Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• 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

New Research Alert: ER-Low Breast Cancer & Endocrine Therapy (2026)

Liu et al. Breast Cancer Res Treat. Published Jan 6, 2026. 

🔬 Key Focus

This study evaluated outcomes and benefits of endocrine therapy (ET) in early breast cancer patients with low estrogen receptor (ER) expression (1%–10%) compared to ER-high and ER-negative cancers. 

📊 Major Findings

🧬 ER-Low Phenotype Is Distinct

ER-low (~4.4% of cases) behaves more like ER-negative disease in HER2-negative patients. Worse breast cancer-free survival compared to ER-high. Similar risk to triple-negative disease in HER2-negative subgroup. 

💊 Endocrine Therapy Benefit Varies by Subtype

📍 HER2-Negative ER-Low:

✔ ET significantly reduced locoregional recurrence & distant metastasis

✔ Improved breast cancer–free survival (BCFS) 

📍 HER2-Positive ER-Low:

❌ No clear survival or BCFS benefit from ET observed 

🧠 Clinical Implications

✅ Consider ET in HER2-negative, ER-low early breast cancer

⚠️ The benefit of ET in HER2-positive ER-low remains uncertain

🧪 ER-low shouldn’t be treated the same as classical ER-high luminal tumors 

📌 Why This Matters

ER-low tumors are being increasingly recognized as a biologically unique subgroup. This research supports more nuanced treatment planning, particularly regarding the value of endocrine therapy based on HER2 status.  

• Poorly differentiated thyroid cancer (PDTC) is an uncommon but important subtype that sits between differentiated thyroid cancer (papillary/follicular) and anaplastic thyroid cancer in terms of aggressiveness.
  
  
  🧠 What defines PDTC?
  Tumors show loss of typical thyroid differentiation
  Often described with insular, trabecular, or solid growth patterns
  More aggressive than papillary or follicular cancer
  Less responsive to radioactive iodine than well-differentiated cancers
  
  
  🔍 How is PDTC diagnosed?
  Definitive diagnosis is made on surgical pathology
  Based on specific histologic criteria (e.g., high mitotic rate, necrosis, insular pattern)
  FNA may suggest aggressive disease but is not always definitive
  
  
  ⚖️ How is PDTC treated?
  
  
  Management requires multidisciplinary, risk-adapted care:
  Total thyroidectomy is usually recommended
  Therapeutic lymph node dissection when nodal disease is present
  Radioactive iodine may be considered, but effectiveness is variable
  External beam radiation and systemic therapy in selected cases
  Close, long-term surveillance
  
  
  📈 Prognosis
  Worse than papillary or follicular thyroid cancer
  Better than anaplastic thyroid cancer
  Outcomes depend on:
  Tumor stage
  Completeness of surgical resection
  Presence of distant metastases
  
  
  🦋 Early recognition and expert pathology review are critical for optimal outcomes.
  
  👨‍⚕️ Dr. Rodrigo Arrangoiz, MD
  Surgical Oncologist – Thyroid, Head & Neck, Breast
  Mount Sinai Medical Center
  
  
  📌 Take-home message:
  Poorly differentiated thyroid cancer is uncommon but serious—timely diagnosis and comprehensive care matter.
  
  
  📚 References
  Lloyd RV et al. WHO Classification of Tumours of Endocrine Organs
  Haugen BR et al. ATA Guidelines for Differentiated Thyroid Cancer. Thyroid
  Volante M et al. Poorly differentiated thyroid carcinoma. Endocr Relat Cancer

• Failure to identify a parathyroid gland during cervical exploration:
  • Is most commonly explained by:
    • Ectopic location rather than true absence
• Large anatomic and surgical series demonstrate that approximately 15% to 16% of parathyroid glands are ectopic:
  • With predictable distributions:
    • Based on embryologic origin (Taterra et al., Surg Radiol Anat, 2019):
      • Consequently, a structured search strategy:
        • Guided by embryology and prevalence data is recommended
• General intra-operative principles:
  • Careful inspection of the orthotopic field:
    • Is mandatory before declaring a gland ectopic
  • Approximately 80% to 90% of parathyroid glands are located within a few millimeters of the posterior thyroid capsule (Taterra et al., 2019):
    • Gentle subcapsular dissection along the posterior surface of the thyroid should be completed before expanding the field
• Intrathyroidal parathyroid glands:
  • Account for 2% to 3% of all glands and up to 20% to 22% of ectopic glands, particularly inferior glands (Phitayakorn & McHenry, Am J Surg, 2006):
    • For this reason, inspection and palpation of the thyroid specimen is considered standard practice in experienced centers (Noussios et al., Exp Clin Endocrinol Diabetes, 2012)
• Reoperative series demonstrate that most “missed” glands:
  • Are found in standard embryologic locations:
    • Most commonly the tracheoesophageal groove, thyrothymic ligament, or superior mediastinum:
      • Emphasizing the importance of a systematic rather than random exploration (Silberfein et al., Arch Surg, 2010)
• Superior parathyroid gland – Evidence-Based search pattern:
  • Typical location:
    • Superior parathyroid glands:
      • Fourth pharyngeal pouch origin:
        • Exhibit limited migration and are therefore relatively constant in position
    • They are typically located on the posterior aspect of the upper thyroid pole:
      • Approximately 1 cm above the intersection of the recurrent laryngeal nerve (RLN) and the inferior thyroid artery:
        • Frequently within the tracheoesophageal groove (Scharpf et al., Surg Oncol Clin N Am, 2016)
  • Common ectopic locations:
    • When ectopic:
      • Superior parathyroid glands are most often displaced posteriorly, rather than inferiorly:
        • Tracheoesophageal or para-esophageal groove the most common ectopic site for superior glands (Noussios et al., 2012; Taterra et al., 2019)
        • Retro-esophageal or retro-pharyngeal space, particularly in undescended glands (Scharpf et al., 2016)
        • Posterior mediastinum, where enlarged glands may descend along the esophagus but remain posterior in relation to the RLN (Phitayakorn & McHenry, 2006)
  • Stepwise surgical approach:
    • If a superior gland is not identified in its orthotopic location, the recommended sequence is:
      • Systematic exploration of the tracheoesophageal groove following the RLN superiorly
      • Blunt dissection of the para- and retro-esophageal spaces
      • Evaluation of the high posterior neck for undescended glands
      • Inspection of the thyroid specimen for an intrathyroidal gland (Noussios et al., 2012; Silberfein et al., 2010)
• Inferior parathyroid gland – evidence-based search pattern:
  • Typical location:
    • Inferior parathyroid glands:
      • Third pharyngeal pouch origin
      • Descend with the thymus and demonstrate significantly greater variability
      • Orthotopically, they are most often located near the lower thyroid pole, anterior to the RLN, frequently within or adjacent to the thyrothymic ligament (Scharpf et al., 2016)
  • Common ectopic locations:
    • Inferior glands account for the majority of ectopic parathyroids:
      • Intrathymic or within the cervical thymus:
        • Approximately 30% of ectopic inferior glands (Phitayakorn & McHenry, 2006)
      • Anterosuperior mediastinum, often contiguous with thymic tissue (Noussios et al., 2012)
      • Intrathyroidal:
        • Accounting for ~ 20% to 22% of ectopic inferior glands (Phitayakorn & McHenry, 2006)
      • High cervical or carotid sheath locations, representing failed embryologic descent (Noussios et al., 2012)
  • Stepwise surgical approach:
    • When an inferior gland is not identified at the lower pole:
      • The thyrothymic ligament should be followed inferiorly toward the thymus
      • A limited cervical thymectomy should be performed when clinically appropriate:
        • Given the high incidence of intrathymic glands
      • The lower thyroid pole and specimen should be inspected for intrathyroidal tissue
      • The carotid sheath and high cervical region should be explored in cases suspicious for undescended glands (Phitayakorn & McHenry, 2006; Silberfein et al., 2010)
• Lessons from re-operative surgery:
  • In contemporary re-operative parathyroidectomy series, previously missed glands were most commonly located in the:
    • Tracheoesophageal groove
    • Thyrothymic ligament
    • Superior mediastinum
  • Confirming that failure is usually related to incomplete exploration of predictable embryologic sites rather than unusual anatomy (Silberfein et al., Arch Surg, 2010)
• Key references:
  • Taterra D, et al. The prevalence and anatomy of parathyroid glands: a meta-analysis. Surg Radiol Anat. 2019.
  • Phitayakorn R, McHenry CR. Incidence and location of ectopic abnormal parathyroid glands. Am J Surg. 2006;191:418–423.
  • Noussios G, et al. Ectopic parathyroid glands and their anatomical, clinical and surgical implications. Exp Clin Endocrinol Diabetes. 2012.
  • Silberfein EJ, et al. Reoperative parathyroidectomy: location of missed glands. Arch Surg. 2010.
  • Scharpf J, et al. Anatomy and embryology of the parathyroid glands. Surg Oncol Clin N Am. 2016.

 Anaplastic thyroid cancer (ATC) is rare (<2%) but represents the most aggressive form of thyroid cancer. It behaves very differently from other thyroid cancers and requires urgent, multidisciplinary care.

🧠 Key characteristics of ATC

Rapidly growing neck mass Often presents with hoarseness, difficulty swallowing, or breathing problems Frequently diagnosed at an advanced stage Can arise from pre-existing differentiated thyroid cancer

🔍 How is ATC diagnosed?

Clinical suspicion due to rapid growth Imaging (CT/MRI) to assess airway and invasion Core needle biopsy or surgical biopsy for confirmation Molecular testing (e.g., BRAF V600E) to guide targeted therapy

⚖️ How is ATC treated?

Management requires a multidisciplinary approach:

Airway protection is often the first priority Surgery when feasible Radiation therapy and systemic therapy Targeted therapy and immunotherapy have significantly improved outcomes in selected patients

📈 Prognosis

Historically poor Modern targeted therapies have changed the landscape, improving survival in carefully selected patients Early referral to specialized centers is critical

🦋 ATC is a medical emergency—time matters.

👨‍⚕️ Dr. Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

Anaplastic thyroid cancer is aggressive, but early recognition and modern therapies are improving outcomes.

📚 References

Smallridge RC et al. ATA Guidelines for Anaplastic Thyroid Cancer. Thyroid Bible KC et al. Targeted therapy in ATC. NEJM NCCN Guidelines: Thyroid Carcinoma

• ADH and atypical lobular hyperplasia (ALH) are now frequently diagnosed with use of core-needle biopsy
• Although atypia can be difficult to distinguish from carcinoma in situ:
  • Pathologic criteria exist to distinguish the two entities
• This distinction is important because, while in situ carcinoma is malignant and may progress to invasive disease:
  • ADH is a non-obligate cancer precursor and often represents a marker of an elevated future breast cancer risk
• ADH is most frequently found by mammography
• Atypia alone, with no other risk factors, confers an approximate:
  • Four-fold to five-fold risk of the development of breast cancer
• Although breast MRI is more sensitive to detect intermediate- and high-grade ductal carcinoma in situ (DCIS) as well as invasive cancers:
  • Breast MRI lacks sufficient diagnostic ability to differentiate ADH versus DCIS or invasive cancers
• Excision is indicated for ADH found on core needle biopsy:
  • As concomitant in situ or invasive cancer will be found in approximately 15% of cases (15% to 30% in some series)
• The 10-year risk of developing a breast cancer after a diagnosis of ADH:
  • Is approximately 17%:
    • Risk is bilateral:
      • Breast cancers developing within 5 years of a biopsy of ADH more likely to occur in the ipsilateral breast than those developing more than 5 years (82% ipsilateral in the first 5 years vs 58% ipsilateral after 5 years)
• The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial:
  • Showed that when atypia is found on a sample obtained with needle biopsy and excision rules out cancer:
    • Tamoxifen reduces the risk of developing breast cancer by about 86%:
      • These patients should therefore be referred for discussion about this endocrine prophylaxis
• Similarly, the Study of Tamoxifen and Raloxifene (STAR, NSABP P-2) trial:
  • Which randomized post-menopausal women to tamoxifen or raloxifene, found that raloxifene provided equivalent risk reduction to tamoxifen with less toxicity (e.g., endometrial cancer)
• References:
  • Coopey SB, Mazzola E, Buckley JM, et al. The role of chemoprevention in modifying the risk of breast cancer in women with atypical breast lesions. Breast Cancer Res Treat. 2012;136:627-633.
  • Heller SL, Moy L. Imaging features and management of high-risk lesions on contrast-enhanced dynamic breast MRI. AJR Am J Roentgenol. 2012;198:249-255.
  • Krishnamurthy S, Bevers T, Kuerer H, Yang WT. Multidisciplinary considerations in the management of high-risk breast lesions. AJR Am J Roentgenol. 2012;198:W132-140.
  • Hartmann LC, Radisky DC, Frost MH, et al. Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. Cancer Prev Res (Phila). 2014;7:211-217.
  • Vogel VG, Costantino JP, Wickerham DL, et al; National Surgical Adjuvant Breast and Bowel Project. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res (Phila). 2010;3:696-706.

Medullary thyroid cancer (MTC) accounts for ~2–4% of all thyroid cancers and is biologically distinct from papillary and follicular thyroid cancers.

🧠 What makes MTC different?

Arises from parafollicular (C) cells, not follicular cells Produces calcitonin, a key tumor marker Does NOT respond to radioactive iodine Can be sporadic (~75%) or hereditary (~25%)

🧬 The genetic connection

Hereditary MTC is associated with RET mutations Seen in MEN2 syndromes (MEN2A, MEN2B, FMTC) All patients with MTC should undergo genetic testing, regardless of age or family history

🔍 How is MTC diagnosed?

Suspicious thyroid nodule on ultrasound Elevated serum calcitonin (often markedly high) Confirmed by FNA biopsy ± calcitonin washout Imaging to evaluate lymph node involvement

⚖️ How is MTC treated?

The cornerstone of treatment is surgery:

Total thyroidectomy Central neck lymph node dissection Lateral neck dissection when nodes are involved

➡️ Radioactive iodine has no role in MTC.

➡️ Targeted systemic therapies are used in advanced disease.

📈 Prognosis

Highly dependent on stage at diagnosis Early detection → excellent long-term outcomes Lymph node and distant spread worsen prognosis

🦋 Early recognition and expert surgical management are critical.

👨‍⚕️ Dr. Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

Medullary thyroid cancer is rare but requires prompt diagnosis, genetic evaluation, and expert surgical care.

📚 References

Wells SA et al. Revised ATA Guidelines for Medullary Thyroid Carcinoma. Thyroid Elisei R et al. Management of Medullary Thyroid Cancer. Lancet NCCN Guidelines: Thyroid Carcinoma