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• Classically, the RLN is identified intraoperatively in Simon’s triangle, which  is formed by:
  • The common carotid artery laterally
  • The esophagus medially
  • The inferior thyroid artery superiorly
• The recurrent laryngeal nerve  crosses the triangle

• Thyroid neoplasms are classified as two or three molecular groups based on the mutational and gene expression profiles:
  • Two molecular groups:
    • BRAF V600E-like
    • RAS-like
  • Three molecular groups:
    • BRAF V600E-like
    • RAS-like
    • Non-BRAF V600E / non-RAS-like
• The BRAF V600E group:
  • Is most commonly represented by:
    • Papillary thyroid carcinoma (PTC)
• The BRAF V600E-like molecular profile includes:
  • The BRAF V600E mutation
  • Gene fusions involving:
    • BRAF, RET, and neurotrophic receptor tyrosine kinase 1/3 (NTRK1/3)
• RAS-like molecular profiles include:
  • NRAS, HRAS, KRAS, EIF1AX, enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1), Dicer 1, ribonuclease III (DICER1), phosphatase and tensin homolog (PTEN) mutations, BRAF K601E, and gene fusions involving peroxisome proliferator-activated receptor gamma (PPARG) and THADA
• When the three-group molecular classification is applied:
  • PAX8::PPARG gene fusion and mutations of EIF1AX, EZH1, IDH1, SOS1, SPOP, DICER1, and PTEN genes are classified as a non-BRAFV600E-/non-RAS-like group
• Encapsulated / circumscribed thyroid tumors with a predominant follicular growth pattern:
  • Generally have a RAS-like molecular profile
• High grade is histologically defined:
  • As the presence of ≥ 5 mitoses per 2 mm2 and / or tumor necrosis.
• Y, yes; N, no; Q, questionable; PDTC, poorly differentiated thyroid carcinoma; ATC, anaplastic thyroid carcinoma; DHGTC, dif- ferentiated high-grade thyroid carcinoma; IEFVPTC, invasive encapsulated follicular variant of papillary thyroid carcinoma; WDT-UMP, well-differentiated tumor of uncertain malignant potential; NIFTP, non-invasive follicular thyroid neoplasm with papillary-like nuclear fea- tures; FT-UMP, follicular tumor of uncertain malignant potential; FTC, follicular thyroid carcinoma; OCA, oncocytic carcinoma of the thy- roid; TERT, telomerase reverse transcriptase; TP53, tumor protein p53; PAX8, paired box 8

• Patients with ILC have worse surgical outcomes compared to patients with invasive ductal carcinoma (IDC):
  • Measured by positive margin rates
  • Mastectomy rates
  • Axillary dissection rates
• Many potential causes:
  • Higher stage at presentation
  • Higher discordance between clinical stage and pathologic stage
  • Lower sensitivity of standard imaging tools
• Patients with ILC have higher positive margin rates compared to patients with IDC:
  • Secondary to:
    • Diffuse growth pattern
    • Low Imaging Sensitivity:
      • Leading to higher positive margin rates

• Positive margins have negative consequences:
  • Significant lower breast satisfaction and sexual well-being at two years among those who require re-excision after breast conservation surgery (BCS)
  • Significant higher rates of surgical site infection (SSI), seroma / hematoma, and fat necrosis
  • Healthcare costs increased 4-fold for patients requiring re-excision
  • Increased risk of recurrence if two addressed
• ILC:
  • Mammographically occult disease
  • MRI significantly underestimates size
  • Positive margins
• Should patients with ILC always choose mastectomy?
  • Historically mastectomy was recommended for ILC specifically because of the diffuse growth pattern
  • More modern series show similar rates of recurrence between BCS with radiation vs. mastectomy for ILC
• Rates of BCS for ILC have increased over time:
  • However the rate for BCS for ILC is lower that for IDC:
    • This is despite large series showing improved outcomes with breast conservation surgery compared to mastectomy:
      • US National Cancer Database Analysis of > 160,000 patients showed same or better overall survival (OS) with BCS compared to mastectomy
      • A Swedish study of nearly 50,000 patients showed improved OS with BCS compared to mastectomy (included 5,893 patients with ILC)
      • The higher rates of nodal positivity in ILC leads to increased likelihood of needing postmastectomy radiation:
        • Implications for radiation and reconstructive complications

• BCS for patients with ILC > 4 cm:
  • BCS trial excluded patients with tumors > 4 cm
  • Retrospective analysis have shown BCT to be safe in IDC greater than 4 cm:
    • But not studied in ILC
  • Patients with ILC are more likely to present with larger tumors than IDC

• In multivariable logistic regression model having larger tumors, higher N stage, HER2+ or triple negative subtype:
  • Were associated with significantly higher risk of recurrence:
    • The type of surgery does not affect these long-term outcomes
  • If negative margins are achieved:
    • There is no difference in recurrence rates for BCT vs mastectomy in ILC cases > 4 cm:
      • Important to note that over 50% of BCT group had positive margins and needed re-excision
• Surgical approaches to reduce positive margin rates in ILC:
  • Oncoplastic surgery:
    • Level 1: local tissue rearrangement only
    • Level 2: parenchymal flaps and skin resection
  • Selective shave margins
• Success rates for re-excision of positive margins after BCS in ILC:
  • Roughly 75%
• Factors associated with successful re-excison

• Positive margins after mastectomy for ILC

Practice-Changing Insights from the SUPREMO Trial at the San Antonio Symposium

The SUPREMO trial (Selective Use of Postoperative Radiotherapy After Mastectomy) presented its long-term results at the recent San Antonio Breast Cancer Symposium, marking a significant moment in the management of intermediate-risk breast cancer. As the only practice-changing presentation at the symposium, this trial provides robust evidence for the de-escalation of chest wall irradiation (CWI) in specific patient populations following mastectomy.

About the Trial:

SUPREMO is a phase III international, multicenter trial designed to assess whether CWI improves overall survival (OS) or reduces recurrence in intermediate-risk breast cancer patients. This group includes patients with tumors exhibiting certain characteristics that make the need for postoperative radiotherapy uncertain【1】【2】.

Key Findings (Median Follow-Up: 9.6 Years):

• Overall Survival (OS):

No statistically significant difference was observed in 10-year OS between patients receiving CWI (81.4%) and those who did not (82.0%). This confirms that CWI does not confer a survival advantage in this population【1】【2】【3】.

• Local Recurrence:

While CWI reduced the relative risk of chest wall recurrence by more than 50%, the absolute reduction in recurrence was less than 2%, deemed clinically insignificant for most patients【2】【3】.

• Subgroup Analysis:

Both node-negative patients (N0) and those with T1-T2 tumors with 1-3 positive lymph nodes (N1) demonstrated no OS advantage with CWI. This suggests that many intermediate-risk patients, previously considered candidates for postoperative radiotherapy, may safely omit this treatment【1】【3】.

Clinical Implications:

The SUPREMO trial supports a tailored, de-escalated approach to radiation therapy in intermediate-risk breast cancer patients. By identifying subgroups unlikely to benefit from CWI, clinicians can reduce treatment-related morbidity while maintaining excellent oncologic outcomes. Patients meeting the following eligibility criteria may particularly benefit from this evidence【1】【2】:

1. pT1-2, N1 Disease: Tumors ≤50 mm with 1-3 positive axillary lymph nodes.

2. pT3, N0 Disease: Tumors >50 mm with no nodal involvement.

3. High-Risk Features in Node-Negative Disease: Tumors >20 mm but ≤50 mm with grade 3 histology and/or lymphovascular invasion (LVI).

Context and Broader Impact:

These findings align with an ongoing shift toward de-escalation strategies in oncology, prioritizing individualized treatment plans that balance efficacy and quality of life. The trial provides additional support for reducing overtreatment, especially in light of advancements in systemic therapies, which may further mitigate recurrence risk in intermediate-risk breast cancer【3】【4】.

Future Directions:

While SUPREMO guides practice for intermediate-risk patients, further research is needed to refine the role of radiotherapy in other subgroups, including those with high-risk features or specific molecular subtypes. Additionally, long-term follow-up beyond 10 years will provide further clarity on late recurrences and survival outcomes【4】.

References:

1. Kunkler, I. H., et al. Postmastectomy Radiotherapy for Intermediate-Risk Breast Cancer: Results from the SUPREMO Trial. Lancet Oncology, 2023.

2. San Antonio Breast Cancer Symposium 2023. SUPREMO Trial Results. [Conference Abstracts and Presentations].

3. Kunkler, I. H., et al. Radiotherapy De-Escalation in Breast Cancer: Lessons from SUPREMO. Journal of Clinical Oncology, 2023.

4. Smith, B. D., et al. Tailored Radiotherapy Approaches in Breast Cancer. Nature Reviews Clinical Oncology, 2023.

• Data from the Early Breast Cancer Trialists’ Collaborative Group:
  • Meta-analysis of adjuvant systemic therapy trials begun in or before 1995:
    • Show a 30% relative reduction:
      • In breast cancer-related mortality:
        • Associated with adjuvant hormonal therapy and with adjuvant chemotherapy
    • Reduced rates of ipsilateral local recurrence, contralateral cancers, and distant metastases in treated patients:
      • Suggest there is eradication of occult residual disease in many patients
    • The absolute survival benefit of adjuvant therapy:
      • Is greater in node-positive than in node-negative patients
    • The absolute survival benefit of chemotherapy:
      • Is greater for younger (less than 50 years of age) than for older women (50 to 69 years of age)

• References:
  • Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet. 2005;365(9472):1687-1717.
  • Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353(17):1784-1792.

• In October 2016:
  • The AJCC (www.cancerstaging.org) published the eighth edition of the AJCC / TNM cancer staging system:
    • Which replaced the seventh edition that had been used by clinicians, cancer registries, and researchers since 2009
  • On January 1st, 2018:
    • Tumor registries officially began using the eighth edition for tumor staging
• Whereas the staging tables for medullary thyroid cancer and anaplastic thyroid cancer:
  • Showed only minimal changes:
    • The rules for the staging of well-differentiated thyroid cancer underwent substantial modifications
• These included the following:
  • An increase of the age cutoff from 45 years to 55 years of age at diagnosis
  • Removal of microscopic extrathyroidal extension as a key component of the staging system
  • No longer mandating assignment of stage III to older patients with microscopic extrathyroidal extension or lymph node metastases
  • Establishment of a new T3b category for tumors of any size that demonstrate gross extrathyroidal extension involving only the surrounding strap muscles
• The AJCC Differentiated Thyroid Cancer Committee carefully considered the possibility of inclusion of molecular markers (specifically, BRAF^V600E and TERTpromoter mutations) in the AJCC prognostic staging definitions:
  • Whereas both of these mutations, particularly when present together, have been shown to be predictors of poor clinical outcomes:
    • They appeared to add only marginal benefit to the traditional anatomic staging factors:
      • Thus, molecular characterization of differentiated thyroid cancers, although providing some prognostic information, were not powerful enough factors to merit upstaging tumors to prognostic stages above those mandated by TNM risk factors
      • Nonetheless, similar to the approach used in the ATA risk-stratification system, molecular results can be used to refine further and individualize risk within risk categories or stages
        
• The three critical factors that determine the prognostic stage groups of the eighth edition AJCC / TNM cancer staging system include the:
  • Age at diagnosis
  • The presence or absence of distant metastases
  • The presence or absence of gross extrathyroidal extension
• Rather than the use of the standard TNM staging tables provided in the AJCC / TNM manual:
  • Tuttle el al find it easier to use the flow diagram in Figure 1 to stage patients rapidly based on the key clinical risk factors:
    • Age at diagnosis
    • Distant metastasis
    • Gross extrathyroidal extension
    • Lymph node metastases
• In patients age < 55 years:
  • This figure rapidly classifies patients as either:
    • Stage I (any T, any N, M0)
    • Stage II (any T, any N, M1)
• In patients age > 55 years:
  • In the older patients, additional factors, such as the presence or absence of distant metastasis, invasion of strap muscles, and extent of gross extrathyroidal extension, are also used to define the prognostic stage groups
• In the eighth edition of the AJCC / TNM cancer staging system:
  • It was anticipated that the majority of patients would be classified as stage I or stage II:
    • Reflecting the excellent outcomes expected in the majority of thyroid cancer patients
    • A smaller number of patients, particularly the older patients with either distant metastases or gross extrathyroidal extension:
      • Were anticipated to do worse and are therefore classified as stage III or IV
• Multiple publications have demonstrated that the eighth edition of the AJCC / TNM cancer staging system:
  • Moved a substantial number of patients into lower prognostic stage groups without affecting the overall survival of those lower-stage groups
  • The patients who remained in the higher-stage groups had poorer prognoses, as expected
  • This resulted in a much better separation of the four prognostic stage groups with respect to survival:
    • Such that 5- to 10-year disease-specific survival (DSS) was:
      • 99% in stage I patients
      • 88% to 97% in stage II patients
      • 72% to 85% in stage III patients
      • 67% to 72% in stage IV patients
• Unlike previous editions of the AJCC / TNM staging system in which there was substantial overlap in survival in patients with stage I, II, and III disease:
  • The eighth edition provides meaningful separation among the prognostic stage groups that appear to be clinically relevant
  • The differences in predicted and published ∼10-year survival rates are best seen when analyzed based on age group (age <55 years vs age ≥55 years):
    • The predicted 10-year DSS has been validated for all age and stage groups, with only the younger (age < 55 years) stage II patients appearing to do more poorly than anticipated
    • The lower-than-anticipated 10-year DSS in the younger patients (age < 55 years) with stage II disease was the result of the stage migration of patients in the 45- to 55-year age group from seventh edition AJCC stage IV to eighth edition AJCC stage II

• Risk stratification begins:
  • Immediately upon identification of a suspicious thyroid nodule
• In the absence of a validated peri-diagnostic risk-stratification system, I use a clinical framework that incorporates:
  • Tumor imaging characteristics, medical team characteristics, and patient preferences to risk stratify patients as:
    • Ideal
    • Appropriate
    • Inappropriate for minimalistic initial management options:
      • Such as active surveillance or thyroid lobectomy
      • This clinical framework address the key factors that differentiate actionable from non-actionable disease

#Arrangoiz #ThyroidSurgeon #ThyroidExpert #ThyroidCancer #DynamicRiskStartification #HeadandNeckSurgeon #CancerSurgeon #MountSinaiMedicalCenter #MSMC

• The administration of neoadjuvant chemotherapy (NAC):
  • Offers several advantages in locally advanced breast cancer:
    • It allows for downstaging the disease:
    • Which can potentially allow for less extensive surgery in the breast and axilla
  • It also provides information regarding the responsiveness of the cancer to systemic therapy while the tumor remains in vivo:
    • Which can guide the course of therapy
• Administering chemotherapy in the neoadjuvant vs. adjuvant setting:
  • Does not change overall survival:
    • As demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and NSABP B-27 trials
• The patient’s response to chemotherapy:
  • However, does offer prognostic information:
    • Particularly in patients with hormone receptor negative (HR-) disease
• Patients who achieve pathologic complete response (pCR):
  • Which is typically defined as no residual invasive disease in the breast or axilla:
    • Appear to have improved event-free survival (EFS) and overall survival (OS) compared with patients with residual disease
    • This finding was demonstrated by a recent meta-analysis that included 36 studies including 5,768 patients with HER2 positive breast cancer:
      • This correlation was strongest in patients with HR- disease
    • Further, among patients with HER2 positive disease that do not have a pCR:
      • The degree of residual cancer burden appears to correlate with outcomes
• Patients with HER2 positive tumors:
  • May complete up to 1 year of HER2-targeted therapy with trastuzamab ± pertuzamab
• When planning surgery:
  • The pre-treatment volume does not need to be excised if the tumor has responded to chemotherapy:
    • However if multifocal disease is present, the satellite lesion(s) should be localized and excised with the index lesion
  • When considering the appropriateness for breast conservation following NAC, the distance between the lesions, location, and breast size must be considered
  • Placement of clips in the index lesion and any satellite lesions prior to initiation of NAC is critical for appropriate surgical planning post-NAC
• References:
  • Rastogi P, Anderson SJ, Bear HD. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008; 10;26(5):778-785.
  • Broglio KR, Quintana M, Foster M, et al. Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis. JAMA Oncol. 2016;2(6):751-760.
  • Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049-1060.
  • Boughey JC, Peintinger F, Meric-Bernstam F, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg.2006;244(3):464-470.

• Adenoid cystic carcinoma (ACC) of the breast:
  • Is a very rare special histological type of breast cancer:
    • Accounting for approximately 0.1% of all breast tumors
  • It is usually triple negative
  • It is much less likely to have nodal involvement
  • Is more common in postmenopausal women:
    • Most cases are in females
    • The median age of onset is:
      • Between 50 and 60 years
    • With a mean age of 66
  • The typical clinical feature is:
    • A single breast tumor / mass:
      • Multiple nodules are rare
    • Most ACCs are located:
      • Under the areola or in the upper outer quadrants
  • ACC of the breast has no characteristic imaging findings:
    • Ultrasound features are those of:
      • A hypoechoic solid or heterogeneous mass
    • On mammography:
      • The case may present as a lobulated mass with sharp or un sharp margins
    • Nevertheless, these clinical and radiographic features may be similar to any breast cancer:
      • Thus making their precise diagnosis difficult for radiologists
  • Histologically:
    • ACC of the breast typically consists of a dual-cell population of:
      • Luminal and myoepithelial-basal cells:
        • Which are generally negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)
    • In addition, some studies have also reported some HR-positive ACC cases:
      • The significance of a positive hormone receptor status is not known:
        • Compared with ACC with negative HR expression, the clinical characteristics and prognosis of this type of ACC are also unknown
  • Distant metastases are rare:
    • However, the lung is the most common site
  • It has a better prognosis than infiltrating ductal triple negative breast cancer:
    • With a 5-year overall survival rate of 88%
    • As prognosis is good:
      • Accurate preoperative diagnosis is important in the determination of suitable treatment

• References
• Treitl D, Radkani P, Rizer M, El Hussein S, Paramo JC, Mesko TW. Adenoid cystic carcinoma of the breast, 20 years of experience in a single center with review of literature. Breast Cancer. 2018;25(1)28-33.
• Welsh JL, Keeney MG, Hoskin TL, et al. Is axillary surgery beneficial for patients with adenoid cystic carcinoma of the breast? J Surg Oncol. 2017;116(6):690-695.
• Kulkarni N, Pezzi CM, Greif JM, et al. Rare breast cancer: 933 adenoid cystic carcinomas from the National Cancer Data Base. Ann Surg Oncol. 2013;20(7):2236-2241.
• Kshirsagar AY, Wader JV, Langade YB, Jadhav KP, Zaware SU, Shekhar N. Adenoid cystic carcinoma of the male breast. Int Surg (2006) 91(4):234–6.
• Pang W, Wang Z, Jin X, Zhang Q. Adenoid cystic carcinoma of the breast in a male: A case report. Med (Baltimore) (2019) 98(32):e16760. doi: 10.1097/MD.0000000000016760
• Tang W, Peng WJ, Gu YJ, Zhu H, Jiang TT, Li C. Imaging Manifestation of Adenoid Cystic Carcinoma of the Breast. J Comput Assist Tomogr (2015) 39(4):523–30. doi: 10.1097/RCT.
• Torrao MM, da Costa JM, Ferreira E, da Silva MV, Paiva I, Lopes C. Adenoid cystic carcinoma of the breast. Breast J (2007) 13(2):206.
• Marchio C, Weigelt B, Reis-Filho JS. Adenoid cystic carcinomas of the breast and salivary glands (or ‘The strange case of Dr Jekyll and Mr Hyde’ of exocrine gland carcinomas). J Clin Pathol (2010) 63(3):220–8. doi: 10.1136/jcp.2009.073908

#Arrangoiz @BreastSurgeon #BreastCancer #AdenocysticCarcinomaoftheBreast #ACC #SurgicalOncologist #CASO #CenterforAdvancedSurgicalOncology #Miami