Lobular Carcinoma: Anatomy, Classification, Epidemiology, Causes, Pathogenesis, Symptoms, Diagnosis, Staging, Treatment and Prognosis

Lobular Carcinoma

~Introduction

Lobular carcinoma is a type of breast cancer that arises from the epithelial cells lining the lobules of the breast, which are responsible for milk production. It accounts for approximately 10–15% of all invasive breast cancers, making it the second most common histological subtype after invasive ductal carcinoma (IDC). Lobular carcinoma has distinct pathological, clinical, and radiological features that differentiate it from ductal carcinoma, including its growth pattern, hormone receptor positivity, and tendency for bilateral and multicentric disease.

Lobular carcinoma exists in two main forms: Lobular Carcinoma In Situ (LCIS) and Invasive Lobular Carcinoma (ILC). While LCIS is considered a marker of increased breast cancer risk rather than a true malignancy, ILC is a fully invasive cancer with unique biological behavior. Understanding lobular carcinoma is essential for accurate diagnosis, effective treatment planning, and long-term patient management.

~Anatomy and Histogenesis

The breast is composed of lobules, ducts, and stromal tissue. Lobules are the milk-producing glands connected to ducts that transport milk to the nipple. Lobular carcinoma originates from the terminal duct-lobular unit (TDLU).

A hallmark feature of lobular carcinoma is the loss of E-cadherin, a cell adhesion molecule encoded by the CDH1 gene. This loss results in reduced cell-to-cell cohesion, giving lobular carcinoma its characteristic single-file growth pattern and diffuse infiltration.

~Classification of Lobular Carcinoma

1. Lobular Carcinoma In Situ (LCIS)

LCIS is a non-invasive lesion characterized by abnormal proliferation of lobular epithelial cells confined within lobules. It is usually incidentally detected during biopsies performed for other reasons, as it rarely forms a palpable mass or produces imaging abnormalities.

LCIS is not considered a direct precursor lesion, but rather a marker of increased risk for developing invasive breast cancer in either breast.

Subtypes of LCIS include:

• Classic LCIS

• Pleomorphic LCIS (more aggressive)

• Florid LCIS

2. Invasive Lobular Carcinoma (ILC)

ILC is a malignant tumor in which cancer cells infiltrate surrounding breast tissue. It often presents insidiously and may be larger at diagnosis due to its diffuse growth pattern.

Histological features include:

• Small, uniform cells

• Single-file or targetoid arrangement

• Minimal desmoplastic reaction

• Absence of tubule formation

~Epidemiology

• Represents 10–15% of invasive breast cancers

• More common in postmenopausal women

• Median age at diagnosis: mid-50s to early 60s

• Increased incidence linked to hormone replacement therapy

• Higher likelihood of bilateral breast involvement

~Etiology and Risk Factors

Risk factors for lobular carcinoma are similar to those of other breast cancers but with some distinctive associations.

Hormonal Factors

• Prolonged estrogen exposure

• Hormone replacement therapy

• Early menarche and late menopause

Genetic Factors

• CDH1 gene mutation (associated with hereditary diffuse gastric cancer)

• BRCA2 mutation (less common than in ductal carcinoma)

Lifestyle and Environmental Factors

• Alcohol consumption

• Obesity (especially postmenopausal)

• Physical inactivity

~Pathogenesis

The molecular hallmark of lobular carcinoma is inactivation of the CDH1 gene, leading to loss of E-cadherin expression. This results in:

• Reduced cell adhesion

• Increased invasiveness

• Diffuse infiltration rather than mass formation

ILC tumors are typically:

• Estrogen receptor (ER) positive

• Progesterone receptor (PR) positive

• HER2 negative

This hormonal sensitivity influences treatment decisions and prognosis.

~Clinical Presentation

Lobular Carcinoma In Situ

• Usually asymptomatic

• Not palpable

• No skin or nipple changes

• Detected incidentally

Invasive Lobular Carcinoma

• Ill-defined breast thickening

• Subtle asymmetry

• Rarely forms a discrete lump

• Nipple inversion or retraction (occasionally)

• Axillary lymph node involvement in advanced cases

ILC is notorious for delayed diagnosis due to its subtle clinical features.

~Diagnostic Evaluation

Imaging

Mammography

• Less sensitive for ILC

• May show architectural distortion rather than a mass

Ultrasound

• Hypoechoic, ill-defined lesions

• Useful for guiding biopsies

Magnetic Resonance Imaging (MRI)

• Most sensitive modality

• Essential for detecting multicentric and bilateral disease

• Helps in surgical planning

Histopathology

Microscopic examination reveals:

• Small uniform tumor cells

• Single-file infiltration

• “Indian file” pattern

• Targetoid arrangement around ducts

• Lack of E-cadherin staining on immunohistochemistry

Immunohistochemistry

• ER positive (majority)

• PR positive

• HER2 negative

• E-cadherin negative (diagnostic feature)

~Staging

Lobular carcinoma is staged using the TNM classification, similar to other breast cancers:

• Tumor size (T)

• Lymph node involvement (N)

• Distant metastasis (M)

ILC has a higher tendency for:

• Bilateral disease

• Unusual metastatic sites (peritoneum, gastrointestinal tract, ovary)

~Treatment

Management of LCIS

• Active surveillance

• Risk-reducing medications (tamoxifen, aromatase inhibitors)

• Bilateral prophylactic mastectomy in high-risk patients (rare)

Management of Invasive Lobular Carcinoma

Surgery

• Breast-conserving surgery (lumpectomy) when feasible

• Mastectomy in extensive or multicentric disease

• Sentinel lymph node biopsy

Radiation Therapy

• Following breast-conserving surgery

• Reduces local recurrence

Systemic Therapy

Hormonal Therapy

• Tamoxifen

• Aromatase inhibitors

• Mainstay of treatment due to hormone sensitivity

Chemotherapy

• Used in high-risk cases

• Less responsive than ductal carcinoma

Targeted Therapy

• HER2-targeted therapy rarely needed due to HER2 negativity

~Prognosis

• Overall prognosis similar to ductal carcinoma

• Better outcomes in hormone receptor-positive cases

• Late recurrences possible

• Long-term follow-up required

Five-year survival rates are favorable when detected early, but advanced-stage disease may have poorer outcomes due to delayed diagnosis.

~Patterns of Metastasis

Unlike ductal carcinoma, lobular carcinoma commonly metastasizes to:

• Peritoneum

• Gastrointestinal tract

• Ovary

• Bone marrow

• Leptomeninges

This unique metastatic pattern requires a high index of suspicion in patients with atypical symptoms.

~Follow-Up and Surveillance

• Regular clinical breast exams

• Annual mammography

• MRI in selected cases

• Long-term endocrine therapy adherence

~Recent Advances and Research

• Molecular profiling for personalized therapy

• CDK4/6 inhibitors in advanced disease

• Improved imaging techniques

• Genetic counseling for CDH1 mutation carriers

~Conclusion

Lobular carcinoma is a biologically distinct and clinically challenging form of breast cancer. Its subtle presentation, diffuse growth pattern, and diagnostic limitations demand heightened clinical awareness. Early detection, accurate pathological diagnosis, and individualized treatment strategies are critical for improving outcomes. With advances in imaging, molecular diagnostics, and targeted therapies, the management of lobular carcinoma continues to evolve, offering hope for better survival and quality of life for affected patients.