Aggressive Breast Cancer Variant Predicts Lymph Node Spread, Study Finds

Invasive lobular carcinoma has long carried a reputation as the gentler cousin of breast cancer. Accounting for roughly 5 to 15 percent of all invasive mammary carcinomas, it is defined biologically by the loss of E-cadherin, a molecular glue protein encoded by the CDH1 gene whose absence leaves tumor cells unable to stick together. The result is a characteristic single-file growth pattern under the microscope and, historically, a clinical profile dominated by hormone receptor positivity, HER2 negativity, low grade, and good responses to endocrine therapy. But a new study from Vietnam adds to a growing body of evidence that this tidy picture conceals a dangerous exception, one that may be slipping through standard risk assessments.

Writing in the open-access journal Heliyon, a team of pathologists and clinicians led by Van De Nguyen reports one of the first systematic analyses of invasive lobular carcinoma variants in a Vietnamese cohort, conducted according to the 2019 World Health Organization classification of breast tumors. Their central finding is striking: the pleomorphic variant of lobular carcinoma, marked by wildly abnormal nuclei and brisk cell division, acts as an independent predictor of axillary lymph node metastasis, the spread of cancer to the lymph nodes under the arm. That independence matters, because it means the variant signals danger even after accounting for tumor size and histological grade, the two conventional yardsticks oncologists reach for first.

The study examined 167 consecutive patients with primary invasive lobular carcinoma who underwent definitive breast surgery with axillary lymph node dissection at K Hospital’s Tan Trieu campus in Hanoi between January 2019 and July 2023. The researchers excluded mixed ductal-lobular tumors, pure in situ lesions, patients who had received neoadjuvant systemic therapy, and recurrent or metastatic disease. Crucially, rather than relying on prior diagnostic reports, two experienced breast pathologists independently re-reviewed hematoxylin and eosin stained sections from archival tissue blocks in a blinded fashion, reaching consensus diagnoses by joint re-review against WHO criteria. Where mixed growth patterns existed, the predominant pattern, occupying at least half of the invasive component, determined the variant assignment.

The cohort split into four groups: classic lobular carcinoma made up 53.9 percent of cases, the pleomorphic variant 22.8 percent, the solid variant 8.4 percent, and a composite category of rare variants, including alveolar, tubulo-lobular, histiocytoid, and signet-ring cell forms, 15 percent. That pleomorphic prevalence is remarkable. In most Western series, pleomorphic lobular carcinoma accounts for only a small minority of lobular cases, often between 2 and 4 percent and rarely exceeding 10 to 15 percent. The authors caution that their figure likely reflects referral bias at a tertiary oncology center, which attracts advanced and biologically aggressive tumors, rather than a true population-level difference, but the enrichment gave them statistical power to interrogate the variant’s behavior in detail.

The molecular portrait of the pleomorphic group diverged sharply from its classic counterpart. While 96.7 percent of classic tumors expressed the estrogen receptor and only 4.4 percent were HER2 positive, the pleomorphic tumors showed estrogen receptor positivity in just 63.2 percent of cases and HER2 positivity in 31.6 percent. Progesterone receptor loss followed the same trend, and the Ki67 proliferation index, a measure of how many tumor cells are actively dividing, averaged 28.2 percent in pleomorphic cases versus 19.3 percent in classic ones. Translated into molecular subtypes using St. Gallen criteria, half of classic tumors were Luminal A, the most indolent category, whereas the pleomorphic group was enriched for HER2-enriched and triple-negative phenotypes, which together made up more than a third of pleomorphic cases but were almost absent among classic tumors.

These molecular differences translated into clinical behavior. The pleomorphic variant was overwhelmingly high grade, with 71.1 percent of cases classified as Grade 3 under the Nottingham system, while not a single classic tumor reached that grade. Most tellingly, 84.2 percent of pleomorphic cases had already spread to axillary lymph nodes at surgery, compared with 58.9 percent of classic tumors and just 42.9 percent of solid variant tumors. Pleomorphic patients also carried the heaviest nodal burden, with 42.1 percent showing four or more involved nodes. On the Nottingham Prognostic Index, which combines tumor size, nodal stage, and grade into a single score, the pleomorphic group averaged 5.61, well into the poor-prognosis range above 5.4, and 65.8 percent of pleomorphic patients fell into the poor category, versus 15.6 percent of classic cases.

The statistical centerpiece of the study is a multivariable logistic regression model. In univariate analysis, larger tumor size, pleomorphic histology, and Grade 3 morphology were all associated with nodal spread. But when the variables were entered together, with the classic variant and Grade 1 as references, only tumor size and histological variant retained significance. Each additional centimeter of tumor raised the odds of nodal metastasis by 73 percent, while the pleomorphic variant carried roughly five times the odds of nodal involvement compared with classic lobular carcinoma, an odds ratio of 5.12 with a confidence interval of 1.11 to 23.62 and a p-value of 0.036. Grade, the traditional prognostic mainstay, lost its independent significance entirely once subtype was accounted for, a result the authors interpret as evidence that grading’s prognostic power in lobular carcinoma depends heavily on which variant is being graded.

The findings align with genomic studies showing that high-grade and pleomorphic lobular carcinomas accumulate dangerous alterations beyond the canonical 1q gain and 16q loss pattern of classic disease, including ERBB2 amplification, TP53 mutations, and complex copy number changes resembling those of high-grade ductal carcinomas. High Ki67 expression in hormone receptor positive disease has also been repeatedly linked to late recurrence and endocrine resistance. The practical implication is that patients with pleomorphic lobular carcinoma may be inadequately served by endocrine therapy alone and, when HER2 positive or otherwise high risk, may require chemotherapy and anti-HER2 targeted agents alongside carefully tailored endocrine strategies, consistent with current treatment guidelines for aggressive breast cancer subtypes.

Equally instructive is what the study found about the solid variant, which some earlier series had lumped with aggressive non-classic forms. In this cohort, solid-pattern tumors were predominantly intermediate grade, strongly hormone receptor positive, HER2 negative, and Luminal A-like, with the lowest nodal metastasis rate of any group and prognostic index scores comparable to classic disease. The authors suggest that solid-pattern lobular carcinoma lacking marked nuclear pleomorphism may behave as an indolent, endocrine-responsive cousin of classic ILC rather than a dedifferentiated high-grade lesion, though the subgroup was small at 14 patients and the conclusion awaits external validation. The study’s limitations, including its single-center retrospective design, modest numbers in rare variant groups, and the absence of long-term survival follow-up, temper firm conclusions. Still, the message for pathology practice is clear: reporting the specific histological variant of invasive lobular carcinoma, not just its grade, could identify high-risk patients who need more intensive axillary staging and systemic therapy, while sparing those with biologically indolent tumors from unnecessary treatment.

Subject of Research: Pleomorphic invasive lobular carcinoma as an independent predictor of axillary lymph node metastasis in breast cancer

Article Title: Pleomorphic variant as an independent predictor of axillary lymph node metastasis in invasive lobular carcinoma

Article References: Pleomorphic variant as an independent predictor of axillary lymph node metastasis in invasive lobular carcinoma. (n.d.). https://doi.org/10.1016/j.heliyon.2026.e45533

Image Credits: AI Generated

DOI: 10.1016/j.heliyon.2026.e45533

Keywords: invasive lobular carcinoma, pleomorphic variant, axillary lymph node metastasis, breast cancer, histological grading, HER2, Ki67 proliferation index, Nottingham Prognostic Index, molecular subtypes, WHO classification, Vietnam, pathology