My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida.
I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016.
Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida.
Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.
When patients are told they have a variant of unknown significance (VUS):
It can often lead to anxiety and overtreatment
It is important to counsel patients that a VUS:
Is not clinically actionable and the majority of VUS are reclassified as benign
Patients should be counseled to update their genetic counselors:
As their family history changes and keep contact information up to date as variantbreclassification does occur
The American College of Medical Genetics:
Has recommended that genetic testing classify genetic variants using the following classification schema:
Deleterious (pathogenic)
Suspected deleterious (likely pathogenic)
Variant of Uncertain Clinical Significance
Genetic variant:
Favor polymorphism:
Likely benign
Polymorphism:
Benign
While deleterious and suspected deleterious mutations BRCA mutations:
Are known to be associated with an increased risk of breast and ovarian cancer:
It is unknown whether a BRCA VUS mutation:
Is associated with an increased risk due to limited available data
As the use of genetic testing increases and as more of the population is tested:
The knowledge base regarding variant pathogenicity constantly grows
Given the amount of data available from many years of BRCA1 / BRCA 2 testing:
The prevalence of VUS among this population has declined to 2% to 5%:
However, among moderate and low penetrance genes:
The number of VUS continues to rise:
As the data expand and knowledge regarding a variant evolves, a variant may be reclassified.
In a study reported in the Journal of the American Medical Association:
25.4% of patients initially diagnosed with a VUS were reclassified over a 12-year period:
Of these patients:
97% were downgraded to benign or likely benign
Three percent of patients (3%):
Were upgraded to pathogenic or likely pathogenic variants
Given this low risk of reclassification to pathogenic mutation:
Risk-reducing mastectomy, salpingo-oophorectomy, or genetic testing of family members are not indicated for this patient
There is currently no established effective screening protocol for pancreatic cancer, even among patients with a deleterious BRCA 2 mutation
References
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
Hall MJ, Reid JE, Burbidge LA, Pruss D, Deffenbaugh AM, Frye C, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233.
Mersch J, Brown N, Pirzadeh-Miller S, Mundt E, Cox HC, Brown K, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266-1274.
The eighth edition of the American Joint Committee on Cancer (AJCC) staging system:
Defines microinvasion as:
Invasion of breast cancer cells:
Through the basement membrane at one or more foci:
None of which exceeds a dimension of 1 mm
DCIS:
Is a Tis lesion:
Is classified as stage 0 cancer
DCIS with microinvasion is considered:
T1mi:
Upstages DCIS from stage 0 to stage I disease:
The earliest stage of invasive cancer:
In the AJCC staging system
By definition:
DCIS does not have the ability to metastasize to axillary lymph nodes or distant sites:
Whereas DCIS with microinvasion does
Axillary metastasis:
Has been reported in 0% to 20% (0% to 28% in some series) of patients:
With DCIS with microinvasion
The incidence of microinvasion in DCIS:
Varies according to:
The size and extent of the index lesion
Lagios et al. (1989):
Reported a 2% incidence of microinvasion in patients with DCIS:
Measuring ≤ 25 mm in diameter
Compared with a 29% incidence of microinvasion:
In those with lesions ≥ than 26 mm
The incidence of microinvasion is also higher in patients with:
High-grade or comedo-type DCIS with necrosis
In patients with DCIS who present with:
A palpable mass
Nipple discharge
Historically, patients with DCIS with microinvasion:
Have been observed to have a worse prognosis:
Compared with those who have DCIS alone
Mirza et al. (2000):
Reported the long-term results of breast-conserving therapy in patients with:
DCIS
DCIS with microinvasion
T1 invasive breast cancers
The 20-year disease-specific survival rates in patients with:
DCIS were better:
Than those among patients with DCIS with microinvasion or with T1 invasive tumors
Patients with microinvasion and those with T1 tumors:
Had similar survival rates
In a retrospective study of 1,248 serially sectioned DCIS tumors, de Mascarel et al. (2002):
Reported a 10.1% incidence of axillary metastases:
In cases of DCIS with microinvasion
Patients with DCIS had a better 10-year distant metastasis-free survival rate:
Than patients with DCIS with microinvasion:
98% and 91%, respectively
The overall survival rate was also better in patients with DCIS compared to DCIS with microinvasion:
96.5% vs. 88.4%
However, the metastasis-free and overall survival rates:
Were worse in patients with invasive ductal carcinoma compared with those with DCIS with microinvasion
These results suggest that DCIS with microinvasion:
Should be characterized as a small invasive tumor with a good outcome:
The therapeutic approach for these patients should be similar to that for patients with invasive cancer
However, more recent studies have pointed toward DCIS with microinvasion having a more similar natural history to pure DCIS than to early-stage invasive disease:
In a review of 393 patients treated at Yale between 1973 and 2004:
There was no statistically significant difference between patients with DCIS and those with DCIS with microinvasion with regard to the presence of axillary metastases (in those who had axillary staging) or the likelihood of recurrence (locoregional and distant) or overall survival (Parikh et al., 2012)
It is typically characterized by slowly progressive swelling of the upper extremity ipsilateral to the axillary node dissection or radiation treatments
The main risk factors for breast cancer-associated lymphedema include:
Dissection / disruption of axillary lymph nodes
Radiation therapy
Local infection
Obesity
Other factors may also contribute
There is no known link between smoking and lymphedema
The American College of Surgeons Oncology Group (ACOSOG) Z1071 study:
Demonstrated that 40% of women with proven involved axillary nodes who underwent neoadjuvant chemotherapy:
Obtain a pathologic complete response in the previously involved nodes
Although the study demonstrated an overall false-negative rate of sentinel lymph node biopsy (SLNB) in this setting to be 12%:
The authors stratified these results and found that if more than two sentinel lymph nodes (SLNs) were removed in patients with dual tracer mapping (blue dye and radioisotope):
The false-negative rate of SLNB then dropped below 10% (6.8%)
With these guidelines, if SLNB is negative after neoadjuvant chemotherapy:
Consideration can be given to SLNB alone
The risk of lymphedema is significantly reduced with SLNB than with a level I / II axillary node dissection:
Odds ratio (OR) 0.33 based on Cochrane Review of three studies comparing SLNB to axillary dissection
Manual lymphatic drainage:
May offer some additional benefit to help with swelling reduction in patients with mild to moderate lymphedema:
But not all studies have found a benefit for this technique
Data are conflicting with regard to the prophylactic use of compression sleeves, prophylactic manual lymphatic drainage, or timing of arm mobilization following surgery
References
Hayes SC, Janda M, Cornish B, Battistutta D, Newman B. Lymphedema after breast cancer: incidence, risk factors, and effect on upper body function. J Clin Oncol.2008;26(21):3536-3342.
Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310(14):1455-1461.
Bromham N, Schmidt-Hansen M, Astin M, Hasler E, Reed MW. Axillary treatment for operable primary breast cancer. Cochrane Database Syst Rev. 2017;1:CD004561.
Patricolo GE, Armstrong K, Riutta J, Lanni T. Lymphedema care for the breast cancer patient: an integrative approach. Breast. 2015;24(1):82-85.
Stuiver MM, ten Tusscher MR, Agasi-Idenburg CS, Lucas C, Aaronson NK, Bossuyt PM. Conservative interventions for preventing clinically detectable upper-limb lymphoedema in patients who are at risk of developing lymphoedema after breast cancer therapy. CochraneDatabase Syst Rev. 2015;2:CD009765.
Brennan MJ, Miller LT. Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema. Cancer 1998; 83(12 Suppl American):2821-2827.
The first generation of larynx preservation chemotherapy trials:
Appeared in the 1990s:
They randomized patients into surgery and radiotherapy or to induction chemotherapy cycles of cisplatin / 5FU:
Patients who responded to chemotherapy then received radiotherapy:
With possible salvage surgery
If they did not respond to the chemotherapy:
They received surgery and postoperative radiotherapy
Generally, the results of these studies showed:
No significant difference in survival:
Between the two treatment arms
The larynx was preserved in:
56% of patients undergoing the experimental chemoradiotherapy arm
In 2000, Pignon et al:
Published a meta-analysis of the first generation of laryngeal preservation chemoradiotherapy trials:
They included T3 laryngeal and hypopharyngeal cancers
There was no statistically significant difference in overall survival:
However, it is important to note:
That there was a trend to benefit from surgery:
Hazard ratio 1.19 intervals (0.97–1.46)
Surgery ± radiotherapy:
Resulted in overall survival of 45%:
Compared to an overall survival from chemoradiotherapy of:
39%
56% of those who survived with chemoradiotherapy:
Managed to avoid laryngectomy:
Giving an overall laryngectomy survival rate of:
23% at five years
Patients treated with chemoradiotherapy:
Had almost double the local recurrence rate:
But less distant metastases than the patients treated with surgery
Analysis of laryngeal cancer patients separately from hypopharyngeal cancer patients:
Showed that laryngeal cancer patients in the surgical arm:
Demonstrated a risk reduction of 32%:
This suggests that advanced laryngeal tumors would be better treated with surgery than chemoradiotherapy:
On the other hand, hypopharyngeal cancer patients showed no difference in survival between the two modalities of treatment
The meta-analysis showed that the overall survival benefit from chemotherapy in addition to radiotherapy:
Was 4% at five years
Concomitant chemotherapy:
Resulted in an 8% overall survival benefit:
Compared to a 4% overall survival benefit from neoadjuvant chemoradiotherapy
Adjuvant chemoradiotherapy:
Resulted in no overall survival benefit
These findings have resulted in the adoption of concomitant chemoradiotherapy as the standard regimen for delivery of chemotherapy when treating laryngeal and pharyngeal cancers:
Recently, an update of this meta-analysis confirmed an overall survival effect of 6.5% for concomitant chemoradiotherapy
References:
The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. New England Journal of Medicine 1991; 324: 1685–90.
Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355: 949–55.
Pignon JP, le Maítre A, Maillard E et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and Oncology 2009; 92: 4–14.
Forastiere AA, Goepfert H, Maor M et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. New England Journal of Medicine 2003; 349: 2091–8.
Management of the axilla continues to evolve in the setting of neoadjuvant therapy
Sentinel lymph node biopsy (SLNB) in clinically node-negative patients after neoadjuvant chemotherapy;
Is feasible and accurate:
A recent systematic review reported a pooled identification rate of:
96% and false negative rate of 6%
These data do not differ from studies evaluating SLNB in early breast cancer without neoadjuvant chemotherapy
Neoadjuvant chemotherapy can result in:
Downstaging of the axilla
Performing the SLNB after chemotherapy:
Decreases the rate of finding a positive sentinel lymph node and subsequent axillary dissection
The ACOSOG / Alliance Z1071 trial involved patients with initially node-positive disease and sought to determine the false negative rate for sentinel lymph node surgery following neoadjuvant chemotherapy in this group of patients:
The false negative rate for the entire cohort was 12%:
But on additional analysis, retrieval of at least two sentinel nodes and the previously biopsied node:
Was associated with a false negative rate of 6.8%:
Therefore, marking the biopsied node with a clip and documenting excision at time of SLNB is recommended
References:
Geng C, Chen X, Pan X, Li J. The feasibility and accuracy of sentinel lymph node biopsy in initially clinically node-negative breast cancer after neoadjuvant chemotherapy: a systematic review and meta-analysis. PLoS One.2016;11(9):e0162605.
Hunt KK, Yi M, Mittendorf EA et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann Surg. 2009;250(4):558-566.
Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310(14):1455-1461.
Boughey JC, Ballman KV, Le-Petross HT et al. identification and resection of clipped node decreases the false-negative rate of sentinel lymph node surgery in patients presenting with node-positive breast cancer (T0-T4, N1-N2) who receive neoadjuvant chemotherapy: results from ACOSOG Z1071 (Alliance). Ann Surg.2016;263(4):802-807.
Platelet transfusion can overcome irreversible blockade (earlier works better for aspirin than ticagrelor); weigh thrombosis risk
DDAVP for vWD Type 1 or uremic dysfunction (watch Na⁺; tachyphylaxis after 1 to 2 doses)
Post-op:
Control blood pressure, avoid NSAIDs, continue local antifibrinolytics when helpful (e.g., pledgets / mouthwash in mucosal cases), and reassess platelet count / function if oozing persists
Quick differentials when the field won’t dry:
Normal PT / PTT, low platelets or recent antiplatelet use → primary hemostasis problem
Primary hemostasis is achieved initially with a platelet aggregation as illustrated. Note that platelet adhesion, shape change, granule release followed by recruitment, and the hemostatic plug at the area of subendothelial collagen and collagen exposure are the initial events for thrombus formation.
The intergroup Radiation Therapy Oncology Group (RTOG 91–11) trial for advanced larynx cancer established:
Concurrent bolus cisplatin with radiation as a standard of care
I mentioned that 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
Patients were randomly assigned to one of three larynx preservation strategies:
Induction cisplatin plus 5-FU followed by radiotherapy
Radiotherapy with concurrent cisplatin
Radiotherapy alone
I mentioned that 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 versus 72% or patients receiving induction chemotherapy followed by radiation and 67% for patients receiving radiation therapy alone:
At a median follow-up of 3.8 years
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
Design and results of Radiation Therapy Oncology Group trial 91–11. (Adapted from Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091–2098.)
Perhaps one of the most striking advances in breast cancer management and understanding:
Came with the molecular profiling of breast cancer:
Characterizing four distinct subtypes:
Based on the landmark paper by Perou et al., in 2000
These define tumor biology and correlate with outcome and are broadly described as:
Luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and basal like:
According to the most common profiles for each subtype:
However, not all tumors within each subtype contain all features
The estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor:
Are used as surrogates to approximate these subtypes and guide clinical care and management decisions
Luminal A:
Most (80% to 85%) of breast cancers express the estrogen receptor (ER-positive) and / or the progesterone receptor (PR+) (75% to 80%) but not HER2:
These cancers tend to be more indolent than other subtypes
Luminal A tumors are associated with the most favorable prognosis:
Particularly in the short term:
In part because expression of hormone receptors:
Is predictive of a favorable response to hormonal therapy
Luminal B:
These breast cancers are ER-positive and / or PR+:
They are further defined by either:
HER2 amplification, or high Ki-67 (an indicator of cellular proliferation)
They tend to have higher grade and more aggressive features than luminal A breast cancers
HER2-enriched:
These breast cancers produce excess HER2 and do not express hormone receptors
These cancers tend to grow and spread more aggressively than other breast cancers and are associated with poorer short-term prognosis compared to ER-positive breast cancers:
However, the recent widespread use of targeted therapies for HER2-positive cancers:
Has reversed much of the adverse prognostic impact of HER2 overexpression:
With 40% to 70% of women achieving a pathologic complete response to combination chemotherapy and targeted anti-HER2 therapies
Basal like:
These tumors are more biologically aggressive:
They are typically characterized by the lack of the ER, PR, and HER2 receptor
These cancers are often found in:
Premenopausal women
Those with a BRCA1 gene mutation
They are nearly two times more common:
In Black women than White women in US
The majority (> 70%) of triple negative breast cancers:
Fall into the basal-like subtype
Triple negative breast cancers:
Have a poorer short-term prognosis than other breast cancer types:
In part because there are currently no targeted therapies for these tumors:
However, a proportion of these tumors are very chemosensitive, exhibiting a pathologic complete response in up to a third of patients
Furthermore, several molecular subtypes of triple negative breast cancer have been described:
These may provide further insights into the varying biologic response and assist in development of therapeutic targets in addition to chemotherapy
737 patients were randomized to either undergo Halsted mastectomy or extended mastectomy with IM node dissection
After 30 years of follow-up:
There was no difference in overall survival or disease-specific survival:
For the patients eligible with T1, T2, T3, N0, and N1 disease:
Who underwent IM node dissection vs. no IM dissection
A 2019 retrospective review of 95 breast cancer patients with clinically detected IM nodes (IMNs) at diagnosis:
Were treated with surgery and radiation, with median follow-up of 43 months:
77 received neoadjuvant chemotherapy:
With IMN normalization in 67.5%
Partial IMN response in 24.6%
The 5-year IMN failure-free survival, disease-free survival, and overall survival were:
96%, 70%, and 84%, respectively
IMN failure-free survival:
Was significantly affected by:
Resection margin status
Size of IMN
Receipt of IMN boost radiation
A recently published meta-analysis in the Annals of Surgery found that axillary staging following neoadjuvant chemotherapy:
Is best performed with a combination approach of sentinel lymph node biopsy (SLNB) with excision of the pre-chemotherapy-marked positive node:
With a false negative rate of 2% to 4%:
The identification rate was 100%
ACOSOG Z1071:
Reported an overall false negative rate of 12.6% when SLNB was performed after neoadjuvant chemotherapy with documented node-positive disease prior to treatment:
The false-negative rate decreased to 6.8%:
When both sentinel node(s) and the clipped node were retrieved at the time of surgery
References:
Veronesi U, Marubini E, Mariani L, Valagussa P, Zucali R. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. Eur JCancer. 1999;35(9):1320-1325.
Kim J, Chang JS, Choi SH, et.al. Radiotherapy for initial clinically positive internal mammary nodes in breast cancer. Radiat Oncol J. 2019;37(2):91-100.
Simons JM, van Nijnatten TJA, van der Pol CC, Luiten EJT, Koppert LB, Smidt ML. Diagnostic accuracy of different surgical procedures for axillary staging after neoadjuvant systemic therapy in node-positive breast cancer: a systematic review and meta-analysis. Ann Surg. 2019;269(3):432-442.
Boughey JC, Ballman KV, Le-Petross HT, et al. Identification and resection of clipped node decreases the false-negative rate of sentinel lymph node surgery in patients presenting with nodepositive breast cancer (T0-T4, N1-N2) who receive neoadjuvant chemotherapy: results from ACOSOG Z1071 (Alliance). Ann Surg. 2016;263(5):802-807.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 