenarios.

Systemic medical therapy in ILC can include endocrine therapy, chemotherapy, and immunotherapy in both the neoadjuvant and adjuvant settings. Endocrine Therapy Given that ILC is overwhelmingly HR-positive, it typically responds well to endocrine therapy. Neoadjuvant endocrine therapy is increasingly used for ILC rather than neoadjuvant chemotherapy, as ILC is less chemosensitive and has a lower pCR rate. Benefits include an improved toxicity profile and possible tumor downstaging, allowing for BCS, while disadvantages include an increased time to response, which delays surgery. The typical duration of neoadjuvant endocrine therapy is 3 to 4 months, with some studies recommending extended treatment to 7.5 months.[8] The type of endocrine therapy is important, as demonstrated by the BIG 1-98 trial, in which 5 years of adjuvant aromatase inhibitor letrozole had better overall survival than tamoxifen in postmenopausal women with invasive breast cancer, and the effect was more pronounced in those with ILC.[43] The ABCSG-8 trial also showed that sequential aromatase inhibitor and tamoxifen therapy was associated with better overall survival than tamoxifen alone in postmenopausal women with ILC.[AACR. Survival Advantage of Anastrozol Compared to Tamoxifen for Lobular Breast Cancer in the ABCSG-8 Study. 2015] Overall, 5 years of adjuvant endocrine therapy reduced the risk of locoregional and distant recurrence and death in early-stage HR-positive breast cancer.[10] Extended endocrine therapy may be considered in high-risk ILC patients. Of concern, several genetic mutations associated with endocrine resistance, eg, ESR1, ERBB2, and FGR1, pose challenges to treatment.[3] Chemotherapy ILC generally responds more poorly to neoadjuvant and adjuvant chemotherapy than IDC due to its low proliferative rate/mitotic index and strong hormone receptor positivity. ILC has a lower pCR rate and is therefore less likely to downstage. Several meta-analyses have demonstrated that adjuvant chemotherapy did not improve overall survival in patients with ILC; however, they did not adjust for estrogen receptor, progesterone receptor, or HER2 status and had short follow-up. A survival benefit may exist in a subset of high-risk estrogen receptor-positive/HER2-negative ILC patients with positive lymph nodes, large tumor size, and lymphovascular invasion, although this requires further study.[11]

ILC generally responds more poorly to neoadjuvant and adjuvant chemotherapy than IDC due to its low proliferative rate/mitotic index and strong hormone receptor positivity. ILC has a lower pCR rate and is therefore less likely to downstage. Several meta-analyses have demonstrated that adjuvant chemotherapy did not improve overall survival in patients with ILC; however, they did not adjust for estrogen receptor, progesterone receptor, or HER2 status and had short follow-up. A survival benefit may exist in a subset of high-risk estrogen receptor-positive/HER2-negative ILC patients with positive lymph nodes, large tumor size, and lymphovascular invasion, although this requires further study.[11] Immunotherapy HER2-positive ILC and IDC are both treated with the monoclonal antibodies trastuzumab and pertuzumab in addition to chemotherapy.[6] A subset of ILC with increased lymphocytic infiltration may be responsive to immunotherapy. These TILs are part of the adaptive immune system and play roles in tumor progression and immune checkpoint blockade. ILC with high TILs is associated with younger age at diagnosis, positive lymph node status, increased proliferation, and poorer prognosis. As such, this population may benefit from immunotherapy targeting TILs.[5][7] Clinical studies, eg, the GELATO trial, are already investigating PD-L1 blockade; in this case, the use of carboplatin with PD-L1 inhibitor atezolizumab in patients with metastatic ILC.[44] CDK4/6 Inhibitors CDK4/6 inhibitors have emerged as a newer class of antineoplastic agents in recent years, exerting their effects by inhibiting the cell cycle to halt tumor progression. This class includes agents, eg, palbociclib, ribociclib, and abemaciclib, which may be used in HR-positive, HER2-negative metastatic breast cancer in conjunction with endocrine therapy.[45] Clinical trials, eg, PALOMA-2, PALLET, and PELOPS, evaluate the efficacy of CDK 4/6 inhibitors with endocrine therapy in this subset of invasive breast cancer.[46][47][ClinicalTrials. Palbociclib and Endocrine Therapy for LObular Breast Cancer Preoperative Study (PELOPS). 2025]

Staging of ILC is the same as that for any invasive breast cancer, utilizing the American Joint Committee on Cancer (AJCC) TNM staging system comprising (T) tumor size, (N) nodal involvement, and (M) metastases. Five stages are described based on TNM staging (0, I, II, III, IV) and integrate biomarkers, eg, estrogen receptor and progesterone receptor expression, HER2 expression, and histologic grade.[48] Routine systemic staging is not indicated. Additional imaging, eg, CT chest, abdomen, pelvis, and bone scan, should be considered for high-risk patients or those with signs and symptoms of metastatic disease.[NCCN. Breast Cancer. 2026] Metastatic disease in IDC is commonly detected on 18F-FDG-PET/CT; however, metastases in ILC are less commonly detected due to its lower metabolic activity. PET/CT with 18F-fluciclovine or 18F-fluoroestradiol, or whole-body diffusion-weighted MRI instead, may be better suited for metastatic ILC.[11]

Prognostication in breast cancer combines the Nottingham Prognostic Index, which evaluates tumor size, grade, and nodal status, with immunohistochemistry testing for estrogen receptor, progesterone receptor, HER2, and Ki67 status. ILC is hard to risk-stratify as these characteristics can be homogenous.[5] Some current prognostic gene assays include Oncotype Dx, MammaPrint, Prosigna, EndoPredict, and LobSig. Of those, only LobSig was developed specifically for ILC, but it requires further validation. Oncotype Dx, for example, produces a recurrence score (RS) that aims to predict the benefit of chemotherapy. ILC typically receives a low-to-intermediate RS, suggesting these tests may not adequately identify high-risk ILC patients.[11] Conflicting data exist regarding disease-free survival (DFS) and overall survival. In one study, ILC had similar rates of DFS but worse OS, especially in estrogen receptor-positive disease, with late relapses after 10 years.[49][50] ILC has a more favorable 5-year survival rate than IDC, but a worse prognosis after 5 years, possibly due to the presence of disseminated dormant cancer cells that cause delayed relapse 10 to 15 years later.[10][51] Contrary to these findings, the MonarchE trial from the European Institute of Oncology in Milan showed no difference in DFS or overall survival between IDC and ILC in a cohort of 15,000 patients.[52] When examining survival trends in more detail, there appear to be small subsets of ILC with worse survival outcomes than IDC, including HER2-positive ILC, triple hormone receptor-negative ILC, and ILC with high tumor-infiltrating lymphocytes.

Surgical complications from either partial mastectomy or mastectomy include bleeding, infection, hematoma, seroma, pain, wound dehiscence, lymphedema, nerve injury, skin flap necrosis, and poor cosmesis. Positive margins requiring re-excision may also occur; one study reported that as many as 65% of patients with ILC required a second surgery.[7] Adverse effects may occur from medical therapy; for example, tamoxifen carries warnings for venous thromboembolism and endometrial cancer, while radiation is known to cause skin changes, shrinking, and discoloration of the exposed tissue. Adverse effects of chemotherapy depend on the specific agent used.

The following clinicians may be involved in the evaluation and management of invasive lobular carcinoma: Geneticist General Surgeon or Surgical Oncologist Plastic Surgeon Pharmacist Oncology nurse or other allied healthcare professionals Radiation oncologist Medical oncologist Pathologist

Patient education should focus on managing risk factors related to exogenous estrogen use (HRT, oral contraceptives), alcohol consumption, diet, and appropriate screening. Patients should also be knowledgeable, if possible, of family history of cancer and other genetic syndromes, which may prompt a referral for genetic counseling in high-risk patients. Patients should obtain screening mammograms per shared decision-making with their physicians. Various medical groups have issued their own recommendations for screening mammograms, and most recommend starting at age 40 for average-risk women.[53] The position of the ASBrS, NCCN, and American College of Radiology (ACR) is for women of average risk to obtain yearly screening mammograms starting at age 40, ceasing when life expectancy is less than 10 years. The American Cancer Society (ACS) and United States Preventive Services Task Force (USPSTF) have each issued their own recommendations for screening mammography. The ACS recommends women with average breast cancer risk begin yearly screening at age 45 and switch to biennial screening at age 55 [ACS. Recommendations for the Early Detection of Breast Cancer. 2023], while the USPSTF recommends biennial screening for women ages 40 to 74.[54] Women with higher-than-average risk and dense breasts may be offered adjunctive imaging, eg, MRI.[ASBRS. Position Statement on Screening Mammography. 2019]

Invasive Lobular Carcinoma Recurrence Surveillance and Screening ILC has a higher risk of distant recurrence after 10 years than IDC and is more likely to metastasize to unusual sites, including the gastrointestinal tract, ovaries, bone, meninges, skin, peritoneum, and orbits.[1][6][7][10][5][55] Patients with a personal history of ILC should be aware of this and alert their physicians to any new clinical signs and symptoms posttreatment. Even so, NCCN and ASCO posttreatment surveillance guidelines, as previously discussed, recommend annual mammography but do not recommend routine PET, CT, bone scans, or laboratory testing in the absence of symptoms.[NCCN. Breast Cancer. 2026][36] MRI may be considered in select patients (eg, dense breasts) for surveillance after treatment.[11] Future Directions The unique tumor biology and molecular features of ILC provide opportunities for targeted therapy and personalization of treatment. Some ILC-specific clinical trials include the ROSALINE trial, which examines the use of neoadjuvant ROS1 inhibitor entrectinib in combination with endocrine therapy in women with estrogen receptor-positive, HER2-negative ILC, and the phase II study ROLo, which evaluates ROS1 inhibition with crizotinib in advanced E-cadherin-negative, estrogen receptor-positive ILC and diffuse gastric cancer.[56][A Okines et al. Abstract P2-07-24: Results from the Phase II Study of ROS1 Targeting with Crizotinib in Advanced E-cadherin Negative Lobular Breast Cancer (ROLo). 2025]

The unique tumor biology and molecular features of ILC provide opportunities for targeted therapy and personalization of treatment. Some ILC-specific clinical trials include the ROSALINE trial, which examines the use of neoadjuvant ROS1 inhibitor entrectinib in combination with endocrine therapy in women with estrogen receptor-positive, HER2-negative ILC, and the phase II study ROLo, which evaluates ROS1 inhibition with crizotinib in advanced E-cadherin-negative, estrogen receptor-positive ILC and diffuse gastric cancer.[56][A Okines et al. Abstract P2-07-24: Results from the Phase II Study of ROS1 Targeting with Crizotinib in Advanced E-cadherin Negative Lobular Breast Cancer (ROLo). 2025] Artificial intelligence (AI) has been increasingly used in recent years in a variety of fields, with new applications in medicine. For instance, AI has been used to aid in imaging identification and pathologic diagnosis of breast cancer. Mammography with a computer-aided detection system analyzes mammographic images and marks suspicious areas for radiologists to evaluate. Arce et al found 80% sensitivity, with common false positives; 88% of mammograms had at least 1 false-positive mark.[57] Raafet et al reported 96.6% sensitivity in detecting ILC, while Amir et al reported 100% sensitivity with 0 false negatives.[58][Raafet et al. Does Artificial Intelligence Aid in the Detection of Different Types of Breast Cancer. 2022] AI has also been utilized in pathology; for instance, a study by Challa et al found that AI-annotated slides significantly reduced review times by pathologists and identified 100% of lymph node metastases.[59] Another AI model accurately predicted CDH1 biallelic mutations common in ILC with 0.95 accuracy.[60] These are only a few examples of potential medical applications of AI, a topic for future study.

ILC accounts for 10% to 15% of invasive breast cancers and arises from lobular units with small, noncohesive cells due to CDH1 mutations, causing E-cadherin loss. Predominantly hormone receptor–positive with luminal A biology and a low mitotic index, ILC demonstrates limited sensitivity to chemotherapy but a favorable response to endocrine therapy. Diffuse growth patterns contribute to subtle clinical findings and reduced sensitivity on mammography, leading to delayed diagnosis, larger tumors, and increased nodal involvement. ILC frequently presents as multifocal, multicentric, or bilateral disease and exhibits atypical metastatic spread to sites such as the gastrointestinal tract and peritoneum. Evaluation requires integration of multimodal imaging, including MRI, and histopathologic confirmation with immunohistochemistry. Management follows stage- and biology-driven strategies incorporating surgery, endocrine therapy, chemotherapy, and radiation. Interprofessional collaboration enhances diagnostic accuracy and treatment outcomes through coordinated, patient-centered care. Physicians, including oncologists, surgeons, and radiologists, guide diagnosis, staging, and treatment selection, while primary care clinicians and advanced practitioners support early detection, risk assessment, and referral. Nurses facilitate patient education, symptom monitoring, and care coordination, and pharmacists optimize systemic therapy, manage adverse effects, and promote adherence. Genetic counselors assess hereditary risk and guide testing decisions. Effective communication and shared decision-making across the team support timely intervention, minimize complications, and ensure appropriate surveillance and follow-up, improving the quality and safety of care.