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• Atypical ductal hyperplasia (ADH):
  • Is a benign proliferative breast lesion:
    • Characterized by filling and distention of ducts by dysplastic monotonous epithelial cells:
      • Forming architecturally complex patterns, including:
        • Cribriform-like secondary lumens or micropapillary formations
  • It is found in approximately 10% of benign breast biopsies
  • It confers a four-fold increased risk of subsequent breast cancer:
    • With a cumulative incidence approaching 30% at 25 years
• Definition and Histopathology:
  • ADH is defined by cytologic and architectural features:
    • Established by Page and colleagues in 1985
  • The lesion shows:
    • Proliferation of dysplastic, monotonous epithelial cells:
      • With architectural complexity and nuclear hyperchromasia
  • The key distinction from ductal carcinoma in situ (DCIS) is quantitative rather than qualitative:
    • ADH shares histologic features with low-grade DCIS but is less extensive
    • If the lesion meets criteria for DCIS in terms of quality but involves fewer than two ducts or measures less than 2 mm:
      • It is classified as ADH
  • This places ADH in a transitional zone between benign and malignant disease:
    • Making it a premalignant lesion
• Epidemiology:
  • ADH:
    • Is found in approximately 10% of core needle biopsy specimens with benign findings
  • Both atypical ductal and atypical lobular hyperplasia:
    • Occur with equal frequency and confer similar breast cancer risks
  • The lesion is typically discovered incidentally on screening mammography:
    • In asymptomatic women
• Risk Factors and Modifiers:
  • Younger age at diagnosis:
    • Is associated with higher subsequent breast cancer risk
  • Family history of breast cancer:
    • May increase risk, though data are conflicting
  • Number of atypical foci significantly impacts risk:
    • Women with ≥ 3 foci have a standardized incidence ratio (SIR) of 5.29 compared to 3.11 for a single focus
  • Dense breasts:
    • Increase risk compared to fatty breasts
• Imaging Characteristics:
  • ADH:
    • Has no pathognomonic imaging appearance and typically mimics findings seen in small cancers
  • Mammographic Features:
    • Clustered microcalcifications:
      • Are the most common finding directly correlated with ADH:
        • Present in 64% to 82% of cases
      • Calcifications of intermediate concern or higher probability of malignancy:
        • Are more frequent when ADH is associated with malignancy
    • May also present as masses, asymmetric densities, or architectural distortion
    • Direct mammographic-histologic correlation:
      • Occurs in approximately 41% of cases
  • Ultrasound Features:
    • Most lesions appear as hypoechoic masses (64%)
    • Irregular shape (51%) and microlobulated margins (49%)
    • No specific posterior acoustic features (53%)
    • Parallel orientation (57%)
    • Presence of calcifications on ultrasound is significantly associated with upgrade to malignancy
  • ADH lesions are typically assigned BI-RADS category 4 (suspicious abnormality):
    • Warranting tissue sampling by core needle biopsy
• Management:
  • Surgical Excision:
    • Surgical excision remains the standard of care for ADH diagnosed on core needle biopsy:
      • Due to upgrade rates of 15% to 30% to DCIS or invasive cancer
    • A 2020 meta-analysis of 6,458 lesions:
      • Found a 29% upgrade rate for surgically excised ADH
    • The Society of Surgical Oncology recommends routine excision:
      • Noting an upgrade rate of at least 20%
  • Emerging Evidence for Selective Observation:
    • Recent literature suggests that select low-risk ADH lesions may be candidates for observation rather than routine excision:
      • Lesions that appear completely removed at biopsy
      • Limited foci:
        • Fewer than 2 to 3 foci
      • No necrosis or significant atypia on pathology
      • Small groups of mammographic calcifications
      • No enhancement on MRI
      • No underlying risk factors:
        • No history of breast cancer
        • No genetic mutation
        • No concurrent high-risk lesions
  • A 2022 study found that selected women with ADH who met predetermined low-risk criteria and were managed nonoperatively:
    • Had a 1.2% index site cancer rate at median 5.2-year follow-up:
      • Comparable to the 1.5% rate in those who underwent surgery
  • A 2025 study applying COMET trial criteria:
    • Found only a 3.43% upgrade to invasive disease in low-risk patients
• Post-Diagnosis Management:
  • For women with confirmed ADH on excisional biopsy:
    • Enhanced surveillance:
      • Annual mammography plus breast MRI screening
    • Risk-reducing medications:
      • Endocrine therapy (tamoxifen or aromatase inhibitors) is strongly recommended by NCCN guidelines:
      • With an 86% risk reduction for women with atypical hyperplasia
    • Lifestyle modifications:
      • Counseling on healthy lifestyle factors
  • Prognosis:
    • ADH confers a relative risk of approximately 4 for future breast cancer compared to women without the diagnosis
    • The absolute risk is substantial and sustained over time:
      • Cumulative Breast Cancer Incidence:
        • 5 years: 6.6% (95% CI 4.4-9.7%)
        • 10 years: 13.9% (95% CI 7.8-23.6%)
        • 25 years: 30% (either DCIS or invasive cancer)
      • The 10-year cumulative incidence is approximately 14.6%:
        • Representing about 1% per year
      • Risk increases with the number of atypical foci present:
        • Women with ≥ 3 foci have nearly double the risk of those with a single focus
    • Important Prognostic Considerations:
      • Risk affects both the ipsilateral and contralateral breast:
        • Though ipsilateral risk may be slightly higher
      • The risk does not plateau but continues to increase linearly over decades
      • Approximately half of subsequent breast cancers:
        • Occur within the first 5 years after ADH diagnosis
      • Both DCIS and invasive cancer contribute to subsequent events
      • The NCCN Breast Cancer Risk Reduction guidelines:
        • Classify women with atypical hyperplasia as high-risk and recommend risk-reducing endocrine therapy for those with life expectancy ≥ 10 years, given the substantial and sustained elevation in breast cancer risk
• References:
  • Atypical Hyperplasia of the Breast — Risk Assessment and Management Options. Hartmann LC, Degnim AC, Santen RJ, Dupont WD, Ghosh K. The New England Journal of Medicine. 2015;372(1):78-89. doi:10.1056/NEJMsr1407164.
  • Updates on Management of Atypical Hyperplasia of the Breast. Klassen CL, Fraker JL, Pruthi S. Mayo Clinic Proceedings. 2025;100(6):1051-1057. doi:10.1016/j.mayocp.2025.01.029.
  • Subsequent Breast Cancer Risk Following Diagnosis of Atypical Ductal Hyperplasia on Needle Biopsy. Menes TS, Kerlikowske K, Lange J, et al. JAMA Oncology. 2017;3(1):36-41. doi:10.1001/jamaoncol.2016.3022.
  • Benign Breast Disease and Breast Cancer Risk in the Percutaneous Biopsy Era. Sherman ME, Vierkant RA, Winham SJ, et al. JAMA Surgery. 2024;159(2):193-201. doi:10.1001/jamasurg.2023.6382.
  • Atypical Hyperplasia of the Breast: Mammographic Appearance and Histologic Correlation. Helvie MA, Hessler C, Frank TS, Ikeda DM. Radiology. 1991;179(3):759-64. doi:10.1148/radiology.179.3.2027988.
  • Imaging Characteristics of and Multidisciplinary Management Considerations for Atypical Ductal Hyperplasia and Flat Epithelial Atypia: Review of Current Literature. Harper LK, Carnahan MB, Bhatt AA, et al. Radiographics : A Review Publication of the Radiological Society of North America, Inc. 2023;43(10):e230016. doi:10.1148/rg.230016.
  • Atypical Ductal Hyperplasia Diagnosed at Sonographically Guided Core Needle Biopsy: Frequency, Final Surgical Outcome, and Factors Associated With Underestimation. Mesurolle B, Perez JC, Azzumea F, et al. AJR. American Journal of Roentgenology. 2014;202(6):1389-94. doi:10.2214/AJR.13.10864.
  • Mucocele-Like Tumors of the Breast as Cystic Lesions: Sonographic-Pathologic Correlation. Kim SM, Kim HH, Kang DK, et al. AJR. American Journal of Roentgenology. 2011;196(6):1424-30. doi:10.2214/AJR.10.5028.
  • Diagnosis of Columnar Cell Lesions and Atypical Ductal Hyperplasia by Ultrasound-Guided Core Biopsy: Findings Associated With Underestimation of Breast Carcinoma. Ahn HS, Jang M, Kim SM, et al. Ultrasound in Medicine & Biology. 2016;42(7):1457-63. doi:10.1016/j.ultrasmedbio.2016.02.009.
  • Society of surgical oncology medical student & trainee primer for breast surgical oncology. Marissa K. Boyle, Julia M. Selfridge, Rachel E. Sargent, et al.
    Upgrade Rate of Percutaneously Diagnosed Pure Atypical Ductal Hyperplasia: Systematic Review and Meta-Analysis of 6458 Lesions. Schiaffino S, Calabrese M, Melani EF, et al. Radiology. 2020;294(1):76-86. doi:10.1148/radiol.2019190748.
  • Risk of Breast Cancer in Selected Women With Atypical Ductal Hyperplasia Who Do Not Undergo Surgical Excision. Kilgore LJ, Yi M, Bevers T, et al. Annals of Surgery. 2022;276(6):e932-e936. doi:10.1097/SLA.0000000000004849.
  • Implications of the COMET Trial for the Management of Atypical Ductal Hyperplasia. Zaveri S, Sun SX, Bevers TB, Albarracin CT, Bedrosian I. Annals of Surgical Oncology. 2025;:10.1245/s10434-025-18236-2. doi:10.1245/s10434-025-18236-2.
  • Atypical Hyperplasia of the Breast: Clinical Cases and Management Strategies. Vegunta S, Mussallem DM, Kaur AS, Pruthi S, Klassen CL. Cleveland Clinic Journal of Medicine. 2023;90(7):423-431. doi:10.3949/ccjm.90a.22098.
    Breast Cancer Risk Reduction. National Comprehensive Cancer Network. Updated 2025-08-29.
  • Use of Endocrine Therapy for Breast Cancer Risk Reduction: ASCO Clinical Practice Guideline Update. Visvanathan K, Fabian CJ, Bantug E, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2019;37(33):3152-3165. doi:10.1200/JCO.19.01472.
    Practice Bulletin Number 179: Breast Cancer Risk Assessment and Screening in Average-Risk Women. Obstetrics and Gynecology. 2017;130(1):e1-e16. doi:10.1097/AOG.0000000000002158.
  • Atypical Ductal or Lobular Hyperplasia, Lobular Carcinoma in-Situ, Flat Epithelial Atypia, and Future Risk of Developing Breast Cancer: Systematic Review and Meta-Analysis. Baker J, Noguchi N, Marinovich ML, et al. Breast (Edinburgh, Scotland). 2024;78:103807. doi:10.1016/j.breast.2024.103807.
  • Trajectory of Subsequent Breast Cancer Diagnoses in a Diverse Patient Cohort With Breast Atypia. Limberg JN, Thomas SM, Dalton JC, et al. Annals of Surgical Oncology. 2024;31(11):7550-7558. doi:10.1245/s10434-024-15788-7.

A cutting-edge study published in npj Breast Cancer today reports validation of the HER2DX genomic test as a robust prognostic tool in first-line advanced HER2-positive breast cancer treated with trastuzumab, pertuzumab, and a taxane (THP). 

🔬 What was done: Researchers combined real-world data from 215 patients across Spanish and Polish cohorts. They assessed baseline tumor tissue using the HER2DX assay to derive genomic scores linked to outcomes in patients receiving standard first-line HER2-targeted therapy (THP). 

📊 Key findings:

• A high ERBB2 mRNA score was associated with significantly longer progression-free and overall survival, as well as higher objective response rates — independent of traditional clinical variables. 

• The team developed a HER2DX metastatic prognostic score that outperformed ERBB2 mRNA levels alone in predicting outcomes, suggesting genomic profiling can further refine risk stratification in advanced disease. 

📈 Implications: This study supports the clinical utility of HER2DX in identifying patients with HER2-positive advanced breast cancer who might derive the greatest benefit from existing first-line therapies — and highlights the growing role of genomic tools in precision oncology. 

Rodrigo Arrangoiz, MD

Surgical Oncologist, Mount Sinai Medical Center (MSMC)

Head & Neck and Breast Cancer Specialist

https://www.nature.com/articles/s41523-026-00909-0

Primary thyroid lymphoma is rare (<2% of thyroid malignancies), but it is crucial to recognize because management is very different from other thyroid cancers.

🧠 Key features

Arises from lymphoid tissue within the thyroid Strongly associated with Hashimoto’s thyroiditis Often presents with rapid thyroid enlargement over weeks Symptoms may include neck pressure, difficulty swallowing, or breathing changes

🔍 How is thyroid lymphoma diagnosed?

Ultrasound may show a diffusely enlarged, hypoechoic thyroid CT/MRI helps assess airway compression and extent Core needle biopsy (or surgical biopsy) is usually required FNA alone may be insufficient for definitive diagnosis

⚖️ How is it treated?

Unlike most thyroid cancers, surgery is NOT the main treatment.

Management typically includes:

Chemotherapy Radiation therapy Multidisciplinary care with medical oncology and radiation oncology

➡️ Surgery is reserved for airway compromise or diagnostic uncertainty.

📈 Prognosis

Depends on histologic subtype (e.g., MALT vs diffuse large B-cell) Many patients, especially with indolent subtypes, have excellent outcomes with appropriate therapy

🦋 Early recognition prevents unnecessary thyroid surgery and enables prompt, effective treatment.

👨‍⚕️ Dr. Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

A rapidly enlarging thyroid—especially in patients with Hashimoto’s—should raise suspicion for thyroid lymphoma and prompt specialist evaluation.

📚 References

Derringer GA et al. Primary thyroid lymphoma. Am J Surg Pathol Stein SA et al. Thyroid lymphoma. Endocrinol Metab Clin North Am NCCN Guidelines: B-Cell Lymphomas

• Invasive lobular carcinoma (ILC):
  • Is the second most common histologic form of breast cancer:
    • Comprising 10% to 15% of invasive tumors
• ILC is pathologically distinct from the much more common invasive ductal carcinoma (IDC):
  • With a unique clinical biology and pathogenesis and resultant implications for diagnosis and treatment
• The mean age at diagnosis of ILC:
  • Is 57 years
• Demonstrated risk factors include:
  • Age at menarche (early)
  • Age at first birth (late)
  • Hormone therapy:
    • Emphasizing the role of estrogen exposure in disease pathogenesis:
      • Which is also observed in most IDCs:
        • But shows a more pronounced association in ILC
• ILC also displays an increased propensity for:
  • Multifocal / multicentric presentation
• The incidence of ILC in the Western world over the past decades has corresponded to trends in the use of hormone replacement therapies:
  • With a sharp increase between 1975 and
    2000 and a decline between 2000 and 2004:
    • But now with an increasing incidence since 2005 with an unclear etiology
• Hereditary ILC:
  • Is rare:
    • But may be seen as a secondary tumor in families with hereditary diffuse gastric cancer syndrome:
      • Caused by a germline mutation in the tumor suppressor:
        • CDH1 gene
  • ILC otherwise accounts for a small minority of the breast cancers associated with known breast cancer susceptibility genes:
    • Comprising less than 5% of breast cancers in patients with BRCA1 or TP53 mutations and less than 10% of breast cancers in those with BRCA2 mutations
• Molecular characteristics of invasive lobular carcinoma (ILC):
  • Classic ILC is characterized by discohesive cells that infiltrate the breast stroma in a distinctive
    single-file pattern:
    • With a limited host inflammatory response [Figure 1 a and b]
  • Several variant (nonclassic) forms of ILC have also been described:
    • Distinguished by morphology:
      • Dispersed, alveolar, solid, trabecular, and mixed
    • Distinguished by cytology:
      • Pleomorphic, apocrine, histiocytoid, signet ring, and tubulolobular
    • They have inactivation of CDH1
    • Frequent mutations in the PIK3CA pathways
    • Gain in chromosome 1q and loss of 16q
    • Majority are luminal A intrinsic subtype

• Over 90% of ILCs are:
  • Estrogen receptor (ER) positive
• At the level of the transcriptome:
  • The majority of ILCs are classified as luminal A
    • This proportion is observed to be slightly lower in more aggressive ILC variants
• HER-2 overexpression is rare:
  • Seen in 3% to 5% of classic ILCs:
    • Although it is more frequent in up to 10% of ILC variants:
      • Particularly the pleomorphic subgroup, and recurrent ILCs
• The more aggressive biology of the pleomorphic subgroup renders it a unique clinical entity:
  • Shown to present at a more advanced stage and more frequently metastasize
• The tumor biology of ILCs, as with all breast cancers:
  • Is of focal importance in both surgical and systemic treatment, as well as long-term outcomes
• Loss of E-cadherin expression:
  • Is the most consistently reported hallmark feature of ILC:
    • Seen in 80% to 90% of cases
    • It is believed to play an early and important role:
      • In disease pathogenesis
  • E-cadherin dysregulation originates from:
    • Mutations in the CDH1 gene located on chromosome 16q22.1:
      • Reported to occur at a frequency ranging from 30% to 80% in ILC
  • E-cadherin is a calcium-dependent transmembrane protein:
    • That forms a crucial component of adherens-type junctions between epithelial cells:
      • The loss of which predisposes to neoplastic proliferation
  • However, E-cadherin positivity does not, by itself, exclude a lobular neoplasm, and not all ILCs harbor CDH1 gene mutations
  • Several other novel mutations have recently been identified as more frequent in ILC compared with IDC:
    • By comprehensive molecular profiling of 817 breast tumors in The Cancer Genome Analysis (TCGA) study:
      • Seen both when comparing all ILCs with IDCs and when limiting comparison with luminal A samples
  • When comparing all cancers, alterations more frequently seen in ILC included:
    • CDH1 (63% in ILC versus 2% in IDC)
    • P1K3CA (48% versus 33%)
    • FOXA1 (7% versus 2%)
    • RUNX1 (10% versus 3%)
    • TBX3 (9% versus 2%)
  • Conversely, GATA3 mutations were enriched in:
    • IDC (5% in ILC versus 13% in IDC)
  • Importantly, when the analysis was limited to luminal A samples only, several alterations remained significantly more common among luminal A ILCs versus luminal A IDCs, as summarized here (Table)

• Staging:
  • All breast cancers are staged using the TNM staging system:
    • As defined by the American Joint
      Committee on Cancer (AJCC)
• Patients are initially staged clinically based on physical examination and imaging findings:
  • They are later staged pathologically based on pathologic data obtained from the surgical specimens
• Tumor size (T):
  • Comprises the first component of the TNM stage
  • Particularly relevant to ILCs:
    • Which more often present as multifocal / multicentric tumors:
      • Final T stage is based on the size of
        the largest mass on surgical pathology:
        • Not an additive sum of multiple tumors if present
  • If bilateral cancers are present, each cancer is staged separately
  • Most studies, including a large Surveillance, Epidemiology, and End Results (SEER) registry analysis of 263,408 women with either IDC or ILC:
    • Have observed a significantly higher likelihood for ILCs to be sized over 2 cm (T2 or higher) at diagnosis compared with IDC
  • Nodal status (N):
    • Known to be an important predictor of prognosis in breast cancer:
      • Is similarly staged both clinically and pathologically
      • The quantification of the size of nodal metastases as either isolated tumor cells (ITCs), micrometastases (sized 0.2 mm to 2 mm), or macrometastases (sized greater than 2 mm):
        • Is relevant in ILC, which has been shown in recent series to independently predict for the presence of micrometastatic disease, another proposed consequence of its discohesive biology
• The M stage:
  • Is determined by the presence of distant metastases:
    • With bone being the most common site of spread for all breast cancer types
    • Other frequent sites of metastasis, common to both IDC and ILC, include:
      • The lungs and central nervous system
    • Interestingly, ILCs display a unique predilection for:
      • Gastrointestinal, peritoneal, and ovarian metastases
  • The commonly ER-positive nature of ILCs also results in:
    • More frequent presentation of late metastases
  • The diagnosis of yet subclinical metastatic cancer in patients with locally advanced disease may be made by:
    • CT, bone scanning, or PET

• Lobular neoplasia:
  • Is an atypical proliferation of small, dyscohesive epithelial cell:
    • Within the terminal duct lobular unit (TDLU):
      • That encompasses both:
        • Atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS)
• The hallmark feature is:
  • Loss of E-cadherin expression:
    • Resulting in cellular discohesion
• Lobular neoplasia:
  • Functions as both a:
    • Risk factor and non-obligate precursor to invasive breast carcinoma:
      • With LCIS conferring a 7-to-10-fold increased risk of breast cancer compared to the general population
• Definition and Classification:
  • The distinction between ALH and LCIS:
    • Is based on the extent of involvement:
      • ALH shows < 50% of acini in the affected TDLU distended by lobular proliferation
      • LCIS shows > 50% of acini in the affected TDLU distended by lobular proliferation with complete filling of at least one lobular unit
    • LCIS is further subdivided into three subtypes:
      • Classic LCIS:
        • Small, monomorphic, non-cohesive cells
        • Typically hormone receptor-positive and HER2-negative
      • Pleomorphic LCIS (PLCIS):
        • Greater nuclear pleomorphism, abundant cytoplasm
        • May be HER2-positive
      • Florid LCIS (FLCIS):
        • LCIS with necrosis and calcifications
• Imaging Diagnosis:
  • Classic lobular neoplasia (ALH and classic LCIS):
    • Is usually not visible on imaging and is typically diagnosed incidentally
    • When imaging abnormalities are present, the most common findings include:
      • Mammography:
        • Grouped amorphous calcifications (most common – 80% of cases)
      • Ultrasound:
        • Irregular, hypoechoic, avascular masses with posterior shadowing (uncommon)
      • MRI:
        • Heterogeneous non-mass-like enhancement with persistent kinetics
  • In contrast, FLCIS and PLCIS are typically imaging targets:
    • Most often manifesting as calcifications
  • Scrupulous radiologic-pathologic correlation is essential for appropriate management decisions
• Evidence-Based Management:
  • Management depends on the subtype and radiologic-pathologic concordance:
    • Classic LN (ALH and Classic LCIS) on concordant core biopsy:
      • Surveillance with imaging is now considered safe and appropriate
      • Surgical excision is not routinely required when radiologic-pathologic correlation is concordant
      • Studies show upgrade rates of only 0% to 5% for pure classic LN with concordant imaging
      • One large series showed 3-year conservative management failure rate of only 6.2%, with no same-quadrant cancers developing
      • Indications for surgical excision:
        • Radiologic-pathologic discordance
        • Concurrent high-risk lesions
    • Pleomorphic LCIS:
      • Requires excision:
        • With consideration for negative margins due to high upgrade rates
    • Florid LCIS:
      • Requires complete surgical excision due to high upgrade rates to invasive carcinoma
• Long-term risk management:
  • Annual breast cancer risk of 1% to 2% with LCIS diagnosis
  • Chemoprevention should be recommended to reduce risk
  • Enhanced surveillance:
    • High-risk imaging screening:
      • Annual mammography plus MRI for appropriate candidates
  • Bilateral prophylactic mastectomy is an option for select high-risk patients
  • Upgrade rates vary by study but range from 0% to 13% for classic LN when radiologic-pathologic correlation is performed
  • Most upgrades occur when discordance exists or when other high-risk lesions are present:
    • The decision between surveillance and excision should involve shared decision-making with consideration of personal and family history, patient preferences, and institutional protocols
• References:
  • Lobular Carcinoma in Situ: Diagnostic Criteria and Molecular Correlates. Sokolova A, Lakhani SR. Modern Pathology : An Official Journal of the United States and Canadian Academy of Pathology, Inc. 2021;34(Suppl 1):8-14. doi:10.1038/s41379-020-00689-3.
  • Non-Invasive Lobular Neoplasia: Review and Updates. Tjendra Y, Susnik B. Seminars in Diagnostic Pathology. 2025;42(4):150883. doi:10.1016/j.semdp.2025.150883.
  • Lobular Neoplasia of the Breast Revisited With Emphasis on the Role of E-Cadherin Immunohistochemistry. Dabbs DJ, Schnitt SJ, Geyer FC, et al. The American Journal of Surgical Pathology. 2013;37(7):e1-11. doi:10.1097/PAS.0b013e3182918a2b.
  • Lobular Neoplasia. Lunt L, Coogan A, Perez CB. The Surgical Clinics of North America. 2022;102(6):947-963. doi:10.1016/j.suc.2022.07.001.
  • Recommendations for Women With Lobular Carcinoma in Situ (LCIS). Oppong BA, King TA. Oncology (Williston Park, N.Y.). 2011;25(11):1051-6, 1058.
  • Atypical Hyperplasia of the Breast — Risk Assessment and Management Options. Hartmann LC, Degnim AC, Santen RJ, Dupont WD, Ghosh K. The New England Journal of Medicine. 2015;372(1):78-89. doi:10.1056/NEJMsr1407164.
  • Management of Lobular Neoplasia Diagnosed by Core Biopsy. Jani C, Lotz M, Keates S, et al. The Breast Journal. 2023;2023:8185446. doi:10.1155/2023/8185446.
  • Update on Lobular Neoplasia. Heller SL, Gao Y. Radiographics : A Review Publication of the Radiological Society of North America, Inc. 2023;43(10):e220188. doi:10.1148/rg.220188.
  • Lobular Carcinoma in Situ of the Breast: Clinical, Radiological, and Pathological Correlation. Scoggins M, Krishnamurthy S, Santiago L, Yang W. Academic Radiology. 2013;20(4):463-70. doi:10.1016/j.acra.2012.08.020.
    Atypical Ductal Hyperplasia and Lobular Neoplasia: Update and Easing of Guidelines. Lewin AA, Mercado CL. AJR. American Journal of Roentgenology. 2020;214(2):265-275. doi:10.2214/AJR.19.21991.
  • Society of surgical oncology medical student & trainee primer for breast surgical oncology. Marissa K. Boyle, Julia M. Selfridge, Rachel E. Sargent, et al.
  • Atypical Lobular Hyperplasia and Classic Lobular Carcinoma in Situ Can Be Safely Managed Without Surgical Excision. Laws A, Katlin F, Nakhlis F, et al. Annals of Surgical Oncology. 2022;29(3):1660-1667. doi:10.1245/s10434-021-10827-z.
  • Observation Versus Excision of Lobular Neoplasia on Core Needle Biopsy of the Breast. Schmidt H, Arditi B, Wooster M, et al. Breast Cancer Research and Treatment. 2018;168(3):649-654. doi:10.1007/s10549-017-4629-2.
  • Lobular Intraepithelial Neoplasia: Outcomes and Optimal Management. Boland PA, Dunne EC, Kovanaite A, et al. The Breast Journal. 2020;26(12):2383-2390. doi:10.1111/tbj.14117.

• Basic principles of systemic adjuvant therapy:
  • Are shared between all breast cancer types and are largely influenced by tumor biology rather than histology
• Generally, hormone receptor–positive
  cancers should receive endocrine therapy:
  • Applicable to the majority of ILCs
• Chemotherapy is typically offered for locally advanced cancers and for early-stage cancers with high-risk features such as:
  • High grade
  • Large size
  • Involved lymph nodes
  • High 21-gene recurrence scores
• Patients with HER-2+ tumors measuring greater than 1 cm:
  • Should receive additional anti-HER-2 targeted therapy as well
• Whereas those with triple negative tumors:
  • Are generally offered chemotherapy for tumors
    greater than 0.5 cm
• Contemporary systemic therapies have been shown to have a significant impact on:
  • Locoregional and distant disease control as well as overall survival
• Tumor biology:
  • Is key in the selection and efficacy of adjuvant therapies
• Most relevant to ILC, with a typically high ER content, are low rates of local recurrence (approximating 3%):
  • Reported among women with ER-positive tumors who receive endocrine therapy in the modern era
• Studies comparing the impact of systemic hormonal and chemotherapy in ILC and IDC are summarized here [Table]
• Importantly, these studies contain a mix of ER-positive and ER-negative patients, and hormone receptor status is apparent as a central determinant of response
• Interestingly, studies of the utility of Oncotype Dx in ILC:
  • Have shown that ILCs rarely (less than 2%) have a high recurrence score compared with rates approximating 20% in IDCs

• Support for adjuvant endocrine therapy:
  • Comes from a number of trials demonstrating a
    significant reduction in risk of recurrence at 15 years:
    • As summarized in a large Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis
  • Although large studies specific to ILC
    patients remain limited, some data suggest a greater benefit with aromatase inhibitors compared with tamoxifen:
    • In a retrospective analysis of the prospective BIG 1-98 trial, a larger magnitude of
      benefit was observed with adjuvant letrozole than with tamoxifen in the ILC subset:
      • With disease-free survival rates of 82% with letrozole versus 66% with tamoxifen at the 8-year follow-up, and overall survival rates of 89% with letrozole versus 74% with tamoxifen
      • This differential response in favor of aromatase inhibitors may be attributed to:
        • A paradoxical de novo resistance to tamoxifen and resultant proliferative response, which has been observed in an in vitro study of lobular carcinoma cell lines
    • However, the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial:
      • Which randomized patients to exemestane alone, or an “early switch” from tamoxifen for a total of 5 years of therapy, showed similar efficacy of both regimens for IDC and ILC
    • There was evidence of an impact of ER content, with suggested benefit from monotherapy for ER-rich patients (quantified by Allred score) compared with a benefit from sequential treatment strategy for
      ER-poor patients, regardless of histology
• There have not yet been any large randomized trials examining the impact of adjuvant chemotherapy regimens specifically for ILC:
  • Although retrospective analyses do not suggest any overwhelming reasons to deny adjuvant chemotherapy to patients with ILC who otherwise have indications for treatment, the poor response of ILCs to chemotherapy in the neoadjuvant setting:
    • Suggests a lower chemosensitivity of these cancers
• In a retrospective study including 3,685 ILCs
  and 19,609 IDCs, divided into groups treated either by adjuvant hormonal treatment alone or
  hormonal and chemotherapy:
  • For the ILC subset, 10-year survival rates were 68% after hormonal treatment alone and 66% with combination therapy (p = .45), suggesting that chemotherapy had limited benefit in postmenopausal patients with lobular cancers already receiving hormonal therapy:
    • However, chemotherapy may hold much greater value for the small minority of ILCs
      with ER– or HER-2+ receptor status
• In a retrospective subset analysis of the prospective phase III Herceptin Adjuvant (HERA) trial of patients with HER-2+ tumors:
  • There was a similar magnitude of benefit observed with 1 year of adjuvant trastuzumab among those with ILC and IDC (disease-free survival HR 0.63 versus 0.77, p = .49) at a median 4 years of follow-up
• Presently, standard treatment with adjuvant trastuzumab is recommended for HER-2+ ILCs

• Classic ILC (represents 60% to 70% of the cases):
  • More likely to have negative lymph nodes (cN0):
    • But is has a higher metastatic burden with more pN2:
      • ≥ 4 lymph nodes positive – 31% of the cases that NST (15%):
        • An adjusted lymph node ratio of 2.26
  • Among patients with SLN positive disease:
    • 68% of ILC showed non-SLN+ disease compared with 46% NST
      • 20% risk of clinical nodal under staging
  • Response to neoadjuvant chemotherapy (NACT) is limited (because most are ER positive and have low proliferation index):
    • PCR is roughly 5% (compared to 15% in matched NST)
    • Less down-staging:
      • ILC is an independent predictor of poor response to NACT
  • Neoadjuvant endocrine therapy (NAET):
    • May be a better option to down-staging but pCR is rare
    • Aromatase inhibitors may be better than tamoxifen
    • CDK4/6 inhibitor could be similar to NST
    • Immune checkpoint inhibitors, HER2 low:
      • Little data available
  • ILC have unique metastatic site:
    • More in the serosa (pleura, peritoneal cavity), GI and GYN and less in the lung, liver, and CNS
    • Wider metastatic spread
    • Recurrence pattern:
      • Early:
        • Less events that ER+ NST but continue to develop over time
      • Late (after 10 years)

• Aggressive variants of ILC:
  • Types:
    • Pleomorphic:
      • High nuclear grade
    • Solid:
      • Solid growth pattern
      • High mitotic counts
    • Histiocytoid
    • Signet Ring
  • More frequently:
    • ER negative, HER2+ (around 10%)
    • High proliferation index
    • High risk Oncotype Dx
  • Current evidence indicates aggressive clinical behaviour and shorter survival:
    • Little evidence on response to therapy
  • Clinical trials of these variants are needed
  • Can be treated as high grade NST:
    • It may be better to avoid NACT even in ER- or HER2+ due to the lack of evidence of response and may result to progression of the disease

• Invasive lobular carcinoma (ILC):
  • Represent roughly 7% to 15% of invasive breast cancers (IBC):
    • Second most common after no special type (NST)
  • More likely to be diagnosed in:
    • Elderly patients:
      • > 60 years of age
    • At advanced staged and with positive lymph node involvement
• ILC has several variants but two main groups:
  • Classic ILC and related variants:
    • Represent 60% to 70% of the cases
    • Variants:
      • Alveolar
      • Papillary
      • Mucinous
      • Tubulolobular
  • Aggressive variants:
    • Represent 30% to 40% of the cases
    • Variants:
      • Pleomorphic
      • Solid
      • Signet ring
      • Histiocytoid
• Aggressive variants:
  • Can behave worse than matched NST
• All variants share characteristic features of ILC:
  • Classic ILC (60% to 70% of the cases):
    • More likely to present with larger tumors, multifocal tumors, and with positive margins after breast conserving surgery (BCS) than NST
    • 95% are ER+, HER2-, low mitosis and a low proliferation index
    • They are grade 1 to 2, luminal A or less likely luminal B
    • The majority of ILC are low and intermediate risk on Oncotype Dx compared to the clinical risk of NST:
      • Onctoype Dx:
        • 1% to 8% of ILC were categorized as high risk but this include all variants of ILC
• Classic ILC:
  • Has a lower diagnostic concordance among pathologists:
    • This may be improved with E-Cadherin IHC
  • Due to is growth pattern, it can be difficult to assess size accurately compared to NST (extent vs tumor burden)
  • Can be more extensive that what is seen on H and E (small foci can be missed)

• Invasive lobular carcinoma (ILC):
  • Is a diverse group of tumors that share common features:
    • Loss of E-cadherin
    • Dyscohesive growth pattern:
      • With less tissue reaction
• They are broadly classified into two main entities:
  • In Situ (LCIS):
    • Three entities:
      • Classic
      • Florid
      • Pleomorphic
• Invasive (ILC):
  • Two entities:
    • Classic
    • Aggressive variants
• Each entity has unique:
  • Histology, clinical behavior, and management decisions
• Classic LCIS:
  • Type A and Type B:
    • Slight differences in histology
    • Same treatment
  • On needle core biopsy (NCB):
    • B3 (lesion of uncertain malignant potential) with atypia:
      • Requires a vacuum assisted excision (VAE) to exclude higher risk lesions
  • LCIS is considered a risk factor for increase risk of developing breast cancer:
    • Requires close follow-up
    • No need for complete excision or negative margins
• Florid LCIS (mass forming or necrotizing LCIS):
  • Mimic solid DCIS or comedo DCIS on H and E:
    • But E-cadherin negative
  • Recommendation:
    • Excision because there is a higher risk of coexisting invasion
    • Margins and radiation therapy should be discussed if no invasion
• Pleomorphic LCIS:
  • High grade nuclei
  • Higher risk of HER2+, ER negative, and invasion
  • B5a indicates a diagnosis of LCIS classified as a “high-grade” or “definite malignancy” based on the “B5” category:
    • Which usually signifies a cancerous finding on a core needle biopsy, meaning the cells are abnormal and considered
  • Requires excision
  • Managed as DCIS