Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Adenoid cystic carcinoma:
  • 0.1% to 1% of all breast cancers
  • Low aggressive malignant potential
  • Myoepithelial differentiation
  • Exhibit tubular, trabecular, cribriform, and / or solid patterns
  • Cribriform is the classic pattern
  • Characterized by MYB-NFIB t(6;9)(q22-23;p23-24)

• Tumor infiltrating lymphocytes (TIL):
  • Recommendations for assessing TILS in breast cancer:
    • Evaluated for the stromal component (% of stromal TIL)
    • Evaluated with the borders of the invasive tumor
    • Exclude TILs outside of the tumor border, around DCIS and normal lobules
    • Lymphocytes and plasma cells, exclude neutrophils
    • Full sections are preferred over biopsies:
      • Cores can be used in the pre therapeutic neoadjuvant setting
    • Average TILs in the tumor area (do not focus on hotspots)
    • The number of TILS correlate with complete pathologic response in the neoadjuvant setting
    • No formal recommendations for a clinically relevant TILS threshold(s) can be given at this stage
• PD-L1 and Breast Cancer:
  • The PD-L1 on tumor cells, when combined with its PD-1 on immune cells:
    • Causes an inhibition of immune response mediated by CD8+ T cells
  • Breast tumor that have PD-L1 tend to have high number of TILs, and the majority are of the triple negative type
• Tumors arising in BRCA 1 carriers:
  • BRCA 1 is involved in:
    • DNA repair
    • Cell cycle regulation
    • Transcriptional regulation
    • Chromatin remodeling
  • Loss of BRCA 1 leads to:
    • Deficiency in repair of DNA doble-strand breaks
  • 75% of all tumors developing in BRCA 1 germ line mutation carriers are TNBC:
    • High histologic grade
    • High proliferation rate
• Residual cancer burden after neoadjuvant chemotherapy (NAC):
  • Parameters required to calculate residual cancer burden (RCB):
    • Submission of the entire area of the tumor bed
    • Tumor dimensions (at least in two dimensions)
    • Percentage invasive carcinoma in the tumor bed
    • Percentage of the in situ carcinoma in the tumor bed
    • The number of positive lymph nodes
    • The largest diameter of nodal metastasis

• It is recommended to repeat ER, PR, and HER2 on invasive TNBC after neoadjuvant therapy
• Distant metastasis in patient with residual disease after NAC:
  • Factors associated with increased distant metastatic rate:
    • Positive pathologic LN status
    • Lymphovascular space invasion (LVSI)
    • Increasing clinical T and N stage
    • Multifocality
    • Extranodal extension

• Basal-like breast cancer:
  • Express genes of basal epithelium and demonstrate low expression of ER and HER2 related genes
  • Often (80%) ER negative, PR negative, and HER2 negative, EGFR positive, CK 5/6 positive
  • Most TNBC are basal-like and the reverse is true
• Clinical presentation:
  • 6% to 27% of all breast cancers are basal-like
  • 1/5 of the cases are seen in younger patients:
    • 20% in patients less than 40 years
  • Often aggressive with poor prognosis
• Pathology:
  • Macroscopic appearance:
    • Mostly well circumscribed masses
    • Geographic necrosis is common

• Pathology:
  • Invasive carcinoma NST with Medullary pattern
  • Solid architecture:
    • No tubule formation
  • High grade and high proliferation:
    • Ki-67 greater than 90%
  • High cell denisty and scant stroma
  • Pushing borders
  • Lymphocytic infiltrate at the tumor edge
  • Geographic or central necrosis
  • Syncytial arrangement, less cytoplasm, basaloid features, nuclei with coarse or vesicular chromatin and prominent nucleoli

• Molecular Pathology in TNBC and Basal-Like:
  • High degree of genetic instability
  • Heterogeneity of gene copy number aberrations
  • 15% to 20% highly express genes of basal epithelium and demonstrate low expression of ER-related gene and HER2
  • TP53 (87%), PTEN mutation / loss (35%), RB1 mutation / loss (20%), Cyclin D1 amplification (58%), and CDK gain (25%)
  • P-cadherin, fatty acid-binding protein 7, c-kit, matrix metal lo-retina se 7, caveolin 1 and 2, metallothionein IX, TFG-beta receptor II
• Histologic types of TNBC:
  • Metaplastic carcinomas
  • Adenoid cystic carcinoma
  • Secretory carcinoma
  • Triple negative tumors of luminal androgen receptor type (AR)
• Metaplastic Carcinoma (MC):
  • A heterogenous group of invasive breast cancer
  • Components, including pindle cells, squamous cells , and matrix production:
    • Low-grade adenosquamous carcinoma
    • Fibromatosis-like metaplastic carcinoma
    • Spindle cell carcinoma
    • Squamous cell carcinoma
    • MC with heterozygous mesenchymal differentiation
    • Mixed metaplastic carcinoma
  • Immunohistochemical profile of MC
    • Positive:
      • AE1/AE3, 34BE12, CK5/6, CK14, p63, CK8/18, CK7, and CK19
    • Negative:
      • CD34, desmin, and SMMHC

• Secretory Carcinoma:
  • Rare low-grade type of breast cancer (< 0.1%) in adolescents
  • Partially circumscribed
  • Three histologic patterns:
    • Solid
    • Micro cystic (cysts simulating thyroid follicles)
    • Tubular
  • Neoplastic cells are uniform, round to polygonal, finely granular or vacuolated cytoplasm containing dense eosinophilia secretion
  • Characterized by fusion gene NTRK-ETV6 t(12;15)(p13;q25)

• Definition:
  • Triple negative breast cancer (TNBC) is a subtype of breast tumor lacking hormone receptors expression and HER2 gene amplification:
    • Represents 24 % of newly diagnosed breast neoplasms
  • TNBC is usually characterized by poor prognosis and lack of wide choice therapeutic agents due to the absence of targetable hormone receptors and HER2 expression:
    • Therefore is considered a very interesting and challenging topic for breast cancer research
  • TNBC is a functional term that defines a wide spectrum of entities:
    • With different biology and clinical behavior, with marked genetic, transcriptional, histologic and clinical differences
  • The definition of a new classification for breast cancer based on its gene expression pattern divided breast tumors into four “intrinsic subtypes”:
    • Luminal subtype:
      • Divided in Luminal A and Luminal B:
        • Characterized by estrogen receptor gene expression
    • The HER2 subtype:
      • Characterized by HER2 gene amplification
    • The so-called basal-like subtype:
      • A particular breast cancer showing positivity for basal and myoepithelial markers and lack of hormone receptors and HER2 gene amplification
    • “Normal breast-like” subtype:
      • With triple-negative phenotype but cellular derivation typical of normal breast epithelium
    • Notably, both the basal-like and normal breast-like subtypes were already recognized as triple negative
• All breast cancers arise in the terminal duct lobular units (the functional unit of the breast) of the collecting duct
• The histological and molecular characteristics:
  • Have important implications for therapy:
    • Several classifications on the basis of molecular and histological characteristics have been developed
• The histological subtypes described here (Figure) are the
  most frequent subtypes of breast cancer:
  • Ductal carcinoma (now referred to
    as ‘no special type’ (NST)) and lobular carcinoma:
    • Are the invasive lesions
  • Their pre-invasive counterparts are:
    • Ductal carcinoma in situ and lobular carcinoma in situ (or lobular neoplasia), respectively
      • The intrinsic subtypes of Perou and Sorlie:
        • Are based on a 50-gene expression signature (PAM50)
      • The surrogate intrinsic subtypes are typically used clinically and are based on histology and
        immunohistochemistry expression of key proteins:
        • Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2
          (HER2) and the proliferation marker Ki-67
      • Tumors expressing ER and / or PR are termed ‘hormone receptor-positive’
      • Tumors not expressing ER, PR and HER2 are called ‘triple-negative’
• The normal breast terminal duct lobular unit:
  • It is formed by two layers:
    • Inner or luminal layer (epithelial cell layer)
    • Outer or basal layer (myoepithelial cell layer)

• Molecular subtypes that are triple negative:
  • Basal-like:
    • TP53 mutations
    • Genetic Instability
    • BRCA mutations
    • Medullary-like histology
    • Poorly differentiated
  • Claudin-low:
    • Largely triple negative
    • Metaplastic
  • Normal breast-like
  • Molecular apocrine
  • Interferon rich

• TNBC can be classified into:
  • Low-grade and high-grade histologic types
• Several histologic types of low-grade TNBC, including:
  • Salivary gland-like tumors of the breast and solid papillary carcinoma with reverse polarity:
    • Are underpinned by specific / pathognomonic genetic alterations
  • In contrast, acinic cell carcinoma and high-grade variants of TNBC have somatic genomic landscape similar to those of conventional TNBC
  • Low- grade variants of metaplastic breast carcinomas (MBCs) are unlikely to be underpinned by specific genetic alterations; however, the genetic analyses performed to date included only a few or single cases
  • Progression to high-grade TNBC has been described in most low-grade forms of TNBC:
    • However, it occurs at a different rate
  • Whereas fairly common in acinic cell carcinoma, it is a rare event in the salivary gland-like tumors of the breast and solid papillary carcinoma with reverse polarity
  • It should be noted that evidence for the presence of PRKD1 E710D mutations or PRKD1/2/3 rearrangements in polymorphous carcinoma of the breast remains to be documented

• Chemoprevention:
  • With a selective estrogen receptor modulator:
    • Such as tamoxifen:
      • Substantially reduces the risk of developing invasive breast cancer in patients with lobular carcinoma in situ (LCIS) and should be offered
• Negative margins are generally not required for classic LCIS:
  • Whereas they are recommended for:
    • Pleomorphic LCIS
• The patient’s future risk of developing breast cancer is:
  • Approximately 1% annually
• Bilateral prophylactic mastectomy:
  • Is generally considered to be more invasive than is required in this setting and, although it could be discussed as an option, should not be routinely recommended
• References:
  • Page DL, Kidd TE Jr, Dupont WD, Simpson JF, Rogers LW. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol. 1991;22(12):1232-1239.
  • Andersen JA. Lobular carcinoma in situ of the breast. An approach to rational treatment. Cancer. 1977;39(6):2597-2602.
  • Akashi-Tanaka S, Fukutomi T, Nanasawa T, Matsuo K, Hasegawa T, Tsuda H. Treatment of noninvasive carcinoma: fifteen-year results at the National Cancer Center Hospital in Tokyo. Breast Cancer. 2000;7(4):341-344.
  • Walt AJ, Simon M, Swanson GM. The continuing dilemma of lobular carcinoma in situ. Arch Surg. 1992;127(8):904-907.
  • Haagensen CD, Bodian C, Haagensen DE. Neoplasia (lobular carcinoma in situ). In Breast Carcinoma: Risk and Detection. Philadelphia, PA: WB Saunders, 1981.
  • Wong SM, King T, Boileau JF, Barry WT, Golshan M. Population-based analysis of breast cancer incidence and survival outcomes in women diagnosed with lobular carcinoma in situ. Ann Surg Oncol. 2017;24(9):2509-2517.
  • Fisher ER, Land SR, Fisher B, Mamounas E, Gilarski L, Wolmark N. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Cancer. 2004;100(2):238-234.

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #LCIS #LobularCarcinomaInsitu #Miami #Mexico

• Radiation techniques for DCIS – Hypofractionation
  • ASTRO evidence-based guideline from 2018:
    • Stage (including DCIS vs invasive breast cancer):
      • Statement KQ1G:
        • Hypofractionation whole breast irradiation (WBI) may be used as an alternative to conventional fractionation (CF) CF-WBE in patients with DCIS
          • Recommendation strength: conditional
          • Quality of evidence: Moderate
          • Consensus: 86%
    • Age, grade, and margins for DCIS:
      • Statement KQ2D:
        • A tumor boost may be used for patients with DCIS who meet any of the following criteria:
          • Age =/< 50 years
          • High grade
          • Close (< 2 mm) or positive margins
        • Recommendation strength: conditional
        • Quality of evidence: Moderate
        • Consensus: 92%
• This two statements from ASTRO rely of data from two randomized trials:
  • The DBCG Hypo Trial:
    • Entry criteria:
      • > 40 years of age
      • BCS for node-negative breast cancer
      • DCIS (13% of the cohort)
    • Primary endpoint:
      • Grade 2 to 3 breast induration assuming no inferiority regarding locoregional recurrence
    • Median follow-up of 7.26 years

• BIG 3-07 / TROG 07.01:
  • Background:
    • Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence.
    • They investigated whether a tumor bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS.
  • Methods:
    • The study was an international, randomized, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK).
    • Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins.
    • They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each center prespecified conventional or hypofractionated WBI.
    • The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42.5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI.
    • Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence.
  • Findings:
    • Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients).
    • Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients.
    • Median follow-up was 6.6 years.
    • The 5-year free-from-local-recurrence rates were 92.7% (95% CI 90·6-94·4%) in the no-boost group and 97.1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001).
    • The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001).
  • Interpretation:
    • In patients with resected non-low-risk DCIS, a tumor bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity.
    • The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control.
    • The international scale of the study supports the generalizability of the results.
• Radiation Techniques for DCIS:
  • Accelerated partial breast irradiation:

• Summary:
  • Moderately hypo-fractionation WBI is a standard treatment
  • Consider boost for:
    • High grade DCIS
    • > 2 cm tumors
    • Positive or < 2 mm margins
    • Pre-menopausal patients
    • Patients less than 50 years of age
  • APBI in DCIS is safe and effective option in ASTRO “suitable”candidates
    • Not all techniques (just validated with external beam radiation)
  • Consider hormone therapy in aggressively minded patients or those wishing to decrease risk of contralateral breast cancer
  • Consider genomic assay assistance to aid in radiation decisions in select patients:
    • Postmenopausal patients with otherwise low-risk disease

• The second generation trials in DCIS:
  • Started to think if there is a sub group of patients that we can omit radiation therapy
• This trials looked into high risk factors for local regional recurrence (LRR) in DCIS:
  • Prognostic factors associated with increased locoregional recurrence:
    • Age less than 50 years
    • Size > than 2 cm
    • Grade 3
    • Positive of close < margins
  • Additional risk factors:
    • Symptomatic:
      • Palpable / bloody discharge
    • Comedo, solid types of DCIS
    • Black race
    • ER and / or PR negative
• What is the optimal surgical margin in DCIS?

• The use of a 2-mm margin as the standard for an adequate margin in DCIS treated with whole-breast irra- diation is associated with lower rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs:
  • Clinical judg- ment should be used in determining the need for further surgery in patients with negative margins narrower than 2 mm.
• The second generation DCIS trials:
  • RTOG 9804:
    • They included:
      • Mammographically detected DCIS
      • Low to intermediate-grade DCIS
      • Less than 2.5 cm
      • Margins =/> than 3 mm
    • This study has two different perspectives:
      • Although the results are significant:
        • Local recurrence (LR) rates without RT are less than 10%

• The second generation DCIS trials:
  • ECOG E5194:
    • From 1997 to 2022:
      • Has only one arm
    • Inclusion criteria:
      • Non-palpable DCIS
      • Cohort 1:
        • Low to intermediate grade DCIS < than 2 cm
      • Cohort 2:
        • High grade DCIS < than 1 cm
      • > 3 mm margins / no residual calcifications on postoperative mammogram
      • Lumpectomy alone:
        • NO radiation
      • Starting in the year 2000:
        • Patients could take tamoxifen

• What can we use to help us determine risk of recurrence in DCIS?
  • Genomic Assays – DCISion RT (Prelude DX):
    • Seven gene biological risk signature developed from three cohorts:
      • UCSF (n=324)
      • Uppsala Univeristy Hospital, Sweden (n=458)
      • University of Massachusetts (n=300)
    • Decision score 0 to 10:
      • Low risk 0 to 3
      • High risk score > 3 to 10
    • This biological signature was validated in a retrospective cohort

• This tool is available but it has not be validated in a prospective clinical trial

• Goals of radiation for DCIS:
  • Prevent local recurrence:
    • Both DCIS and invasive
  • Avoid mastectomy
  • Minimum toxicity
• Seminal first generation trials of radiation therapy after breast conserving surgery (BCS) for DCIS:

• Radiation therapy is associated with a roughly 50% relative risk reduction in local recurrence and absolute risk reduction of 15%:
  • In these studies most patients did not receive tamoxifen

• The first generation seminal trials:
  • Were conducted in the 1980’s and 1990’s
    • Many patients had symptomatic DCIS:
      • With palpable tumors of bloody nipple discharge:
        • Screening mammogram was uncommon
    • 10% to 20% of patients had a positive or close margins
    • Greater than 1/3 of the patients had high grade DCIS
• The DCIS patients that we see in our clinics today are:
  • Smaller, low grade, and are diagnosed earlier:
    • Because of the screening mammograms
• The effect of tamoxifen on local control:

• In the NSABP B 24 trial in multivariable analysis:
  • Young age and no tamoxifen were adverse prognostic factors

• Long-term outcomes of invasive ipsilateral breast cancer recurrences after lumpectomy in the NSABP B-17 and B-24 randomized trials for DCIS:

• Anastrozole vs Tamoxifen in DCIS (IBIS-II DCIS Trial):
  • 2980 postmenopausal women
  • 71% of the patients received radiation therapy
  • Randomization:
    • Anastrozole vs tamoxifen
  • Median follow-up:
    • 7.2 years
  • 144 breast cancer recurrences
  • The non-inferiority of anastrozole was established:
    • But its superiority to tamoxifen was not
  • Adverse effects:
    • Anastrozole:
      • More fractures, musculoskeletal events, hypercholesterolemia, and strokes
    • Tamoxifen:
      • More muscle spasms, gynecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses
• NSABP B-35 Trial

• Summary of radiation therapy in DCIS:
  • If prevention of ipsilateral breast tumor recurrence (IBTR) is the primary goal:
    • Tamoxifen cannot replace the impact of radiation therapy on local control after BCS
  • Tamoxifen may further decrease local regional recurrence risk after BCS therapy with radiation and significantly reduce contralateral breast cancer
  • In postmenopausal women less than 60 years of age:
    • Anastrozole may be more effective than tamoxifen

• Instead of trying to identify patients with underlying invasion:
  • Let’s find a way to mark the sentinel lymph node (SLN) in advance
• Senti nel Lymph Node Dissection in DCIS and how to
• Not to do it
• The SentiNot Trial
  • Concept:
    • Inject supraparamagnetic iron oxide particles (SPIO) at the primary operation:
      • Mark the SLN but do not remove it
    • If pathology report shows invasion:
      • Then we can go back and perform the SLNB
  • A multicenter cohort study:
    • Has been completed
  • Multicenter randomized trial:
    • Is ongoing

• Conclusion of SentiNot:
  • 77.2% of patients avoided upfront DCIS
  • Higher detection rate, nodal yield and accuracy
  • Incremental cost containment

• Myth:
  • Nipple blebs are caused by trauma from shallow infant latch
• Science:
  • Blebs appear as:
    • Small white, yellow, or red blisterlike lesions on the surface of a nipple
  • They are inflammatory lesions that may occlude a nipple orifice:
    • They reflect underlying ductal inflammation and microbiome disruption with biofilm formation
  • Blebs are associated with:
    • Hyperlactation (oversupply)
    • Pumping (which alters the breast microbiome)
    • C-section births (which also alter the breast microbiome),
    • Other characteristics of individual variation in microbiome expression
  • Blebs are not related to infant trauma or latch in any way
  • Because blebs are very painful:
    • Moms often believe the infant has a poor latch or otherwise has contributed to the problem:
      • However, this represents an association rather than causation
• Treatment:
  • Asymptomatic blebs do not require any specific treatment
  • Blebs causing milk obstruction warrant treatment:
    • To reduce underlying ductal inflammation and decrease the viscosity of milk
  • Sunflower lecithin by mouth:
    • Is effective for breastmilk emulsification and can help to both treat and prevent blebs
  • Therapeutic ultrasound can also be used to reduce breast inflammation
  • Symptomatic blebs occluding an orifice:
    • Should be treated with oral lecithin as well as a topical medium-potency steroid:
      • Such as 0.1% triamcinolone cream
  • Blebs should not be routinely unroofed with a sterile needle or other means:
    • As this may transiently relieve milk obstruction in an associated ductal orifice but will also cause local tissue trauma and can lead to scarring (Figure):
    • This scarring can result in permanent occlusion of the nipple orifice
  • Patients should be instructed not to attempt to squeeze out a bleb or pick at it with their fingernails, as this can cause bleeding and further trauma

#Arrangoiz #Doctor #Surgeon #CancerSurgeon #BreastSurgeon #SurgicalOncologist #MountSinaiMedicalCenter #MSMC #Miami #Mexico #BreastCancer #MilkBlebs

• Oncocytic follicular cell–derived thyroid carcinomas as a group can include many different entities:
  • Oncocytic papillary thyroid carcinomas (PTC)
  • Oncocytic encapsulated follicular subtype of PTC
  • Oncocytic poorly differentiated carcinoma
  • Oncocytic medullary thyroid carcinoma
• The term “oncocytic carcinoma of the thyroid”:
  • Is used in the new World Health Organization (WHO) to refer to:
    • Invasive malignant follicular cell neoplasms:
      • Composed of at least 75% oncocytic cells:
        • In which the nuclear features of PTC and high-grade features are absent
  • This term replaces Hürthle cell carcinoma:
    • A misnomer given that Hürthle actually described parafollicular C cells
  • Oncocytic cells:
    • Have abundant granular eosinophilic cytoplasm:
      • Secondary to a marked accumulation of dysfunctional mitochondria
  • Oncocytic carcinoma of the thyroid (OCA):
    • Represents the malignant counterpart of oncocytic adenoma
    • Accounts for approaching 2% to 5% of differentiated thyroid carcinomas in the USA
    • Can occur anywhere in the thyroid
    • Usually presents as a slowly enlarging painless solitary thyroid nodule
    • Thyroid ultrasound cannot distinguish between oncocytic adenoma and OCA:
      • Though larger tumors have a higher rate of malignancy
    • There are no known risk factors for developing OCA
    • The mean age at diagnosis is approaching 60 years:
      • Which is roughly 10 years later than the mean age of diagnosis for patient with follicular thyroid carcinoma
    • OCA, although more common in women (with a 1.6 to 1 female-to-male ratio):
      • Has a lower female-to-male ratio than is seen with follicular thyroid carcinoma
    • Histologically:
      • OCAs are encapsulated tumors with capsular and / or vascular invasion and at least 75% oncocytic cells (Figures)
    • OCAs are subclassified into:
      • Minimally invasive:
        • Those with capsular invasion only
      • Encapsulated angioinvasive
      • Widely invasive:
        • Those with gross invasion through the gland
    • When evaluating OCA, it is important not only to document extent of invasion, but also to evaluate for progression to oncocytic poorly differentiated thyroid carcinoma:
      • Thus, all tumors should be assessed for increased mitotic activity (3 or more mitoses per 10 high-power fields / ~ 2 mm2) and tumor necrosis
    • OCA can metastasize to lymph nodes:
      • However, some authors have shown that most of the so-called lymph nodes metastasis of OCA represent tumor plugs in veins in the neck and not lymph nodes involved by tumor
      • The important clue is the almost perfect roundness of these tumor plugs compared to oval or somewhat irregular outline for nodal metastases
    • OCA (like follicular thyroid carcinoma) usually spreads to distant sites via blood vessels:
      • Distant metastasis at presentation are seen in 15% to 27% of patients with OCA:
        • In up to 40% of tumors with extensive vascular invasion
  • Prognostic parameters for OCA include:
    • Patient age, tumor size, vascular invasion, extrathyroidal extension, and the presence of distant metastases:
    • Distant metastases at diagnosis are the most important prognostic factor for OCA
  • For OCA, the 5-year overall survival has been reported to be 85%:
    • But only 24% among patients with distant metastases at diagnosis compared to 91% for patients with M0 disease at diagnosis
  • Although it is not clear that OCA is more aggressive than follicular thyroid carcinoma after adjusting for variables such as patient age, gender, and tumor stage:
    • Due to decreased efficacy of radioactive iodine with OCA compared to follicular thyroid carcinoma:
      • Treating OCA is currently more difficult once there is disease recurrence
  • Benign and malignant oncocytic thyroid tumors:
    • Have both been shown to harbor homoplasmic or highly heteroplasmic (> 70%) mitochondrial DNA mutations in complex I subunit genes of the electron transport chain
    • Additionally, OCAs demonstrate widespread chromosome losses that result in near-genome-wide haploidization with or without subsequent genome endoreduplication:
      • Chromosomal changes have been found to be associated with extent of invasion:
        • Most OCAs with capsular invasion only or focal vascular invasion have been shown to be diploid
        • Whereas tumors with extensive vascular invasion and widely invasive tumors:
          • Are usually polysomic and nearly always demonstrate chromosome 7 amplification
          • Additionally, the near-haploid state has been shown to be maintained in metastases, implying selection during tumor evolution
        • OCAs have also been shown to have recurrent DNA mutations, including RAS mutations (though at a lower rate than is seen with follicular thyroid carcinoma), EIF1AX, TERT, TP53, NF1, and CDKN1A, among others

#Arrangoiz #Doctor #Surgeon #CancerSurgeon #HeadandNeckSurgeon #ThyroidSurgeon #SurgicalOncologist #ThyroidAwarenessMonth #ThyroidCancer #MountSinaiMedicalCenter #MSMC #Miami