Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

Most thyroid nodules are benign, and most people with thyroid nodules will never develop thyroid cancer.

Still, certain factors are associated with a higher risk and deserve closer evaluation.

☢️ Strongly Associated Risk Factors

Radiation exposure to the head and neck, especially during childhood or adolescence Prior therapeutic radiation for benign or malignant conditions Family history of thyroid cancer (especially first-degree relatives)

🧬 Genetic & Medical Factors

Certain inherited syndromes (rare, but important) Medullary thyroid cancer associated with RET mutations Autoimmune thyroid disease (e.g., Hashimoto’s thyroiditis) increases nodule prevalence; cancer risk remains low but evaluation is important

👥 Demographic Factors

Female sex (thyroid cancer is more common in women) Age (extremes of age can influence behavior and management)

🧠 Important clarification for patients

Having risk factors does NOT mean you have cancer.

➡️ Most patients with thyroid cancer have no identifiable risk factors.

➡️ Risk factors help guide how carefully we evaluate, not whether we panic.

🔍 What matters most?

High-quality ultrasound Appropriate biopsy when indicated Expert interpretation and risk-adapted management

👨‍⚕️ Dr. Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

Risk factors inform evaluation — ultrasound and pathology drive decisions.

📚 References

Haugen BR et al. ATA Guidelines for Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid Schneider AB et al. Radiation exposure and thyroid cancer. J Clin Endocrinol Metab SEER Cancer Statistics Review

Extended Endocrine Therapy in Very Young (≤40) Node-Positive HR+ Early Breast Cancer

Very young, node-positive, hormone receptor–positive (HR+) early breast cancer patients represent a uniquely high-risk subgroup, largely driven by persistent ovarian function and aggressive tumor biology. Emerging long-term data suggest that patients who remain premenopausal after completing 5 years of ovarian function suppression (LHRHa)–based endocrine therapy may derive clinically meaningful benefit from extended endocrine treatment.

In this population, extended endocrine therapy was associated with:

Improved invasive breast cancer–free survival (IBCFS) • 5-year IBCFS: 85% vs 78% • Hazard ratio (HR): 0.63, indicating a 37% relative risk reduction Improved distant recurrence–free survival (DRFS) • 5-year DRFS: 91% vs 83% • HR: 0.49, corresponding to a 51% relative reduction in distant relapse

Importantly, these efficacy gains were achieved without a major increase in long-term toxicity. Rates of fractures and cardiovascular events remained low (~1%), reinforcing the favorable therapeutic index of prolonged endocrine therapy in carefully selected young patients.

Clinical Implications

Chronologic age ≤40 years, node-positive disease, and persistent premenopausal status after 5 years identify a subgroup with sustained estrogen-driven recurrence risk. Extended endocrine therapy should be actively discussed in this setting, with shared decision-making that incorporates: Residual recurrence risk Tolerance of prior endocrine therapy Bone health and cardiovascular risk monitoring These data further support a risk-adapted, biologically driven approach to endocrine duration rather than a fixed 5-year strategy in very young patients.

Key References

Pagani O, et al. Long-term outcomes of adjuvant endocrine therapy in premenopausal women with hormone receptor–positive breast cancer. New England Journal of Medicine. 2014;371:107–118. Francis PA, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. New England Journal of Medicine. 2018;379:122–137. Regan MM, et al. Extended follow-up of the SOFT and TEXT trials: recurrence patterns and long-term toxicity. Journal of Clinical Oncology. 2022;40:3697–3708. Burstein HJ, et al. Endocrine therapy for hormone receptor–positive breast cancer: ASCO guideline update. Journal of Clinical Oncology. 2023.

Thyroid cancer is one of the most treatable cancers—and outcomes are excellent for the vast majority of patients.

📈 Survival in perspective

Overall 5-year survival >98% for most differentiated thyroid cancers Papillary thyroid cancer (the most common type) has >95% long-term survival Many patients live normal, full lives after treatment

🧠 What drives these excellent outcomes?

Several factors work in patients’ favor:

Slow tumor growth for most thyroid cancers Early detection with high-resolution ultrasound Accurate risk stratification (ATA / TI-RADS) Highly effective surgery when indicated Selective use of radioactive iodine and tailored follow-up

⚖️ Modern management matters

Today, thyroid cancer care focuses on:

✔️ Avoiding overtreatment for low-risk disease

✔️ Escalating treatment only when biology and risk justify it

✔️ Preserving quality of life without compromising cure

🦋 What this means for patients

A thyroid cancer diagnosis is serious—but not all thyroid cancers are the same.

The key is individualized, evidence-based care by an experienced team.

👨‍⚕️ Dr. Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

With proper evaluation and treatment, most patients with thyroid cancer do extremely well.

📚 References

SEER Cancer Statistics Review Haugen BR et al. ATA Guidelines for Differentiated Thyroid Cancer. Thyroid Tuttle RM et al. Risk-Adapted Management of Thyroid Cancer. Lancet Diabetes Endocrinol

• Surgical excision of an area of atypical duct hyperplasia (ADH) found on core needle biopsy:
  • Is recommended to rule out underlying occult breast cancer:
    • Which can be found in 15% to 30% of patients
• Studies consistently show higher rates of upgrade to DCIS (2/3 of the cases) compared to invasive carcinoma (1/3 of the cases)
• A multivariable model assessing predictors for risk of upgrade at the time of excision of ADH found that:
  • Lesions that were less than 50% removed by core biopsy, compared to those with greater than 90% removed:
    • Had a significantly higher risk of upgrade (OR 3.8)
  • Similarly, ADH with individual cell necrosis (OR 4.3) and with multiple foci of atypia on core biopsy (OR 2-3 foci 2.1; OR >3 foci 3.6 compared to 1 foci) were more likely to have a subsequent upgrade
• ADH is associated with an increased risk of future development of breast cancer when identified on a core needle biopsy or at time of surgery:
  • With a relative risk of approximately 4
• Increasing number of foci of atypia:
  • Has also been reported to be associated with increasing future breast cancer risk
• A study by Degnim and colleagues combined outcomes for women with a history of atypical hyperplasia from the Mayo Clinic and the Nashville Cohort:
  • In the combined analysis, among women with ADH, the relative risk of breast cancer was 2.65 with 1 foci, 5.19 with 2 foci, and 8.94 with >3 foci, p<.001
• As the vast majority of subsequent cancers in this population are estrogen positive:
  • Patients with ADH may benefit from chemoprevention as demonstrated in the NSABP P-1 study:
    • Which demonstrated a 49% reduction in the development of invasive breast cancer in high-risk patients with the use of tamoxifen compared to placebo (p<0.00001), with the greatest benefit seen in women with atypical hyperplasia or lobular carcinoma in situ:
      • However, tamoxifen did not effect overall survival
• References
  • Mooney K, Bassett LW, Apple SK. Upgrade rates of high-risk breast lesions diagnosed on core needle biopsy: a single-institution and literature review. Modern Pathol. 2016;29(12):1471-1484.
  • Pena A, Shah SS, Fazzio RT, Hoskin TL, Brahmbhatt RD1, Hieken TJ, at al. Multivariate model to identify women at low risk of cancer upgrade after a core needle biopsy diagnosis of atypical ductal hyperplasia. Breast Cancer Res Treat.2017;164(2):295-304.
  • Hartmann LC, Degnim AC, Santen RJ, Dupont WD, Ghosh K. Atypical hyperplasia of the breast – risk assessment and management options. NEJM. 2015;372(1):78-89.
  • Degnim AC, Dupont WD, Radisky DC, et al. Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women. Cancer. 2016;122(19):2971-2978.

• Warthin’s tumors most commonly present as an asymptomatic, slowly growing round or oval mass usually affecting men in the 5th and 6th decade:
  • The male to female ratio ranges from 2.6:1 to 10:1
  • They occur rarely in patients of  African American origin
  • The average size of Warthin’s tumor at diagnosis is about 2.5 centimeters
  • The great majority of these tumors are located in the lower pole of the parotid gland:
    • Tail of the parotid.
  • In about 10% to 12% of cases, there is bilateral tumor development:
    • Which is commonly synchronous
  • In about 6% of cases:
    • Multiple Warthin’s tumors may be observed in one parotid gland
  • They may occur simultaneously with pleomorphic adenomas, various types of carcinoma and malignant lymphomas
  • In large registries, Warthin’s tumors located outside of the parotid gland account for about 8% of the cases:
    • Case reports concern particularly cervical lymph nodes, the submandibular gland, and the larynx:
    • • The author assume that more attention is paid to these rather rare locations than to the numerous Warthin’s tumors located in the parotid gland which are extirpated worldwide

• These tumors are well encapsulated lesions with cystic and solid areas:
  • These tumors consist of an oncocytic epithelial cell component arranged in double layers:
    • Which develops cysts and papillary projections, and a variable amount of lymphoid tissue often with germinal centers:
      • The immunoprofile of the lymphocyte subsets is similar to that in normal or reactive lymph nodes.
  • A few Warthin’s tumors (about 8%) show areas of squamous cell metaplasia and regressive changes

• Several studies showed that a significant number of patients suffering from Warthin’s tumor are smokers, in contrast to patients with other salivary gland tumors:
  • The great majority of patients with Warthin’s tumor had a history of over 20 years of smoking:
    • The odds ratio for the incidence of Warthin’s tumor among current smokers compared with never smokers was 8.3
    • Compared with never smokers, clearly higher odds of Warthin’s tumor was observed in heavy smokers (more than 30 pack-years) (odds ratio=24.1) than patients who smoked less than 30 pack-years (odds ratio=4.9)

• Warthin’s tumor consists of oncocytic cells containing numerous mitochondria frequently showing structural abnormalities and reduced metabolic function:
  • Smoking can lead to damage to mitochondrial DNA due to the development of numerous reactive oxygen species
  • In this context, a high rate of deleted mitochondrial DNA has been detected in the oncocytic cells of Warthin’s tumor

• The role of hormones in the etiology of this disease has also been discussed:
  • In some malignant salivary gland diseases and even in Warthin’s tumor progesterone receptors have been found
  • A correlation with sex hormones could possibly play an important role in the development of those tumors and provide an explanation for the dominance of the male gender
  • However, it must be considered that more males than females used to smoke so that the role of the individual factors remains unclear and the intrinsic factor stimulating the development of Warthin’s tumor is still unknown

Rodrigo Arrangoiz MS, MD, FACS a head and neck surgeon / surgical oncologist and is a member of Mount Sinai Medical Center in Miami, Florida:

• He is an expert in the management of salivary gland neoplasms:

  • If you have any questions about salivary gland neoplasms  please fill free to ask Dr. Arrangoiz

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

#Arrangoiz

#HeadandNeckSurgeon

#SurgicalOncologist

#Surgeon

#CancerSurgeon

#CirujanodeCabezayCuello

#CirujanoOncologo

• Excisional biopsy:
  • Is recommended for most ADH lesions diagnosed on core needle breast biopsy (CNB)
• The chance of upgrade at excision to ductal carcinoma in situ (DCIS) or invasive carcinoma:
  • Is generally in the 12% to 22% range in the literature
• The need for routine excision of pure flat epithelial atypia (FEA) has been less clear:
  • Some authors have reported an upgrade rate of 9.6% following excision of lesions that show pure FEA without ADH when the vast majority of biopsies were done with a 14-gauge spring-loaded core biopsy device
  • It is not clear that biopsy with a vacuum-assisted device would yield the same results
  • In fact, in one study reporting biopsy of low-risk calcifications with a vacuum-assisted device, pure FEA never resulted in an upgrade to malignancy
  • An article from the Mayo Clinic showed that FEA does not seem to convey an independent risk of breast cancer beyond that of associated proliferative disease without atypia or associated ADH
• The risk of upgrade at surgical excision for ADH:
  • Has been reported to correlate with the number of ducts or terminal duct lobular units involved on vacuum-assisted core biopsy;
    • With 2 or fewer foci of involvement:
      • There was no upgrade on excision
    • With 4 or more foci of involvement:
      • There was a strong probability of upgrade to ductal carcinoma in situ or invasive carcinoma at excision
• Work continues to try to define a low-risk group who could potentially avoid excisional biopsy:
  • Particularly those with small areas of calcifications completely removed with core needle biopsy and only focal ADH on pathology
• Apocrine metaplasia, florid epithelial hyperplasia of the usual variety, and columnar cell change without atypia:
  • Do not confer a significant risk of upgrade and do not require excision
• References
  • Eby PR, Ochsner JE, DeMartini WB, Allison KH, Peacock S, Lehman CD. Is surgical excision necessary for focal atypical ductal hyperplasia found at stereotactic vacuum-assisted breast biopsy? Ann Surg Oncol. 2008;15(11):3232-3238.
  • Ely KA, Carter BA, Jensen RA, Simpson JF, Page DL. Core biopsy of the breast with atypical ductal hyperplasia: a probabilistic approach to reporting. Am J Surg Pathol. 2001;25(8):1017-1021.
  • Khoumais NA, Scaranelo AM, Moshonov H, Kulkarni SR, Miller N, McCready DR, et al. Incidence of breast cancer in patients with pure flat epithelial atypia diagnosed at core-needle biopsy of the breast. Ann Surg Oncol. 2013;20(1):133-138.
  • Said SM, Visscher DW, Nassar A, Frank RD, Vierkant RA, Frost MH, et al. Flat epithelial atypia and risk of breast cancer: a Mayo cohort study. Cancer. 2015;121(10):1548-1555.
  • McGhan LJ, Pockaj BA, Wasif N, Giurescu ME, McCullough AE, Gray RJ. Atypical ductal hyperplasia on core biopsy: an automatic trigger for excisional biopsy? Ann Surg Oncol. 2012;19(10):3264-3269.

• Generalities:
  • Warthin tumor (WT) is the second most common benign parotid gland tumor:
    • After pleomorphic adenoma
  • Almost exclusively arises in the parotid gland:
    • Classically in the tail (inferior pole)
  • Distinctive for its strong association with smoking and for being bilateral or multifocal:
    • More often than any other salivary gland neoplasm
  • Malignant transformation:
    • Is exceedingly rare (< 1%)
  • Growth is usually slow and indolent:
    • Many tumors are discovered incidentally on imaging
• Epidemiology:
  • Accounts for 5% to 15% of all parotid tumors
    • Account for 10% to 30% of benign parotid neoplasms, depending on population
• Peak incidence:
  • 6th to 7th decades of life
  • Historically showed strong male predominance (≈ 5:1):
    • Now closer to 1.5 to 2:1:
      • Reflecting increased smoking prevalence among women
  • Bilateral tumors:
    • ~ 7% to 10%
  • Multifocal within the same gland:
    • Up to 12% to 20%
• Risk Factors
  • Established:
    • Cigarette smoking:
      • Strongest known risk factor
      • Smokers have a 7 to 8× increased risk compared with non-smokers:
        • Risk correlates with duration and intensity of exposure
  • Possible / Associated Risk Factors:
    • Older age
    • Male gender (historically)
    • Prior radiation exposure:
      • Weak association:
        • Far less than pleomorphic adenoma
    • Chronic inflammatory or immune-related processes (hypothesized, not proven)
• Pathology:
  • Gross Pathology:
    • Well-circumscribed, encapsulated, soft mass
    • Frequently cystic, often containing brown, turbid (“motor oil”) fluid
  • Histopathology (defining features):
    • Biphasic tumor composed of:
      • Epithelial component
        • Papillary and cystic architecture
        • Bilayered oncocytic epithelium – luminal columnar oncocytic cells, basal cuboidal cells
      • Lymphoid stroma:
        • Dense lymphoid tissue with germinal centers
    • No true myoepithelial component
    • Mitoses and atypia are absent in classic WT
• Molecular Features:
  • Unlike pleomorphic adenoma, lacks recurrent driver translocations
  • Mitochondrial DNA mutations described (consistent with oncocytic phenotype)
  • Increasing evidence suggests WT may represent a tumor-like reactive process rather than a true neoplasm
• Clinical Presentation:
  • Painless, slow-growing preauricular or infra-auricular mass
  • Often fluctuant due to cystic nature
  • Facial nerve dysfunction is exceptional and should raise concern for alternative diagnoses
  • Bilateral or synchronous contralateral lesions strongly suggest WT
• Imaging Characteristics (supportive, not diagnostic):
  • Ultrasound:
    • Well-defined, hypoechoic, often cystic with internal septations
  • CT:
    • Well-circumscribed, cystic or cystic-solid lesion, tail of parotid
  • MRI:
    • T1: low–intermediate signal
    • T2: heterogeneous, often high signal
  • Characteristically shows high uptake on Tc-99m pertechnetate scans (classic but rarely used today)
• Diagnosis:
  • Fine-needle aspiration (FNA) is usually sufficient:
    • Typical findings:
      • Oncocytic epithelial cells + lymphoid background
    • Diagnostic accuracy is high when classic features are present
  • Core needle biopsy rarely needed
  • Important to correlate with imaging and clinical setting (older smoker, tail of parotid)
• Management:
  • Observation:
    • Appropriate in selected patients when:
      • Diagnosis is secure:
        • Concordant clinical + imaging + FNA
      • Asymptomatic or minimally symptomatic
      • No cosmetic concern
      • No facial nerve dysfunction
      • Patient preference supports surveillance
    • Rationale:
      • Benign behavior
      • Very low malignant transformation risk
      • Many tumors grow minimally or plateau
  • Surgical Management:
    • Indications:
      • Diagnostic uncertainty
      • Symptomatic tumor:
        • Pain, rapid growth, infection
      • Cosmetic deformity
      • Patient anxiety or preference
      • Very large lesions
    • Surgical options:
      • Partial superficial parotidectomy
      • Extracapsular dissection (ECD) in well-selected cases
      • Facial nerve preservation is standard
      • Total parotidectomy rarely required
      • Neck dissection:
        • Not indicated
    • Adjuvant therapy:
      • None
• Prognosis:
  • Excellent
  • Recurrence is uncommon and usually reflects:
    • Multifocal disease
    • Development of a new metachronous WT
  • Long-term survival equivalent to general population
• Key Teaching Points for Surgeons:
  • Tail of parotid + smoker + cystic mass = think Warthin
  • Bilaterality strongly favors WT
  • Observation is acceptable and evidence-based in selected patients
  • Avoid overtreatment:
    • Facial nerve morbidity must be weighed against benign biology
• Key References:
  • Barnes L, Eveson JW, Reichart P, Sidransky D. WHO Classification of Tumours of the Head and Neck. IARC Press; 2017 / 2022 (5th ed.).
  • Ellis GL, Auclair PL. Tumors of the Salivary Glands. AFIP Atlas of Tumor Pathology.
    Seifert G, Donath K. The Warthin tumor: a multifocal disease. Virchows Arch A Pathol Anat Histopathol. 1996.
  • Eveson JW, Cawson RA. Warthin’s tumour (cystadenolymphoma) of salivary glands: a study of 78 cases. Oral Surg Oral Med Oral Pathol.
  • Schwalje AT, Uzelac A, Ryan WR. Growth rate characteristics of Warthin tumors. Otolaryngol Head Neck Surg. 2015.
  • Quer M, et al. ESMO–EURACAN Clinical Practice Guidelines for salivary gland cancer. Ann Oncol. 2022.
  • Witt RL, et al. Observation of Warthin tumors: a safe alternative to surgery. Otolaryngol Head Neck Surg.

• Breast cancer is a heterogeneous disease:
  • Comprising multiple biological entities, each with distinct pathology, features, and clinical implications
• Gene expression profiling in breast cancer has identified four or five main molecular subtypes of breast cancer recognized as distinct biological entities:
  • Luminal A subtype:
    • ER positive [ER], progesterone receptor [PR] positive and HER-2 negative with low Ki-67 [< 14%]
  • Luminal B subtype:
    • ER positive, PR positive, and HER-2 negative with high Ki-67 [> 14%]
  • Basal-like / triple-negative subtype:
    • ER negative, PR negative, and HER-2 negative
  • HER-2-amplified subtype:
  • Which can be further divided by ER status into:
    • ER negative, HER-2 positive
    • ER positive, HER-2 positive
• Classifying breast cancer into these subtypes has led to a paradigm shift in how patients are currently stratified and treated

• Arterial Anatomy of the Breast – A Practical Summary for Breast Surgeons
  • Understanding the arterial supply of the breast is essential for:
    • Oncologic resections
    • Reconstructive planning
    • Oncoplastic surgery
    • Complication avoidance
  • The breast receives a rich, redundant blood supply primarily from branches of the:
    • Subclavian and axillary arterial systems:
      • Which explains its generally good healing capacity:
        • But also the risk of bleeding if anatomy is not respected
• Primary Arterial Sources:
  • Internal Mammary (Internal Thoracic) Artery:
    • Most important medial blood supply to the breast
    • Arises from the:
      • Subclavian artery
    • Gives rise to anterior intercostal perforators, especially:
      • 2nd to 4th intercostal perforators:
        • Dominant contributors
    • Supplies:
      • Medial breast
      • Retroareolar complex
    • Key surgical relevance:
      • Critical during medial lumpectomies
      • Important for nipple-areolar complex (NAC) viability
      • Used as recipient vessels in free flap breast reconstruction
  • Lateral Thoracic Artery:
    • Branch of the axillary artery
    • Runs along the lateral chest wall
    • Supplies:
      • Lateral breast
      • Skin and glandular tissue
    • Key surgical relevance:
      • At risk during axillary dissection
      • Important contributor in lateral oncoplastic flaps
  • Thoracoacromial Artery (Pectoral Branch):
    • Branch of the axillary artery
      Supplies:
      • Upper outer quadrant
      • Pectoralis major muscle
    • Key surgical relevance:
      • Important during subpectoral dissection:
      • Preservation helps reduce skin flap ischemia
  • Posterior Intercostal Arteries:
    • Arise directly from the thoracic aorta
    • Provide deep perforating branches
    • Supply:
      • Deep parenchyma
      • Chest wall interface
    • Key surgical relevance:
      • Contribute to deep tissue perfusion
      • Source of bleeding during deep resections
• Perforator System and Anastomoses:
  • The breast has an extensive subdermal and intraparenchymal anastomotic network
  • Major perforators:
    • Medial (internal mammary)
    • Lateral (lateral thoracic)
  • Clinical implications:
    • Explains tolerance of wide local excisions
    • Allows for oncoplastic rearrangements
    • Supports skin- and nipple-sparing mastectomy when flaps are well designed
• Surgical Implications for Breast Surgeons:
  • Breast-Conserving Surgery:
    • Medial tumors:
      • Respect internal mammary perforators
    • Lateral tumors:
      • Anticipate supply from lateral thoracic artery
  • Mastectomy (Skin- or Nipple-Sparing):
    • Preserve:
      • Subdermal plexus
      • Medial perforators
    • Excessive cautery near the NAC increases ischemia risk
  • Oncoplastic Surgery:
    • Knowledge of arterial territories guides:
      • Pedicle choice
      • Flap orientation
      • Central and medial pedicles rely heavily on internal mammary perforators
  • Reconstruction:
    • Internal mammary vessels are preferred recipient vessels for free flaps
    • Axillary system preservation is important in implant-based reconstruction
• Key Take-Home Points:
  • Breast arterial supply is dual and redundant, centered on:
    • Internal mammary system (medial dominance)
    • Axillary system (lateral dominance)
    • 2nd to 4th internal mammary perforators are the most critical vessels
    • Surgical planning should always consider vascular territories, especially in:
      • Re-operations
      • Radiation-treated breasts
      • Large resections or complex oncoplastic cases
• References:
  • Arterial Anatomy of the Breast
    • Cunningham L.The anatomy of the arteries and veins of the breast.
      J Surg Oncol. 1977;9(1):71–85.
      → Classic anatomic description of breast vascular supply.
    • Salmon RJ. Vascularization of the breast and implications for surgery.
      Surg Clin North Am. 1990;70(4):877–885.
      → Foundational surgical anatomy review.
    • Hall-Findlay EJ. Breast anatomy and vascular supply.
      Clin Plast Surg. 2002;29(3):371–384.
      → Highly cited reference for oncoplastic and reconstructive surgery.
    • Sappey M. Traité d’Anatomie Descriptive. Paris: Delahaye; 1874.
      → Early detailed descriptions of breast perforators (historical reference).
    • Taylor GI, Palmer JH. The vascular territories (angiosomes) of the body.
      Br J Plast Surg. 1987;40(2):113–141.
      → Angiosome concept applied to breast perfusion and flap design.
  • Internal Mammary & Perforator Anatomy:
    • Cormack GC, Lamberty BG. The arterial anatomy of skin flaps.
      Edinburgh: Churchill Livingstone; 1994.
      → Describes internal mammary perforators relevant to breast surgery.
    • Saint-Cyr M, Wong C, Schaverien M, et al. Perforator flaps: anatomy, technique, and clinical applications. Plast Reconstr Surg. 2009;124(1 Suppl):e1–e17.
      → Detailed perforator anatomy with relevance to NAC perfusion.
    • Hamdi M, Van Landuyt K, Monstrey S, Blondeel P. Pedicled perforator flaps in breast reconstruction. Semin Plast Surg. 2006;20(2):73–83.
  • Surgical & Oncoplastic Relevance:
    • Losken A, Hamdi M. Partial breast reconstruction: current perspectives. Plast Reconstr Surg. 2009;124(3):722–736.
      → Links vascular anatomy to oncoplastic pedicle choice.
    • Clough KB, Kaufman GJ, Nos C, Buccimazza I, Sarfati IM. Improving breast cancer surgery: a classification and quadrant-based approach. Plast Reconstr Surg. 2010;125(2):418–428.
    • Mast BA. Breast reduction and mastopexy: pedicle selection and vascular considerations. Clin Plast Surg. 1996;23(3):567–576.
  • Nipple–Areolar Complex (NAC) Perfusion
    • van Deventer PV, Graewe FR. Blood supply of the nipple–areolar complex. Plast Reconstr Surg. 1984;74(4):499–504.
    • Russo V, Della Corte A, et al. Nipple–areola complex vascular anatomy and surgical implications. Aesthetic Plast Surg. 2017;41(2):267–274.
  • Reconstruction-Focused References:
    • Blondeel PN, Morris SF, Hallock GG, Neligan PC. Perforator Flaps: Anatomy, Technique, and Clinical Applications. St. Louis: Quality Medical Publishing; 2006.
  • Nahabedian MY. Breast reconstruction and internal mammary vessels.
    Plast Reconstr Surg. 2012;130(4):883–891.
    

• Atypical ductal hyperplasia (ADH):
  • Is a proliferative epithelial lesion of the terminal ductal lobular unit:
    • That typically demonstrates low-grade cytologic atypia and monomorphism combined with epithelial architectural complexity (i.e., cribriforming)
• Histologically:
  • ADH and low-grade DCIS are virtually identical:
    • The distinction between them is based primarily on:
      • The quantity of atypia present
    • Currently, the consensus criteria recommend that a diagnosis of DCIS be reserved for:
      • Lesions that circumferentially involve two or more membrane-bound spaces (typically ducts) or that measure more than 2 mm in linear extent
    • A diagnosis of ADH is rendered for:
      • Morphologically identical lesions that fall short of these quantitative criteria
• Atypical ductal hyperplasia (ADH):
  • Is identified in:
    • 8% to 17% of all core needle breast biopsy specimens
  • Because the distinction between ADH and DCIS relies on the quantity of atypia:
    • Sampling is an important concern for ADH
      diagnosed on CNB
• Multiple studies of upgrade rates for
  excision of ADH on CNB, including recent studies with primarily large core biopsy techniques:
  • Show persistent upgrade rates of 10% to 30%:
    • Leading to a recommendation for
      excision as the standard of care
• Surgical excision remains the standard of care after a core biopsy diagnosis of ADH:
  • However, given that the majority of ADH cases diagnosed by percutaneous biopsy are not upgraded to cancer:
    • Routine excision may represent
      overtreatment
    • Therefore, as has been done for other high-
      risk lesions identified on CNB, recent research efforts have attempted to identify factors associated with a low risk of cancer upgrade in order to define a favorable subgroup of
      women who may avoid surgical excision with minimal risk of a missed invasive carcinoma
• Several groups have worked to identify features of
  women with ADH on CNB who have a very low risk (5%) of upgrade to cancer:
  • Nguyen et al. previously published criteria by which ADH lesions found on core biopsy could be triaged according to the risk of upgrade to
    an associated carcinoma:
    • In their series of 140 patients, a
      number of factors were significantly correlated with the rate of upgrade to carcinoma including:
      • Removal of less than 95% of calcifications in the absence of an associated mass
      • Involvement of two or more terminal duct-lobular units
      • The presence of significant cytologic atypia
      • The presence of necrosis
    • Use of these combined criteria led to:
      • An upgrade rate of 3% for the subset of women with low-risk features
  • Ko et al, also developed a scoring system to predict malignancy in patients with a diagnosis of ADH on CNB:
    • They found that age older than 50 year, micro-calcification on mammography, size on imaging greater than 15 mm, and a palpable lesion were independent predictors of malignancy
    • The presence of focal ADH was a negative predictor
  • Similar criteria also have been reported by Pena et al. from the Mayo Clinic:
    • In this series of 399 patients, the overall upgrade rate was:
      • 16.1%
    • The features on core biopsy most strongly associated with upgrade were:
      • Percentage of the lesion removed
      • Individual cell necrosis
      • Number of ADH foci in the core biopsy specimen
    • A low-risk subgroup was identified by:
      • The absence of individual cell necrosis
      • Either one focus of ADH with 50%
        removal or more / or more than one focus with 90% removal of the sample
    • Using these criteria, approximately one third
      of women were identified as low risk for upgrade, and the actual upgrade rate in this group was 4.9%
  • Individual cell necrosis:
    • Also has been suggested by prior studies showing its association with cancer upgrade
  • Pena et al. also evaluated the performance of the Ko et al. and Nguyen et al. criteria and found that both models successfully identified women with a low risk of upgrade:
    • However the proportion of women assessed to be at low risk was substantially smaller than with the Pena model
• The long-term safety of prospectively omitting surgical excision was recently reported by Menen et al. for the low-risk subgroup of women defined by the criteria of Nguyen et al:
  • In this series of 175 patients, all meeting
    the low-risk criteria, 125 were observed, and 50 underwent excision
  • During a median follow-up period of 3 years, 14
    breast cancer events were noted:
    • In the surgery group, breast cancer developed in six women (12%), compared with seven cancers (5.6%) in the observed group
    • Notably, approximately 75% of the cancer events occurred in the ipsilateral breast, and the majority were outside the index site
  • These data suggest that observation rather than surgical excision after a core biopsy diagnosis of ADH may be a safe option for a select subgroup of patients meeting the low-risk radiologic and histologic criteria:
    • However, close monitoring and the use of chemoprevention still are indicated because ADH is a marker of increased risk for breast
      carcinoma
• Caution with omitting surgical excision is further
  highlighted by the results reported by Deshaies et al:
  • In their large retrospective study of 422 ADH cases, the following six factors independently associated with cancer upgrade were identified:
    • Severe ADH
    • Mammography for ipsilateral symptoms
    • Mammographic lesions other than
      microcalcifications alone
    • Co-diagnosis of papilloma
    • Use of a 14-gauge needle
    • ADH diagnosis performed by
      pathologists with low volume
  • Of the 422 biopsies, 128 were judged to be low risk because they did not present any
    of these six characteristics, yet the upgrade frequency at surgery was substantial (17.2 vs 31.3% for the whole
    group):
    • Thus, these authors were unable to identify a
      subgroup of patients for whom excision could confidently be omitted with a low risk of upgrade
    • Notably, this study did not include the proportion of the lesion removed with
      needle biopsy, which appeared to be a key factor in the other aforementioned models that succeeded in identifying a low-risk subgroup
• Despite recent research efforts to identify a low-risks group:
  • Surgical excision remains the standard of care after a CNB diagnosis of ADH:
    • Particularly in the presence of an associated mass lesion and radiologic-pathologic
      discordance
  • Although promising, the vast majority of
    these data have been in retrospective studies, with only one single-institution prospective study investigating a limited number of women:
    • Therefore, the standard approach remains surgical excision until further prospective studies confirm the validity of these criteria
  • For women with ADH diagnosed by CNB, surgical excision is not the only relevant clinical decision in patient management:
    • For these women, estimation of their long-
      term breast cancer risk is important so they can be advised on surveillance and prevention strategies
    • Unfortunately, commonly used breast cancer risk models, such as the Gail model and the Tyrer-Cuzick model:
      • Do not predict risk very accurately for individual women with atypical hyperplasia
  • For this reason, absolute risk estimation is recommended:
    • Based on data from the Mayo Clinic and Nashville Cohorts:
      • The risk is approximately 1% per year for women with ADH
    • The Partners Cohort has found a somewhat higher risk:
      • Approximately 1.7% per year, for women with ADH
    • In contrast, recent data from
      the Breast Cancer Surveillance Consortium found a lower annual average risk of breast cancer for women with ADH:
      • Only 0.6% per year, although these data included only invasive breast cancer events and excluded DCIS
    • Further work is ongoing to optimize accurate risk assessment for women with ADH
• Another factor shown to stratify long-term risk for women with ADH is the number of ADH foci present within the benign breast biopsy
  specimen:
  • With increasing risk related to increasing foci of
    atypia, observed in both the Mayo Clinic and the Nashville Cohorts
  • This finding was challenged by the Nurses’
    Health Study, in which the number of ADH foci did not have a significant impact later on breast cancer risk
  • Risk estimation is relevant because a lifetime risk greater than 25% would indicate use of magnetic resonance imaging (MRI) for breast cancer screening, whereas risk below that threshold would not
• Regardless of the means used to estimate long-term breast cancer risk for women with ADH, prevention therapy should be discussed:
  • For younger women with an anticipated long life expectancy and a long at-risk period
    for breast cancer:
    • Prevention therapy should be strongly
      recommended because their cumulative risk probably exceeds 25%
  • For older women with competing morbidity,
    prevention therapy is unlikely to have any impact on survival and minimal benefit for quality of life because most breast cancers that would develop are likely to be hormonally sensitive:
    • However, prevention therapy should be
      recommended for the majority of women with ADH because their long-term risk is substantial, and prevention medications result in a 70% reduction in breast cancer
      risk
• Long-term counseling of women with ADH
  should include some discussion of long-term breast cancer risk, surveillance strategies, and options for prevention therapy