Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Primary treatment with concurrent chemotherapy and radiation therapy has been accepted widely as a standard of care:
  • Since the publication of the Meta-Analysis of Chemotherapy on Head and Neck Cancer in 2000:
    • This meta-analysis was later updated in 2009:
      • Involving an analysis of 50 trials:
        • That showed an absolute survival benefit of 6.5% at 5 years:
          • Associated with administering chemotherapy concurrently with radiation
• Bolus cisplatin (100 mg/m2 on days 1, 22, and 43) concurrent with radiation therapy:
  • Has been extensively studied:
    • May be considered the standard to which other chemotherapy regimens are compared in clinical research
  • The intergroup trial conducted by Adelstein and colleagues was influential in establishing this regimen (bolus cisplatin 100 mg/m2 on days 1, 22, 43 concurrent with radiation therapy) as a standard of care (Figure)

• In a three-arm randomized phase III trial of 295 patients with locally advanced (unresectable) stage M0 head and neck squamous cell carcinoma:
  • The treatment groups were radiation therapy alone (70 Gy) versus identical radiation plus concurrent cisplatin (100 mg / m2 administered intravenously on days 1, 22, and 43) versus a split course of radiation with cisplatin plus 5-FU
  • With a median follow up of 41 months:
    • The concurrent cisplatin / radiation arm had a significant advantage in:
      • Survival at 3 years compared with radiation alone:
        • 37% versus 23%, p = .014
    • Survival in the split-course concurrent arm:
      • 27% was not significantly better than that in the radiation arm
      • This improved efficacy comes at the cost of an increased incidence of acute toxicities, including:
        • Mucositis and nausea / vomiting:
          • Four toxic deaths occurred among 95 patients enrolled in the cisplatin chemoradiation arm
• The intergroup Radiation Therapy Oncology Group (RTOG 91–11) trial for advanced larynx cancer (Figure):

• Established concurrent bolus cisplatin with radiation as a standard of care
• The study was open to patients with:
  • Squamous cell carcinoma of the glottic or supraglottic larynx
• Patients with T1 disease or large-volume T4 disease:
  • Were excluded
• Median follow-up of the study was:
  • 3.8 years
• Patients were randomly assigned to one of three larynx preservation strategies:
  • Induction cisplatin plus 5-FU followed by radiotherapy:
    • Patients with less then partial response after 2 cycles of PF:
      • Underwent laryngectomy followed by adjuvant radiotherapy
  • Radiotherapy with concurrent cisplatin
  • Radiotherapy alone
• The dose of radiotherapy to the primary tumor and clinically positive nodes was:
  • 70 Gy in all treatment groups
• Severe or life-threatening mucositis in the radiation field:
  • Was almost twice as common in the concurrent treatment group compared with either the radiotherapy alone group or the sequential treatment group
• The primary endpoint of the study was:
  • Preservation of the larynx
• The rate of laryngeal preservation was:
  • 84% for patients receiving radiotherapy with concurrent cisplatin
  • 72% for patients receiving induction chemotherapy followed by radiation
  • 67% for patients receiving radiation therapy alone
• Distant metastases were reduced in patients who received either:
  • Concurrent chemoradiotherapy or induction chemotherapy followed by radiotherapy:
    • Compared with patients who received radiotherapy alone
• Overall survival was not significantly different among the three treatment groups:
  • The lack of an overall survival difference between the three groups:
    • May be due to the contribution of salvage laryngectomy in all groups:
      • As well as a 2% increase in the incidence of death that may have been related to treatment in the concurrent chemoradiotherapy group compared with the other two treatment groups
• It is important to recognize that the primary endpoint of the study was larynx preservation:
  • Not overall survival
• The current standard of care for larynx preservation:
  • Remains concurrent high-dose cisplatin and radiation for patients who fit the eligibility criteria that were used in RTOG 91–11

• The Groupe d’Oncologie Radiotherapie Tete et Cou trial:
  • Is important because it evaluated the concomitant approach in patients with:
    • Oropharynx cancer only (Figure)
  • A total of 226 patients were randomly assigned to either radiation therapy alone (70 Gy) or radiation therapy (70 Gy) with concurrent carboplatin and infusion 5-FU
  • Significant benefits in 5-year:
    • Overall survival:
      • 22% versus 16%, p = .05
    • Locoregional control:
      • 48% versus 25%, p = .002
        • Were noted in the combined treatment arm
    • Complete responses were observed in a significant number of patients:
      • Thus avoiding the sequelae and short-term morbidity of surgical resection

• Phase II trials also support the feasibility of administering other chemotherapy regimens concurrently with radiation therapy for patients with locoregionally advanced head and neck cancer, including but not limited to:
  • Cisplatin plus paclitaxel
  • Cisplatin plus infusional 5-FU
  • 5-FU plus hydroxyurea
  • Carboplatin plus paclitaxel
  • Paclitaxel, 5-FU, and hydroxyurea
• The role for cetuximab in combined modality therapy:
  • Was established when Bonner and colleagues randomly assigned 424 patients with locoregional advanced head and neck squamous cell cancer to treatment with:
    • Radiation therapy alone or radiation therapy with concurrent weekly cetuximab (Figure)

• Investigators were required to choose between one of three radiotherapy fractionation regimens:
  • With a total dose of 70 to 76.8 Gy
• With a median follow-up of 54 months:
  • The combined treatment group had significantly improved:
    • 3-year locoregional control:
      • 47% versus 34%, p < .01
    • 3-year overall survival:
      • 55% versus 45%, p = .05
        • Compared with the group that received radiation therapy alone
• Cetuximab was associated with an increased risk of:
  • Severe acneiform rash (17%) and severe infusion reaction (3%)
• While cetuximab and radiotherapy is a valid treatment option for this patient population:
  • Retrospective studies have suggested that cetuximab may be associated with inferior outcomes compared with cisplatin and carboplatin plus infusional 5-FU:
    • Riaz et al., 2016; Shapiro et al., 2014
• Recently, two randomized phase III trials were conducted to test if cetuximab may serve as a non-inferior and less toxic alternative to cisplatin in combination with radiation for patients with localized HPV-positive oropharyngeal carcinomas (which possess superior clinical outcomes with cisplatin chemoradiation compared to HPV-negative patients; Ang et al., 2010):
  • The De-ESCALaTE HPV trial:
    • Restricted enrollment to low risk HPV-positive patients (less than 10 pack-year smoking history):
      • They observed a significantly superior 2-year overall survival with cisplatin over cetuximab:
        • 97.5% versus 89.4%; hazard ratio 5.0 [95% CI 1.7-14.7]; p=0.001; Mehanna et al., 2018
  • RTOG 1016 also demonstrated that among HPV-positive oropharyngeal cancer patients:
    • Cetuximab failed to meet the pre-specified non-inferiority criteria for overall survival compared to cisplatin:
      • Estimated 5-year overall survival of 77.9% [95% CI 73.4-82.5] with cetuximab versus 84.6% [95% CI 80.6-88.6] with cisplatin; Gillison et al., 2018
  • Both trials also demonstrated that toxicity rates were not significantly lower with cetuximab
  • Taken together, these prospective data argue strongly for prioritizing the use of cisplatin in these clinical settings and reserving the use of cetuximab with radiation in those who are not cisplatin-candidate

#Arrangoiz #CancerSurgeon #HeadandNeckSurgeon #SurgicalOncologist #LarynxCancer #MountSinaiMedicalCenter #MSMC #Miami #Mexico

• Immunohistochemical features suggestive of progression:
  • Proliferation index (Ki-67):
    • DCIS grade 2 / DIN 2 have a low proliferation index
    • DCIS grade 3 / DIN 3 have a high proliferation index

• Immunohistochemical features suggestive of progression:
  • Protein markers:
    • Hormone receptor status:
      • ER, PR, HER2
    • Other protein markers:
      • COX2, p16, p53, etc
  • The majority of the protein markers correlated with grade:
    • But are associated with significant heterogeneity

• At this point in time we do not have a single robust biomarker:
  • That can predict the risk of progression of DCIS to IBC
• Can combinations of biomarkers predict the risk of progression (clinico-pathological prediction models)?
  • Unclear clinical validity of prediction models combining biomarkers (Schmitz, R. Cancers. 2022):
    • They lack of external validation
    • They do not include the option of active surveillance
• Molecular features suggestive of progression:
  • Gene expression analysis:
    • Intrinsic subtypes of DCIS:
      • Higher frequency of luminal B and HER2 subtypes
      • They are NOT prognostic of recurrence in DCIS
    • Gene expression differs extensively across tumors:
      • No specific gene expression profile exists that can predict progression in DCIS
      • Confounded by intrinsic subtypes?
      • The intrinsic subtypes are related to different pathways:
        • One of the pathways is tumor micro environment
  • Genetic alterations:
    • There are increase in genetic alterations in the progression from usual ductal hyperplasia to IBC:
      • P53 mutation within the epithelial cell
    • DCIS is a genetically advanced lesion with marked intratumoral heterogeneity:
      • The higher the grade (grade 3 DCIS / DIN3) the more genetic alterations identified

• The majority of the studies on molecular analysis in DCIS are describing synchronous alterations:
  • They are comparing tumor cells from the DCIS or IBC from the same lesion
  • Not subsequent events from the same (untreated) lesion
• In these lesions DCIS and IBC share most genetic mutations and copy number alterations:
  • Most common mutations:
    • PIK3CA and TP53
• No known genetic mutations can differentiate progressive from indolent DCIS:
  • Progression of DCIS varies from patient to patient
    • The lack of clear genetic alterations helping us identify progression points us towards:
      • Tumor micro environment and stroma
• Summary:
  • DCIS is a very heterogenous disease
  • Biological question is what drives or inhibits progression of DCIS
  • The majority of studies describes observations of varying events
  • Synchronous DCIS and IBC share most genetic alterations:
    • Though not universal, but case to case based
  • No known genetic alterations / morphological features can estimate risk of progression:
    • Leading interest towards micro environment
  • Awaiting active surveillance studies

• DCIS is a proliferation of malignant epithelial cells:
  • Confined to the mammary ducts and without evidence of invasion through the basement membrane
• They arise from ductal epithelium:
  • In the region of the terminal ductal–lobular unit
• DCIS had previously been considered one stage in the continuum of histologic progression from ADH to invasive carcinoma:
  • It is now understood that DCIS comprises a heterogeneous group of lesions:
    • With variable histologic architecture, molecular and cellular characteristics, and clinical behavior (Figure)
• Malignant cells proliferate until the ducts is obliterated:
  • There may be associated breakdown of the myoepithelial cell layer of the basement membrane surrounding the ductal lumen
• DCIS has also been linked with changes in the surrounding stroma:
  • Resulting in fibroblast proliferation, lymphocyte infiltration, and angiogenesis
• Thus, although the process is poorly understood:
  • Most, but not all, invasive ductal carcinomas are believed to arise from DCIS:
    • Therefore, DCIS is considered a nonobligate precursor of invasive breast carcinoma with a variable risk of progression:
      • Depending on a combination of pathologic factors:
        • These factors include:
          • Growth pattern, histologic grade, presence or absence of necrosis, size of the lesion, margin status, and expression of tumor biomarkers (estrogen and progesterone receptors)

• Common growth patterns of DCIS include:
  • Solid, cribriform, micropapillary, and papillary
  • Cribriform, solid, and micropapillary:
    • Are the more common subtypes:
      • Two or more patterns coexist in up to 50% of cases
• Nuclear grading is based on:
  • The size, texture, and nucleoli
• Similar to invasive carcinoma, three grades are recognized for DCIS:
  • Low-grade lesions:
    • Are characterized by a proliferation of monotonous cells with well-defined cell borders:
      • Uniformity of nuclear features is the key feature
  • Intermediate grade lesions:
    • Have nuclear features are in between low and high grade:
      • Central (comedo) necrosis is most frequently associated with high-grade lesions:
        • Less frequently found in intermediate lesions and very rarely present in low-grade lesions
  • High-grade DCIS is composed of pleomorphic cells with variable nuclear size and shape:
    • Mitoses are frequent in individual cells and comedonecrosis is common
  • Both the World Health Organization (WHO) and the College of American Pathologists (CAP):
    • Recommend that architectural and nuclear features and the presence of comedonecrosis should be evaluated independently of one another and all of these features should be included in pathology reports
• Since DCIS only rarely forms a grossly visible mass:
  • Measurement of lesion size is typically done by microscopic evaluation:
    • The pathologist must be able to reconstruct the specimen to estimate size of the lesion:
      • This is a difficult task and requires that the histologic sections be submitted in orderly fashion to permit such reconstruction:
        • Even so, it is sometimes difficult to assess lesion size when small foci of DCIS are scattered throughout the resected specimen:
          • As most recurrences of DCIS probably represent persistence of DCIS following incomplete removal:
            • The evaluation of margins is not trivial
      • Routine specimen mammography and careful sectioning of the specimen are required
      • The most common approach involves the application of different colored inks to the surfaces of a specimen that has been oriented by the surgeon
      • The specimen is then submitted for histologic examination in serial sections and the shortest distance between DCIS and the inked margin is reported as the margin width
• In a joint consensus statement, the Society of Surgical Oncology (SSO), the American Society for Radiation Oncology (ASTRO), and the American Society of Clinical Oncology (ASCO):
  • Recommended the margin width for breast-conserving surgery for DCIS to be 2 mm based on data from patients treated with adjuvant whole-breast radiation:
    • A 2-mm margin was determined after comparison to narrower margin widths demonstrated a significant decrease in in-breast recurrence:
      • However, the panel recommended exercising clinical judgment based on other clinical and imaging factors when determining the need for reoperation for re-excision for patients with margins < 2 mm
• In addition to tumor factors:
  • Stromal features have also been found to be prognostic in DCIS lesions:
    • The presence of periductal fibrosis has been associated with increased likelihood of recurrence
    • Stromal tumor-infiltrating lymphocytes (TILs):
      • Have been found to be associated with:
        • Younger age, larger tumor size, higher nuclear grade, comedonecrosis, and estrogen receptor negative status
• Given all of these considerations, the pathology report in cases of DCIS should include a large amount of data:
  • The College of American Pathologists (CAP) has recommended use of a template form to ensure that all histopathologic data are reported:
    • Such a form would typically include histologic pattern, nuclear grade, presence of necrosis, distance to margin, size, presence of calcifications, and status of estrogen and progesterone receptor expression

• In the curative intent setting:
  • Concurrent chemoradiation is associated with risk of severe acute and long-term toxicities
• The combined results of four prospective trials:
  • Indicate that the rate of acute treatment-related death for standard cisplatin based chemoradiation:
    • For locally advanced head and neck squamous cell carcinoma:
      • Is approximately 4%:
        • 22 treatment related deaths among 545 patients
• Acute mucositis in the radiation field:
  • Can compromise nutritional intake severely,  and placement of a percutaneous gastrostomy tube:
    • Often is an effective strategy to improve nutrition in this setting
• Dermatitis in the radiation field:
  • Varies in severity among patients:
    • This issue has received increasing attention since the 2006 Food and Drug Administration approval for the use of cetuximab concurrent with radiation therapy for persons with head and neck squamous cell carcinoma
• Long-term complications of chemoradiation can include:
  • Xerostomia
  • Hypothyroidism
  • Trismus
  • Pharyngeal stricture
  • Osteoradionecrosis
• Although xerostomia remains a common long-term symptom after treatment:
  • The incidence of xerostomia with intensity-modulated radiation therapy:
    • Appears to be lower than the incidence associated with three-dimensional conventional radiotherapy
• Regarding hypothyroidism, in a review of 118 patients who participated in phase I / II trials of sequential chemotherapy and radiation for stage III / IV head  and neck cancer:
  • Elevated levels of thyroid-stimulating hormone  were detected in 45% of patients:
    • At a median of 24 months after radiation therapy
• Stricture requiring pharyngoesophageal dilation:
  • May occur in up to 21% of patients who receive definitive radiotherapy
    • The primary tumor site in the hypopharynx or oropharynx:
      • Has been identified as a risk factor for pharyngeal stricture in retrospective studies
• Fibrosis of the muscles of mastication:
  • As a consequence of chemoradiation may result in trismus:
    • Although the retrospective nature of this data has limited the ability to clearly establish risk factors for trismus
• For patients receiving combined modality therapy, accurate and comprehensive measurement of treatment-associated adverse events is challenging:
  • In clinical trials, traditional methods of toxicity reporting describe the frequency and severity of cumulative adverse events during the treatment interval.
  • The National Cancer Institute Common Toxicity Criteria for Adverse Events is a widely used method for toxicity reporting of this nature:
    • However, it is recognized that traditional methods probably do not fully summarize the extent and magnitude of acute and long-term adverse events
    • To address these concerns, a new reporting system (“TAME”) designed to account for the multiplicity and time dimensions of adverse events has been developed
• In a retrospective analysis of five trials for patients with head and neck cancer that was performed by the RTOG, the newer method appeared better able to distinguish between the acute toxicity burdens among treatment groups compared with traditional methods for summarizing adverse events

• Non-invasive follicular thyroid neoplasm with papillary-like nuclear features:
  • NIFTP is the pathological definition of a type of noninvasive follicular cell-derived thyroid neoplas:
    • That was first described in 2016
  • This topic post-dated the 2015 ATA thyroid nodule and DTC guidelines:
    • But a subsequent ATA task force statement in 2017 supported adoption of the NIFTP nomenclature for this entity
  • In 2017, NIFTP were classified as a distinct category in the revised WHO Classification of Tumors of Endocrine Organs:
    • Corresponding to a neoplasm with very low malignant potential
  • NIFTP:
    • Comprise approximately 2.1% to 9.6% of follicular cell derived thyroid neoplasms;
      • With relatively lower incidence in Asia than in North America and Europe
  • NIFTP:
    • Are characterized by validated histological inclusion and exclusion features (Table):
      • The original NIFTP validation study excluded tumors:
        • Measuring ≤ 1 cm
        • Those with oncocytic features
    • However, as subsequent literature has shown that tumors measuring ≤ 1 cm (micro-NIFTPs) or with oncocytic features (oncocytic-NIFTPs):
      • Demonstrate similar clinical behavior to those of original NIFTP these features also are included in the tumor’s current pathological definition
  • The initial definition of NIFTP had required the presence of < 1% papillae:
    • But subsequent experience has shown this feature can be associated with:
      • Lymph node metastases:
        • Therefore, the diagnostic criteria have been revised to require that papillae are absent
  • It is recommended to carefully examine the entire tumor capsule interface and tumor:
    • To exclude the possibility of invasive features and presence of papillae
  • NIFTPs:
    • Often coexist with one or more NIFTPs or other thyroid malignancies in the ipsilateral or contralateral lobes.
  • Studies assessing the molecular profile of NIFTPs:
    • Have shown them to be clonal neoplasms
  • Molecular alterations are present in approximately 78% of cases:
    • With approximately 30% to 54% of NIFTP tumors:
      • Harboring a RAS mutation:
        • NRAS mutations most common:
          • Followed by HRAS and rarely KRAS mutations
      • However, the NRAS mutations seen in NIFTPs may also be identified in FTCs and IEFVPTC:
        • Therefore, they are nonspecific
    • A small subset of NIFTP cases have been shown to harbor:
      • PAX8::PPARc fusions
      • THADA fusions
      • BRAF K601E mutations
    • Some studies also have explored miRNA expression in NIFTP cases:
      • Demonstrating that two mi-RNAs (miR-10a05p and miR-320e):
        • Can effectively discriminate between NIFTP and the infiltrative follicular variant of PTC:
          • Further studies are required to validate these findings
  • While NIFTPs are characterized by:
    • A follicular growth pattern and nuclear features of PTC:
      • They are associated with extremely low malignant potential
    • Several multiinstitutional series (largest sample, n = 363), including several that reclassified DTCs as NIFTP upon retrospective analyses:
      • Have mostly reported zero risk of disease persistence / recurrence:
        • Over a mean or median follow-up of up to 11.8 years
    • Lymph node metastases:
      • Have been seen in < 5% of the total cohort and in only a few series
    • Only one retrospective analysis of 102 cases showed the presence of distant metastases (to the lungs) in one case:
      • Although this study was limited by incomplete follow-up (80%) and a high proportion of patients who received more aggressive care (total thyroidectomy and radioiodine ablation)
  • At present, there are no available data comparing the clinical benefits and harms of various short- and long-term monitoring strategies in patients with NIFTP tumors

• Surgical Management of DCIS (2024 to 2025 Update):
  • Re-excision vs Mastectomy:
    • Re-excision is indicated for positive (ink-on-tumor) margins after lumpectomy;
      • Unless specific skin-only or fascia-only circumstances justify margin acceptance:
        • Always document clearly
    • Total mastectomy is appropriate when negative margins cannot be achieved, or if disease is diffuse or multifocal:
      • Most mastectomy patients do not require radiotherapy after DCIS resection
  • Reference:
    • American Cancer Society. Treatment of ductal carcinoma in situ (DCIS). accessed June 2025.
  • Reference:
    • American Society of Breast Surgeons. “Margins in Breast Conservation Surgery: Resource Guide.” 2024.
  • Axillary Management:
    • Avoid ALND (axillary lymph node dissection):
      • In pure DCIS without clinical / radiologic evidence of invasion or nodal disease
    • SLNB (sentinel lymph node biopsy):
      • Omit for pure DCIS treated with BCS when there’s no clinical / radiological suspicion of invasion:
        • Nodal involvement is very low
      • Perform or strongly consider if:
        • Mastectomy is planned (because SLNB is not feasible afterward if invasion is unexpectedly found)
        • There’s high suspicion of invasion (e.g., palpable mass, abnormal imaging / biopsy)
        • Excision location could compromise future SLN (upper-outer quadrant /axillary tail)
    • References:
      • American Society of Breast Surgeons, “Management of the Axilla: Position Statement.” 2024.
      • American Cancer Society. Treatment of ductal carcinoma in situ (DCIS). accessed June 2025.
      • NCCN-derived peer-reviewed statement, “Strong consideration for SLNB with mastectomy or mapping-compromising locations,” published in Annals of Surgical Oncology (exact citation not available; institutional statement)
    • Emerging data:
      • Older patients ≥ 50 with radiologically normal axilla undergoing mastectomy:
        • Suggest SLNB may be omitted, but this is not yet in guidelines and must be individualized
      • Reference:
        • Madak-Erdogan et al., Annals of Surgical Oncology, 2023
  • De-escalation and Active Surveillance:
    • Early results from COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) randomized trial in low-risk DCIS:
      • At 2 years active surveillance ± endocrine therapy yielded non-inferior rates of invasive progression compared to surgery /RT:
        • Patient-reported outcomes are pending
      • Long-term outcomes:
        • Not yet available
      • Active surveillance:
        • Should only be considered within clinical trials or carefully selected settings
    • Reference:
      • Narod et al., Journal of Clinical Oncology, 2025; and associated JAMA Oncology report 2025.
• Margins in DCIS:
  • Standard Adequate Margin:
    • For pure DCIS (and DCIS with microinvasion) treated with BCS plus whole-breast radiotherapy:
      • A negative margin of ≥ 2 mm is recommended:
        • Wider margins do not further reduce ipsilateral breast tumor recurrence (IBTR)
    • Reference:
      • Morrow M, Van Zee KJ, Solin LJ, et al. “Society of Surgical Oncology–American Society for Radiation Oncology–American College of Surgeons consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ.” Journal of Clinical Oncology. 2016;34(33):4040–4046.
      • American Society of Breast Surgeons. “Margins in Breast Conservation Surgery: Resource Guide.” 2024.
  • Margin-Width Decision Chart:
    • Ink-positive margins:
      • Re-excision required
        • Reference: American Society of Breast Surgeons. 2024.
    • < 2 mm but still negative:
      • With WBRT planned, re-excision generally not required, unless there are complicating features:
        • Multifocality, specimen fragmentation, APBI plans
      • Reference: American Society of Breast Surgeons. 2024.
    • ≥ 2 mm:
      • Adequate:
        • No evidence to support further wider excision
      • Reference: American Society of Breast Surgeons. 2024.
    • If RT is omitted (e.g., in select older or low-risk patients):
      • Retrospective data suggest wider margins correlate with lower local events:
        • But no definitive guideline threshold exists
        • Document discussions clearly
      • Reference: American Society of Breast Surgeons. 2024.
    • Mixed Invasive + DCIS:
      • Treat according to invasive cancer standards:
        • “No ink on tumor” is adequate, even if DCIS is near the edge
      • Reference: American Society of Breast Surgeons. 2024.
    • DCIS with Microinvasion (≤ 1 mm):
      • Manage margins like pure DCIS:
        • Aim for ≥ 2 mm margin with whole-breast RT
      • Reference: American Society of Breast Surgeons. 2024.
    • Margin Exceptions:
      • Skin-only or fascia-only positive margins after full-thickness excision may be acceptable without re-excision if no residual breast parenchyma remains:
        • Document rationale
      • Reference: American Society of Breast Surgeons. 2024.
    • Atypical ductal hyperplasia (ADH), ALH, or classic LCIS at / near the margin:
      • Should not prompt re-excision:
        • Re-excise based solely on DCIS or invasive cancer margins
      • Reference: American Society of Breast Surgeons. 2024.
    • New Evidence (PRECISION Cohort):
      • PRECISION pooled international cohort (≈ 47,000 DCIS cases) demonstrated that:
        • Margins < 2 mm are associated with higher 10-year ipsilateral events compared to ≥ 2 mm, although absolute differences are modest, supporting the 2 mm standard with RT
      • Reference:
        • PRECISION Collaboration. “Margin width and local recurrence in DCIS: pooled analysis of international cohorts.” BMJ. 2023;383:e076022.
        • PRECISION Collaboration. PubMed; PMID 37903527.
• References:
  • Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology–American Society for Radiation Oncology–American College of Surgeons consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ. Journal of Clinical Oncology. 2016;34(33):4040–4046.
  • American Society of Breast Surgeons. Margins in Breast Conservation Surgery: Resource Guide. 2024. Available from: https://www.breastsurgeons.org/docs/statements/asbrs-rg-margins.pdf
  • American Society of Breast Surgeons. Management of the Axilla: Position Statement. 2024. Available from: https://www.breastsurgeons.org/docs/statements/management-of-the-axilla.pdf
  • American Cancer Society. Treatment of ductal carcinoma in situ (DCIS). Accessible via: https://www.cancer.org/cancer/types/breast-cancer/treatment/…dcis.html (Accessed June 2025).
  • Narod SA, et al. COMET trial early outcomes — active surveillance versus surgery/radiation in low-risk DCIS. Journal of Clinical Oncology. 2025.
  • PRECISION Collaboration. Margin width and local recurrence in DCIS: pooled analysis of international cohorts. BMJ. 2023;383:e076022.
  • PRECISION Collaboration. PMID: 37903527.
    Madak-Erdogan Z, et al. Considerations regarding omission of SLNB in selected DCIS mastectomy patients. Annals of Surgical Oncology. 2023.

• One in eight women in the United States (US):
  • Will be diagnosed with breast cancer in her lifetime:
    • 20% to 25% of these newly diagnosed cases;
      • Will be DCIS
• In 2025:
  • An estimated 59, 080 cases of DCIS:
    • Will be diagnosed in US
• Widespread use of screening mammography:
  • Has resulted in a 10-fold increase in the reported incidence of DCIS since the mid-1980s:
    • However, since 2003:
      • The incidence of DCIS has declined in women aged 50 years and older:
        • Possibly due to decreased use of hormone replacement therapy
      • The incidence of DCIS in women aged under 50 years:
        • Continues to increase
  • Approximately 1 in every 1,300 mammography examinations performed in US:
    • Will lead to a diagnosis of DCIS:
      • Representing 17% to 34% of all mammographically detected breast cancers
  • Before the introduction of screening mammography,:
    • Most cases of DCIS were not detected:
      • Until a palpable mass formed:
        • But today 80% to 85% of DCIS cases are detected on screening mammography
• The incidence of DCIS in autopsy studies is higher than in the general population:
  • Suggesting that not all DCIS lesions are clinically significant:
    • Supporting concerns that most of the increase in DCIS incidence is due to the detection of nonaggressive subtypes:
      • That are unlikely to progress to invasive cancer
• The median age reported for patients with DCIS:
  • Ranges from 47 to 63 years:
    • Similar to that reported for patients with invasive carcinoma
  • However, the age of peak incidence for DCIS:
    • 96.7 per 100,000 women:
      • Occurs between the ages of 65 and 69 years:
        • Which is younger than for invasive breast cancer:
          • For which peak incidence:
            • 453.1 per 100,000 womem:
              • Occurs between the ages of 75 and 79 years
• The frequency of first-degree relatives having breast cancer (10% to 35%) as well as rates of deleterious mutations in the breast cancer–associated (BRCA) genes are:
  • Similar for patients with DCIS as for women with invasive breast cancer
• Other risk factors for DCIS:
  • Including older age, proliferative breast disease, increased breast density, nulliparity, older age at primiparity, history of breast biopsy, early menarche, late menopause, long-term use of postmenopausal hormone replacement therapy, and elevated body mass index in postmenopausal women:
    • Are the same as those for invasive breast cancer

• Key Sonographic Features Suggestive of Malignancy:
  • Based on contemporary radiology references:
    • Hypoechoic echotexture
    • Posterior acoustic shadowing
    • Irregular or spiculated margins
    • Angular or microlobulated margins
    • Taller-than-wide orientation:
      • Non-parallel to skin
    • Thick echogenic halo:
      • Suggests desmoplastic reaction
    • Ductal extension or branching pattern
    • Intra-lesional calcifications
    • Increased stiffness on elastography:
      • High shear-wave values
    • Low apparent diffusion doefficient (ADC) values on diffusion-weighted imaging (DWI)
  • These align with standard teaching but are now reinforced by quantitative imaging advances such as elastography and DWI
• Caveats — Not Exclusively Malignant:
  • Well-defined smooth borders and posterior acoustic enhancement can appear in both benign and malignant lesions:
    • Interpretation must rely on the whole feature set
  • Layering or “teacup” micro-calcifications on mammography typically lean benign, despite ultrasound appearance; correlation remains essential
• Integrated Imaging Approach:
  • A sonographic mass that appears benign on mammography should be evaluated primarily based on B-mode ultrasound features rather than mammographic impression
  • Use of color Doppler improves specificity for malignancy in non-mass-like lesions without reducing sensitivity
• Quantitative Imaging Enhancements:
  • Diffusion-weighted imaging (DWI):
    • Apparent Diffusion Coefficient (ADC) values provide quantitative assessment:
      • Malignant lesions typically show mean ADC ≈ 1.03 ×10⁻³ mm²/s, benign ≈1.5 ×10⁻³ mm²/s; ADC <1.0 ×10⁻³ mm²/s strongly favors malignancy
      • Recent meta-analysis confirms ADC’s usefulness for distinguishing lesions, though exact thresholds vary:
        • Most protocols now use ≥ 1.5T MRI with b-values around 800 s/mm²
    • Shear-wave elastography (SWE):
      • Mean values for malignancies often exceed 133 to 153 kPa (e.g., ~167 kPa), aiding differentiation
• Full References:
  • Malherbe K. Breast Ultrasound. StatPearls, updated 2024 – Highlights classic sonographic features: hypoechoic texture, shadowing, margins, etc Verywell Health, “Breast Cancer Ultrasound: How It Works and What Results Mean.” (2022) – Discusses overlap of benign/malignant features and interpretive context.
  • Tarigan VN et al. 2025 systematic review: DWI (ADC) helps distinguish benign vs malignant lesions; ADC measurement challenges remain.
    Kwon M et al. (2024) – Mean ADC ~0.982 ×10⁻³ mm²/s for cancers; SWE stiffness ~167.7 kPa.
    Surov A et al. (2019) – Pooled ADC values show malignant lesions average 1.03 ×10⁻³ mm²/s vs benign 1.5 ×10⁻³ mm²/s; benign rarely under 1.0 ×10⁻³ mm²/s.
  • Stavros AT. Breast Ultrasound, 2004 – Covers foundational ultrasound interpretation concepts. Cardenosa G. Clinical Breast Imaging: The Essentials, 2015 – Classic reference listing the ten ultrasound signs of malignancy.
  • Tarigan VN et al. (2024) Frontiers in Oncology – Color Doppler specificity enhancement in non-mass lesions.

• Throughout the American Thyroid Association (ATA) 2025 Thyroid Cancer Guidelines:
  • The 5th edition of the WHO Classification of Thyroid Tumors has been utilized for descriptions of the types of non-anaplastic follicular cell-derived thyroid carcinomas and NIFTP
• Approximately 90% of thyroid cancer cases are well differentiated and are classified based on the predominant histomorphology:
  • However, they now also can be categorized based on their molecular profiles
• Four main types of DTC include:
  • Follicular thyroid carcinoma (FTC)
  • Invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC)
  • Papillary thyroid carcinoma (PTC)
  • Oncocytic thyroid carcinoma (OTC)
• PTC is the most common type of DTC:
  • PTC is typically indolent and associated with excellent long-term survival:
    • 96% at 5 years
    • 93% at 10 years
    • Greater than 90% at 20 years
  • Overall, mortality rates for PTC are:
    • 1% to 6.5%
  • Overall recurrence rate of 15% to 35%:
    • Tumor recurrence typically occurs in the:
      • Tumor bed
      • Cervical lymph nodes
      • Distant sites (rarely)
  • PTCs have characteristic nuclear features:
    • Core elements fall into three buckets (per WHO 5th ed. framework and modern scoring systems):
      • Size / shape/ crowding:
        • Nuclear enlargement
        • Elongation / ovality
        • Overlapping / crowding
        • Pseudostratification at the papillary edges
          • These are low-power cues to look closer
      • Membrane irregularities:
        • Nuclear grooves (longitudinal folds)
        • Intranuclear cytoplasmic pseudoinclusions (INCIs):
          • Round, sharply circumscribed, eosinophilic inclusions:
            • Caused by cytoplasmic invagination
        • Irregular nuclear contours / notches
        • Notes for practice:
          • Grooves are sensitive but not specific
          • INCIs are more specific for PTC when true (focus and multiple planes help)
      • Chromatin changes:
        • Chromatin clearing with peripheral margination:
          • The classic “Orphan Annie-eye” look
        • Fine (“powdery”) chromatin with micronucleoli
        • Apparent thickened nuclear membrane on H&E
        • Clearing can be mimicked by Hashimoto thyroiditis or fixation artifact:
          • So it needs to be interpreted with the full nuclear constellation
    • How pathologists operationalize this:
      • In follicular-patterned lesions (e.g., NIFTP vs infiltrative FV-PTC), a 3-category nuclear score is applied:
        • Size / shape
        • Membrane irregularities
        • Chromatin features
      • A score ≥ 2 supports PTC-type nuclear features
      • NIFTP requires papillary-type nuclei (score ≥ 2) and strict architectura l/ invasion criteria
    • WHO 2022 emphasizes first deciding whether PTC-type nuclei are present before subtyping;
      • This step drives nomenclature:
        • Low-risk neoplasm vs malignancy
    • Molecular correlations you’ll see in reports:
      • BRAF V600E–driven tumors (classic / tall-cell subtypes):
        • Tend to show florid nuclear features:
          • Grooves (longitudinal folds)
          • INCIs
          • Glassy nuclei
      • RAS-mutated follicular-patterned tumors:
        • Often have subtler nuclei
    • Papillary thyroid carcinomas (PTC) can present as:
      • Infiltrative and encapsulated tumors
    • Molecular studies have shown that most PTCs (90%) develop by:
      • The activation of a Mitogen-Activated Protein Kinase (MAPK) pathway-event:
        • This activation occurs via mutually exclusive mutations in:
          •  BRAF or RAS oncogenes
      • A subset of PTCs is acquired by gene fusions involving:
        • Rearranged during transfection (RET) or (less commonly) other receptor tyrosine kinases
      • Oncogenic mutations at BRAF^V600E:
        • Are the most common in PTC
      • A minority can show non-V600E mutations:
        • Such as BRAF^K601E or BRAF fusions
      • The IEFVPTC is an encapsulated and invasive follicular-patterned tumor:
        • Based on its tendency for vascular invasion, distant metastasis, and molecular profile:
          • It can behave similarly to FTC
• Histologically, FTCs are encapsulated follicular patterned tumors:
  • Without the nuclear features of PTC
  • They are characterized by the presence of:
    • Vascular:
      • Limited or extensive
    • Capsular invasion:
      • Vascular invasion involving vessels within the tumor capsule
    • Widely invasive:
      • Extensive invasion of the thyroid parenchyma beyond the tumor capsule
  • These tumors are mostly driven by activating mutations in:
    • RAS oncogenes (NRAS > HRAS > KRAS), PAX8::PPARγ fusions, EIF1AX mutations, PIK3CA mutations, or loss of PTEN expression:
      • BRAF^V600E and RET fusions typically are not seen in FTC
    • Expression of PAX8::PPARγ fusions oncoprotein:
      • Occur in 25% of FTC:
        • In which the thyroid transcription factor PAX8 drives the expression of PPARγ:
          • A receptor involved in adipocyte biology
    • Mutations in DICER1:
      • Which encodes a ribonuclease in the processing of microRNA precursors:
        • Occur in RAS-like thyroid neoplasms and are prevalent in FTC
      • DICER1 mutations can also be seen in subsets of PTC, differentiated high-grade thyroid carcinoma (DHGTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC)
• With greater recognition of the unique genomic features of OTC (previously known as Hürthle cell carcinoma) and different clinical behavior from classical forms of FTC:
  • These tumors are now considered a third form of DTC:
    • Rather than a subtype of FTC in the current WHO classification:
      • They account for ∼ 3% of all DTC
  • An “oncocyte” is an enlarged polygonal cell with an abundant granular eosinophilic cytoplasm, round nuclei with even chromatin pattern, and prominent nucleoli:
    • As defined by WHO:
      • Oncocytic neoplasms are usually encapsulated and composed of ≥ 75% oncocytic cells
    • Oncocytic features can be identified in some PTC or FTC cells at lower frequencies
  • Most of these tumors are larger in size; however, smaller tumors can be identified
  • Like FTC, the presence of invasive characteristics:
    • Tumor capsule and / or vascular invasion:
      • In an encapsulated oncocytic neoplasm:
        • Is diagnostic of OTC
    • OTCs can be classified as:
      • Minimally invasive
      • Encapsulated angio-invasive
      • Widely invasive
  • Genomically, OTCs are characterized typically by:
    • A near-haploid genome
    • Mitochondrial DNA mutations:
      • Commonly involving genes encoding Complex 1 of the mitochondrial respiratory chain
    • Mutations in DAXX and ATRX:
      • Involved in telomere length
    • OTCs can also have mutations that activate:
      • Mammalian target of rapamycin (mTOR) and MAPK signaling
    • Like PTC and FTC:
      • More aggressive OTCs can have mutations in the:
        • TERTpromoter or TP53
    • Clinically, some studies have shown that OTCs have a greater tendency toward lymph node metastases while retaining a predilection for distant metastases, and unlike FTC:
      • OTCs often are not radioiodine-avid despite retaining other differentiated features:
        • Such as Tg secretion and TSH receptor expression
• The 5th edition of the WHO Classification of Thyroid Tumors:
  • Also introduces a new category of high-grade follicular cell derived, non-anaplastic carcinoma that includes:
    • PDTC and DHGTC.
  • By molecular analysis, poorly differentiated thyroid cancer and DHGTC:
    • Harbor driver mutations in BRAF (BRAF^V600E) and RAS genes:
      • In some cases may show gene fusions:
        • Often RET and NTRK3
    • Additional mutations in the:
      • TERT promoter, PIK3CA, and TP53 are commonly identified
  • DHGTC has been defined by certain authors as a:
    • “Thyroid malignancy” that is recognized as DTC but in which certain histological and cytopathologic features are present that justify the lesion being classified as “high-grade”
    • The DHGTCs are invasive, high-grade carcinomas:
      • That show one of the following two histological features:
        • Mitotic count ≥ 5 per 2 mm²
        • Tumor necrosis
  • By contrast, thyroid carcinomas classified as PDTC are follicular cell-derived tumors that show a minor component of DTC (papillary, follicular, oncocytic):
    • Show solid and / or insular growth pattern with presence of either:
      • Necrosis or ≥ mitotic count of 3 per 2 mm², and lack the usual histological characteristics and aggressiveness of ATC
  • In both cases, clinical behavior is considered:
    • Intermediate between DTC and ATC

• Citation: Ghi MG et al. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer: a phase II–III trial. Annals of Oncology, 1 September 2017; 28(9): 2206–2212. DOI: 10.1093/annonc/mdx299
• Key Findings:
  • Design:
    • A randomized phase II–III study comparing:
      Induction TPF (docetaxel, cisplatin, 5‑FU) followed by concomitant treatment (either chemoradiation [CCRT] or cetuximab/RT),
      versus concomitant treatment alone (CCRT or cetuximab/RT without induction)
  • Participants:
    • 414 patients analyzed (206 in the induction arm, 208 in the no‑induction arm)
  • Outcomes (median follow-up ~ 44.8 months):
    • Overall Survival (OS):
      • Significantly improved with induction:
        • Hazard Ratio (HR) 0.74; 95% CI, 0.56–0.97; P = 0.031
    • Progression-Free Survival (PFS):
      • Significantly better in the induction (IC) arm (P = 0.013)
    • Complete Response Rates:
      • Higher in the induction arm (P = 0.0028)
    • Locoregional Control:
      • Also significantly improved (P = 0.036)
    • Treatment Compliance:
      • Not adversely affected by induction therapy 
• Summary for Head and Neck Surgeons
  • Publication:
    • This is an official, peer-reviewed publication, no longer merely an abstract
  • Significance:
    • It remains the only phase II–III trial reporting a statistically significant survival benefit (OS, PFS), better response rates, and improved locoregional control when adding TPF induction before chemoradiation, without harming treatment compliance
  • Clinical Interpretation:
    • These results strengthen the hypothesis that carefully administered TPF induction can offer meaningful benefit:
      • But they differ from the negative phase III findings of PARADIGM and DeCIDE
    • This raises important questions about variations in trial populations, concurrent treatments (cisplatin vs. cetuximab), and trial settings
  • Regulatory and Guideline Context:
    • While promising, broader adoption must weigh this one positive study against other evidence
    • Induction TPF remains non-standard but can be considered within multidisciplinary discussions:
      • Especially for patients with high-risk features or when organ preservation is a priority