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

Mast cell tumours are the most frequently diagnosed cutaneous malignancy in dogs, accounting for an estimated 16 to 21 percent of all skin neoplasms. They arise from mast cells, immune cells rich in inflammatory mediators such as histamine and heparin, and typically present as masses in the skin or the tissue beneath it. Their biological behaviour spans an extraordinary range: some are cured permanently by simple surgical excision, while others ulcerate, recur locally and spread to lymph nodes, liver and spleen. Paraneoplastic effects driven by the release of mast cell granules can produce itching, bruising, skin swelling and gastrointestinal signs, complicating the clinical picture. Two histological grading systems, the three-tier Patnaik scheme and the two-tier Kiupel scheme, are widely used to predict behaviour, and both have been shown to be consistently prognostic, particularly when applied together.

Golden Retrievers have repeatedly been identified as a breed at increased risk of MCTs, and germline genetic studies have pinpointed risk variants in genes including GNAI2 and a hyaluronidase gene in US Golden Retrievers. Yet until now, no epidemiological study had specifically characterised MCT frequency, clinical features and survival within the breed in the United States. The GRLS, a prospective cohort of 3,044 Golden Retrievers enrolled between June 2012 and April 2015 and balanced by sex across five geographic regions, offered a uniquely powerful opportunity. Dogs were followed annually with owner and veterinarian questionnaires, biological samples and a dedicated biopsy submission pathway, with histopathology reviewed by two blinded veterinary pathologists. The study’s primary cancer endpoints include haemangiosarcoma, lymphoma, osteosarcoma and high-grade MCT, with high grade defined as Patnaik grade 3 or Kiupel high.

The headline numbers are striking. Of the 3,044 dogs, 164, or 5.39 percent, were diagnosed with a total of 234 mast cell tumours, yielding an incidence rate of 5.58 per 1,000 dog years at risk. A lifetable analysis revealed that young dogs were rarely affected: 99.1 percent of the cohort reached five years of age without an MCT diagnosis. Annual incidence risk peaked at 1.39 percent in dogs aged greater than eight to nine years, before declining in the oldest age groups. The authors note that this decline mirrors patterns seen in other veterinary and even human cancers, where incidence falls in extreme old age, possibly reflecting cellular senescence, stem cell exhaustion or a cancer-resistant phenotype, though diagnostic bias in geriatric patients may also contribute.

Compared with incidence figures from a mixed-breed insured population in Sweden, the Golden Retriever rate appears up to tenfold higher, which the researchers interpret as evidence of a genuine and substantial breed predisposition rather than an artefact of geography or study design. The practical message for owners is clear: vigilance for skin masses, particularly as dogs enter middle and older age, is warranted, and any new lump should prompt veterinary investigation rather than a wait-and-see approach. The median age at first diagnosis in the cohort was just over eight years.

The tumours themselves were predominantly low grade. Cutaneous tumours accounted for 70.5 percent of events and subcutaneous tumours for 16.7 percent, with the remainder being metastatic entries, mucosal or visceral primaries, or digital masses. The most common anatomical locations were the torso, limbs and head and neck, consistent with distributions reported in multi-breed populations. Histopathological grading was available for nearly all cutaneous tumours, and the most frequent grade was the intermediate-low P2KL category. Overall, only 47 of the 234 tumours, or 20.1 percent, met the study’s high-grade definition, a proportion consistent with previous reports of 22 to 26 percent high-grade disease in broader populations. Notably, the findings do not support earlier suggestions that Golden Retrievers are disproportionately prone to high-grade tumours.

Recurrence and spread were comparatively uncommon. Most dogs, 84.2 percent, had a solitary tumour, while 15.9 percent developed new de novo masses at distinct sites, with a median interval of 368 days between the first and subsequent tumours. Local recurrence occurred in just under five percent of cases, and documented metastasis in 9.8 percent, most often to lymph nodes. Critically, every dog with metastatic disease had at least one high-grade tumour; no dog with only low-grade MCTs was found to have spread. The authors suggest this could influence clinical staging recommendations, since extensive staging appears to have low diagnostic yield in low-risk patients, although the absence of standardised staging protocols means some metastases may have gone undetected.

The survival analysis produced the study’s most reassuring result. Median lifespan was 11.68 years in dogs diagnosed with MCT and 11.75 years in the remaining cohort, a difference that was not statistically significant. Median survival time from first MCT diagnosis to death from any cause was 1,367 days, and only 19 dogs, or 11.6 percent, had MCT recorded as their cause of death. Overall survival probabilities after diagnosis were 81.7 percent at one year, 70.0 percent at two years and 40.6 percent at five years. When the analysis was stratified, however, the prognostic weight of tumour biology became evident: the presence of metastasis, a high histological grade, or local recurrence were each associated with statistically significantly reduced survival, while the development of additional de novo tumours was not. Nearly 90 percent of the dogs that died from their disease had at least one high-grade tumour.

The researchers acknowledge several limitations. Cohort recruitment relied on word-of-mouth and snowball sampling, dogs were required to have three-generation pedigrees, and participating owners were highly engaged, with subsidised histopathology likely boosting diagnostic rates relative to the wider population. Treatment details were largely unavailable, precluding analysis of therapeutic impact, and the number of MCT-related deaths was too small for multivariable modelling. Nevertheless, the study’s general-practice setting gives it a realism that insurance-claim and referral-based studies lack. Its overall message is one of measured optimism: for most Golden Retrievers, a mast cell tumour diagnosis is not life-limiting, low-grade disease carries an excellent prognosis with prompt and appropriate management, and the findings justify early investigation and treatment of skin masses rather than fatalism. As the GRLS cohort continues to yield data, it is cementing its role as one of the most valuable resources in comparative oncology, with implications that may ultimately extend to human mast cell disorders and cancer research more broadly.

Subject of Research: Epidemiology, clinical features and survival of mast cell tumours in Golden Retrievers enrolled in the Golden Retriever Lifetime Study

Article Title: Mast cell tumours in the Golden Retriever Lifetime Study: a cohort study assessing frequency, clinical features and survival

Article References: Stratton, Z. V., Brodbelt, D. C., Guillén, A., O’Neill, D. G., Labadie, J., Swafford, B., & Taylor, C. (2026). Mast cell tumours in the Golden Retriever Lifetime Study: a cohort study assessing frequency, clinical features and survival. Veterinary Oncology, 3(1), Article 10. https://doi.org/10.1186/s44356-026-00060-9

Image Credits: AI Generated

DOI: 10.1186/s44356-026-00060-9

Keywords: Golden Retriever, mast cell tumour, canine cancer, veterinary oncology, Golden Retriever Lifetime Study, dog lifespan, histological grading, Kiupel, Patnaik, metastasis, incidence, survival analysis