Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

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.

Expanded Role of BRCA Testing and Adjuvant PARP Inhibition in Early Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • In the OlympiA trial:
    • Adjuvant therapy with olaparib vs placebo demonstrated a benefit in overall survival, invasive disease‒free survival, and distant disease‒free survival in eligible patients with early breast cancer and gBRCApathogenic variants.
  • With the expanded role of BRCA testing in early breast cancer, completion of testing in eligible patients is critical
  • Given the survival benefit of adjuvant PARP inhibition in this population:
    • Patient and healthcare professional education on the importance of genetic testing and benefits of therapy is key
#Arrangoiz #BreastSurgeon #Surgeon #SurgicalOncologist #BRCAMutation #MountSinaiMedicalCenter #MSMC #Miami #Mexico

Olaparib as Adjuvant Therapy in Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • The safety and efficacy of olaparib as adjuvant therapy was evaluated in the phase 3 OlympiA trial:
    • That enrolled patients with a germline BRCA mutation and HER2 negative, high-risk, early-stage breast cancer:
      • Who had completed definitive local treatment and at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, a taxane, or both (prior platinum for previous cancer or as adjuvant /neoadjuvant breast cancer treatment was permitted)
  • Patients were randomly assigned (1:1) to receive:
    • Olaparib tablets 300 mg orally twice daily or placebo
  • Treatment was continued for up to 1 year or until disease recurrence or unacceptable toxicity occurred
  • In this study, patients with high-risk, early stage breast cancer were identified using the following criteria: 
    • Patients who received prior neoadjuvant chemotherapy:
      • Triple-negative breast cancer (TNBC):
        • They needed to have residual invasive cancer in the breast and / or the resected lymph nodes (nonpathologic complete response) at the time of surgery
      • Hormone receptor–positive breast cancer:
        • They needed to have residual invasive cancer in the breast and / or the resected lymph nodes (nonpathologic complete response) at the time of surgery:
          • Additionally, they needed a score of 3 or more based on pretreatment clinical and post-treatment pathologic stage, ER status, and histologic grade (Table)
    • Patients who received prior adjuvant chemotherapy:
      • TNBC:
        • They needed to have node-positive disease or node-negative disease with the primary tumor measuring 2 cm or more
      • Hormone receptor–positive, HER2 negative breast cancer:
        • They needed to have 4 or more pathologically-confirmed positive lymph nodes
Early Breast Cancer Stage, Receptor Status, and Grade Scoring Requirements for OlympiA Enrollment
  • Updated results, representing a median follow up of 3.5 years, were published in October 2022:
    • A significant improvement in OS was observed in the olaparib group compared to the placebo group:
      • HR, 0.68; 98.5% CI, 0.47-0.97; P = 0.009:
        • Four-year OS rates were 89.8% with olaparib and 86.4% with placebo
    • Continued benefit in terms of invasive disease free survival (IDFS) and distant DFS (DDFS) were demonstrated with olaparib versus placebo
    • In subset analyses, OS, IDFS, and DDFS benefits were observed across major subgroups
#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #MountSinaiMedicalCenter #MSCM #Miami #Mexico #BreastCancer

Hereditary Breast Cancer Syndromes

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • A number of hereditary syndromes:
    • Are associated with an increased risk of breast cancer
  • The most common involve mutations of the:
    • BRCA1 and BRCA2 genes
  • The risk of breast cancer among women with BRCA1 mutations:
    • Approaches 80%, with ovarian cancer risk as high as 45%
  • BRCA2 carriers:
    • Have slightly lower rates of both breast (up to 60%) and ovarian (up to 25%) cancers
  • Male breast cancers:
    • Are more likely to be BRCA2 if the man is found to be a gene carrier
  • Less than half of the hereditary cancers are secondary to non-BRCA genetic mutations
  • Cowden Syndrome:
    • Is associated with PTEN mutations and has an autosomal dominance inheritance pattern
    • Individuals have an increased lifetime risk of:
      • Breast cancer (20% to 50%):
        • With most diagnosed before age 50 years
      • As well as high rates of benign breast disease
    • Follicular thyroid and endometrial cancers:
      • Are commonly seen in association with this syndrome as well
    • Screening includes surveillance of the kidneys and colon, as they are increased in risk for cancers of these organs as well
  • Peutz-Jeghers syndrome:
    • Is characterized by mutations in STK11 and also demonstrates autosomal dominant inheritance
    • Individuals have a breast cancer risk of 55%:
      • Along with elevated rates of both ovarian and uterine cancer
    • These individuals often have:
      • Multiple hamartomatous polyps throughout the gastrointestinal tract:
        • As well as multiple melanin deposits in the mouth, lips, fingers, and toes
  • Li-Fraumeni syndrome:
    • Is characterized by mutations of the TP53:
      • A suppressor gene and is also inherited in an autosomal dominant pattern
    • These individuals have strikingly high rates of malignancy:
      • With 50% of individuals diagnosed with cancer by age 30, and 90% diagnosed with cancer by age 70
    • Malignancies include:
      • Breast:
        • With the majority diagnosed by age 45 years
      • Sarcomas, osteosarcomas, leukemias, brain tumors, and adrenocortical tumors
    • Radiation-induced tumors have been seen frequently among these patients:
      • Leading many radiation oncologists to advise against breast-conservation therapy in women with Li-Fraumeni diagnosed with breast cancers
  • References:
    • Economopoulou P, Dimitriadis G, Psyrri A. Beyond BRCA: New hereditary breast cancer susceptibility genes. Cancer Treat Rev. 2015;41:1-8.
    • Issacs C, Peshkin BN, Schwartz M. Genetic testing and management of patients with hereditary breast cancer diseases of the breast. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 4th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2010:224-247.
    • National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic / Familial High-Risk Assessment: Breast and Ovarian. Available at http://www.nccn.org.
    • Ready K, Arun B. Breast cancer syndromes: counseling and management. In: Babiera GV, Skoracki RJ, Esteva FJ, eds. Advanced Therapy of Breast Disease. 3rd ed. Shelton, CT: People’s Medical Publishing House-USA; 2012:29-38.

Risk Factors for Papillary Thyroid Carcinoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO

  • Radiation exposure:
    • Radiation exposure of the thyroid during childhood:
      • Is the most clearly defined environmental factor:
        • Associated with benign and malignant thyroid tumors
    • Potential sources of radiation exposure include:
      • Therapeutic uses of radiation (eg, treatment of childhood malignancies)
      • Environmental exposure secondary to:
        • Fallout from atomic weapons (eg, Nagasaki / Hiroshima, Japan)
        • Nuclear power plant accidents (eg, Chernobyl)
      • In the past, ionizing radiation was used to treat a wide variety of benign conditions of the head and neck:
        • Although this practice essentially ceased in the late 1950s to early 1960s due to increased appreciation of the carcinogenic effects of radiation on the thyroid
  • Family history:
    • A history of thyroid cancer in a:
      • First-degree relative
    • Family history of a thyroid cancer syndrome:
      • Familial polyposis
      • Carney complex
      • Multiple endocrine neoplasia type 2 [MEN2]
      • Werner syndrome
      • Cowden syndrome
  • A family history:
    • Increases the risk that a nodule may be malignant
    • In one study, there was a 10-fold increased risk of thyroid cancer in relatives of thyroid cancer patients
    • In a second report, the standardized incidence ratio for papillary cancer was 3.2 with an involved parent, 6.2 with an involved sibling, and 11.2 for a female with an involved sister
  • Other:
    • A number of other possible (but not proven) risk factors have been reported
    • Their relative importance appears to be small but not completely defined
    • Potential risk factors include the following:
      • Occupational and environmental exposures
      • Hepatitis C-related chronic hepatitis (odds ratio [OR] 12.2 in one report)
      • Increased parity and late age at first pregnancy
      • Obesity or overweight 

BRCA Mutation Carriers

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Carriers of the BRCA1 deleterious mutation are more likely than both controls and carriers of the BRCA2 mutation:
    • To have high-grade, receptor-negative tumors (and, in particular, triple-negative tumors):
      • Containing necrosis, with higher mitotic counts and shorter tumor-doubling times
  • Carriers of the BRCA1 mutation have lesions that are more likely to have:
    • Pushing margins and that are less likely to be spiculated:
      • Making them harder to detect on mammography and more likely to be detected by MRI than mammography
  • Women with a strong family history of both early-onset breast cancer and ovarian cancer in first-degree relatives:
    • Is consistent with hereditary breast and ovarian cancer syndrome, and the presence of triple-negative disease is most consistent with the history and diagnosis for a carrier of the BRCA1 deleterious mutation
  • Although few studies have evaluated preoperative breast MRI in BRCA carriers after breast cancer has already been diagnosed:
    • Breast MRI has been shown to have a survival benefit in the high-risk screening setting, and the lifetime risk of cancer developing in the contralateral breast (which can also be mammographically occult):
      • Is nearly 40% in this population
    • Breast MRI is a reasonable preoperative option to evaluate the contralateral breast if the woman has dense breasts, risk of being a BRCA carrier, and consequent risk of disease being present or developing in the contralateral breast:
      • However, for patients who opt for bilateral mastectomy, breast MRI preoperatively is not mandatory
  • Although genetic testing has become more widespread and easier to perform in recent years:
    • Performing a genetic test without counseling by someone who has genetic training and expertise is not appropriate
  • As some BRCA mutations are known to be deleterious, others are variants of undetermined significance:
    • This means, as the name suggests, that it is unclear whether the patient is at any greater risk of cancer, and if so, by how much
    • This must be part of the discussion because 5% to 10% of mutations are these variants of undetermined significance, and patient perceptions of their own risk in that setting are high, mandating proper education
  • Although women with BRCA mutations have bilateral mastectomy as an option to treat a known cancer and prevent a contralateral one:
    • The American Society of Clinical Oncology / Society of Surgical Oncology consensus statement on prophylactic mastectomy considers a significant family history an appropriate indication for prophylactic mastectomy, even in the absence of a diagnosed mutation
  • Women who have a diagnosed deleterious mutation and those who have not been tested but have a strong family history are also considered appropriate for risk-reducing surgery
  • References:
    • Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. Ann Surg Oncol. 2006;13:1296-1321.
    • Kaas R, Kroger R, Peterse JL, Hart AA, Muller SH. The correlation of mammographic and histologic patterns of breast cancers in BRCA1 gene mutation carriers, compared to age-matched sporadic controls. Eur Radiol. 2006;16:2842-2848.
    • Lakhani SR, Reis-Filho JS, Fulford L, et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res. 2005;11:5175-5180.
    • Murray ML, Cerrato F, Bennett RL, Jarvik GP. Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions. Genet Med. 2011;13:998-1005.
    • Plevritis SK, Kurian AW, Sigal BM, et al. Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging. JAMA. 2006;295:2374-2384.

Incidence of Papillary Thyroid Carcinoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • In a report based upon the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2018:
    • The incidence of papillary cancer:
      • Increased from 4.8 to 14.9 per 100,000:
        • Stabilized:
          • Then appeared to decline to approximately 13.5 per 100,000 by 2018
  • The death rates:
    • 0.5 per 100,000 male and female per year:
      • Did not change significantly
  • The 5-year relative survival:
    • Remains quite high:
      • At 98.3 percent (2011 to 2017 data)
  • The precise reasons for the increase, apparent plateau, and subsequent decrease in incidence rate in papillary thyroid cancer are unknown
  • The initial increase in thyroid cancer incidence in the United States:
    • Was seen in males and females, and in persons of all racial and ethnic backgrounds
  • The usual female-to-male ratio of papillary thyroid cancer is:
    • Approximately 2.5:1:
      • With most of the female preponderance occurring during the:
        • Fourth and fifth decades of life
  • The increased incidence was thought to partially reflect earlier detection of subclinical disease (ie, small papillary cancers):
    • Secondary to more widespread use of neck ultrasonography and fine-needle aspiration (FNA) of very small thyroid nodules:
      • However, an analysis of the National Cancer Institute’s SEER database:
        • Found an increase in the rates of differentiated thyroid cancer of all sizes, including tumors greater than 4 cm
    • Subsequently, there has been a move in the medical community away from the previous widespread practice of immediate biopsy of very small asymptomatic suspicious nodules incidentally detected on imaging
    • More selective use of FNA in small thyroid nodules along with more judicious use of thyroid ultrasonography, in general, could lead to a decrease in incident rates:
      • However, another primary cause of thyroid cancer (as yet unidentified) has not been excluded

BRCA Mutation Carries Screening Recommendations and Risk Reducing Strategies

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Women with BRCA1 / BRCA 2 mutations:
    • Are at an increased lifetime risk of both:
      • Breast and ovarian cancer
  • Patients with a known BRCA 1 / BRCA 2 mutation:
    • Are recommended to undergo increased imaging surveillance with:
      • Annual breast MRI screening from age 25 to 29
      • Annual mammogram and breast MRI screening from age 30 to 75
  • Options for risk reduction among BRCA carriers include:
    • The use of chemoprevention or risk-reducing surgery:
      • The subset of patients with a BRCA2 mutation receiving tamoxifen in the NSABP P1 study:
        • Had a 62% reduction in breast cancer risk relative to placebo (relative risk [RR] 0.38, 95% CI 0.06-1.56)
    • A more recent case-control study of women with BRCA mutations:
      • Showed a 50% reduction in breast cancer risk associated with tamoxifen use, and was effective in both BRCA1 and BRCA2 mutation carriers (odds ratio [OR] 0.63 [BRCA 2] vs. 0.38 [BRCA 1])
  • Because the onset of ovarian cancer for BRCA2 carriers tends to be up to 10 years later than that in BRCA1 carriers:
    • BSO is recommended at the completion of childbearing or age 40 to 45
  • The recommended age for BRCA1 mutation carriers:
    • To undergo BSO is age 35 to 40
  • In the PROSE study:
    • Women with BRCA 1 / BRCA 2 mutations who underwent bilateral risk reducing mastectomy (RRM) for breast cancer risk reduction:
      • Were compared to controls who did not undergo prophylactic surgery
    • Bilateral RRM reduced the risk of breast cancer by approximately 90% in women with intact ovaries and 95% in women with prior or concurrent BSO
  • While retrospective analyses have confirmed a similar degree of breast cancer risk reduction in BRCA1 / BRCA 2 mutation carriers following bilateral RRM:
    • This procedure is not significantly associated with reduced all-cause mortality
  • A recent prospective study of 3,722 women with BRCA 1 and 2 mutations demonstrated that BSO was associated with a significantly reduced risk of breast cancer for BRCA 2 mutation carriers diagnosed prior to age 50 (age-adjusted HR 0.18, p = 0.007):
    • However, the same effect was not seen for BRCA1 mutation carriers undergoing BSO (age-adjusted HR 0.79, p = 0.051)
  • References
    • National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Genetic/familial assessment: breast and ovarian, Version 1.2018. October 3, 2018 https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdfAccessed November 8, 2019.
    • Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371-1388.
    • Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen SL, et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet. 2000;356(9245):1876-1881.
    • Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van ‘t Veer L, Garber JE, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22(6):1055-1062.
    • Li X, You R, Wang X, Liu C4, Xu Z5, Zhou J, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: a meta-analysis and systematic review. Clin Cancer Res. 2016;22(15):3971-3781
    • Kotsopoulos J, Huzarski T, Gronwald J, Singer CF, Moller P, Lynch HT, et al. Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2016;109(1).

BRCA 1 and BRCA 2 Mutations

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Women with pathogenic BRCA1 or BRCA 2 germline variants:
    • Have a high lifetime risk of breast cancer as well as a high risk of ipsilateral second breast cancer and contralateral breast cancer events
  • A subgroup analysis of high-risk women on chemoprevention with tamoxifen showed:
    • A reduction in the incidence of breast cancer in women with pathogenic BRCA2, but not BRCA1, gene variants [1,2] 
  • The majority of women with pathogenic BRCA2 gene variants who develop breast cancer:
    • Will have ER+ tumors:
      • Unlike women with pathogenic BRCA1 variants:
        • Who have a higher percentage of ER- and PR- breast cancers
  • Denosumab (Prolia®, Xgeva®):
    • Is a human, anti-RANKL monoclonal antibody:
      • That blocks the progesterone-induced increase in Ki-67 and may have a future role as a chemoprevention agent:
        • However, the FDA has not yet approved denosumab for chemoprevention [1]
  • Bilateral risk-reducing mastectomy:
    • Is the most effective means to prevent BRCA1- or BRCA 2-associated breast cancer:
      • But it does not impact all-cause mortality
    • In addition, breast-conserving therapy is a safe option with similar mortality rates [1]
  • Bilateral risk-reducing oophorectomy:
    • Prior to development of a breast cancer in premenopausal women with pathogenic BRCA1 or BRCA 2 variants:
      • Is associated with a 77% reduction in all-cause mortality [1]
    • Other studies have also shown a 25% to 50% reduction in breast cancer risk in patients with pathogenic BRCA1 or BRCA 2 variants after bilateral risk-reducing oophorectomy [4]
  • Women with BRCA1 and BRCA 2 pathogenic variants diagnosed with unilateral breast cancer under the age of 50:
    • Have an increased risk of contralateral breast cancer
  • Aromatase inhibitor use was associated with decreased contralateral breast cancer risk among patients with BRCA1 or BRCA 2 pathogenic variants (HR 0.44, p=0.004):
    • Whereas tamoxifen was not [5] 
  • References:

Risk of Contralateral Breast Cancer in BRCA Positive Patients

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • The annual risk for BRCA mutation carriers to develop breast cancer is:
    • Estimated to be 2.1%
  • The risk of contralateral breast cancer:
    • At 20 years post initial breast cancer diagnosis is:
      • 41% in BRCA1 mutation carriers
  • Age at diagnosis:
    • Does affect risk of contralateral breast cancer:
      • Women under 40 are at highest risk
  • Tamoxifen:
    • Has been shown to decrease the risk of contralateral breast cancer overall
  • Phillips et al:
    • Report that estrogen receptor status of the initial breast cancer diagnosis:
      • Did not affect contralateral breast cancer risk:
        • However the status was missing in over 50% of the cohort
    • In addition, women found to be at the highest risk were:
      • Those diagnosed with initial breast cancer under age 50
      • Those with 2 or more family members with history of breast cancer
      • Intact ovaries
        • The 15-year risk of contralateral breast cancer was 68% in these women:
        • These women should be counseled about risk reducing contralateral mastectomy and salpingo-oopherectomy
  • The strongest predictor of contralateral risk was oophorectomy
  • Contralateral prophylactic mastectomy is a controversial area in breast surgical oncology, and patient decision-making around this process continues to be studied
  • References
    • Metcalfe K, Gershman S, Lynch HT, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2011;104(9):1384–1392.
    • Phillips KA, Milne RL, Rookus MA, et al. Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2013;31(25):3091-3099.
    • Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416.

Are Thyroid Nodules in the Isthmus Cytologically or Molecularly Different from Nodules in the Thyroid Lobes?

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Jasim S, Golding A, Bimston D, et al. Cytologic and molecular assessment of isthmus thyroid nodules and carcinomas. Thyroid. Epub 2024 Nov 11; doi: 10.1089/thy.2024.0254. PMID: 39527399.
  • Background:
    • Isthmus thyroid nodules:
      • While less frequent than lobar nodules may carry a higher risk of thyroid cancer and be associated with more aggressive histopathologic features than nodules in either thyroid lobe
    • The underlying reasons for these could be the anatomical location, thin thyroid tissue, and unique lymphatic drainage
    • However, a recent study demonstrated potentially different molecular signatures:
      • With higher ERK and lower thyroid differentiation scores (TDSs) in isthmus as compared to lobar papillary thyroid carcinoma (PTC)
    • Whereas most thyroid nodules are cytologically benign:
      • Approximately 20% to 30% have a Bethesda III or IV cytology:
        • Considered indeterminate thyroid nodules (ITNs):
          • Demonstrating a risk of malignancy ranging from 13% to 34%
    • Historically, surgical intervention was the mainstay for these ITNs:
      • Though most are histopathological benign:
        • Hence, molecular testing has emerged to guide the management of ITNs, of which the Afirma genomic sequencing classifier (GSC) uses exome-enriched RNA sequencing:
          • Providing data on gene and exon expression, mitochondrial expression, loss of heterozygosity, and detection of expressed gene variants and fusions to provide diagnostic information for Bethesda III /IV, and potentially prognostic information for Bethesda V and GSC-suspicious nodules
    • This study demonstrates the cytologic and molecular differences between nodules and PTC based on isthmus or lobar location
  • Methods:
    • This observational study analyzed two cohorts in a complementary manner:
      • Afirma thyroid nodule database (n = 177,227) with genome wide differential expression analysis to decipher transcriptomic differences between isthmus and lobar nodules
      • Histopathology reports (n = 583) of classic PTC (n = 389) and infiltrative follicular subtype of PTC (IF-PTC) (n = 194) from Afirma discovery cohorts and thyroid cancer patients treated at an integrative endocrine surgery community care practice for molecular differences between isthmic and lobar cancers
      • For molecular difference assessment, 54 gene expression signatures were evaluated, including activity scores of 50 hallmarks of cancer pathways, BRAF-like to RAS-like molecular score (BRS), ERK signaling, TDS, and follicular to mesenchymal transition score
      • For pathway enrichment analysis, transcriptome-wide differential expression analysis using 26,268 genes was conducted to identify genes upregulated and downregulated in isthmus nodules by using the Wilcoxon rank-sum statistical test. Deconvolution of bulk gene expression data was used to estimate levels of infiltrating immune cells
  • Results:
    • There were 8527 (4.8%) isthmus nodules identified in the Afirma database
    • Isthmus nodules were twice as likely to be Bethesda V / VI (8.2% vs. 4.3%, P<0.0001) and had twice the frequency of BRAF V600E (21% vs. 10.6%, P<0.0001), an increased frequency of ALK/NTRK/RET fusions (4.6% vs. 2.5%, P<0.0001) and SPOP variants (1.5% vs. 0.8%, P<0.0001):
      • While demonstrating a lower frequency of NRAS mutations (7.8% vs. 13.2%, P<0.0001), PAX8/PPAR-gamma fusions (1.1% vs. 2.3%, P<0.0001, and RET variants (0.06% vs. 0.53%, P = 0.001) than lobar nodules
    • Isthmus nodules also demonstrated higher BRS, ERK activity, and FMT scores (P<0.0001 for all) but lower inflammation immune activity scores on transcriptome and genomewide analysis
    • Complementarily, isthmus nodules showed downregulation of immune response regulation genes on pathway enrichment analysis (OR, 0.74; P<0.001) relative to lobar nodules
    • As compared to lobar IF-PTCs (n = 181), those from the isthmus (n = 13) demonstrated higher BRS, ERK activity, and FMT scores (P<0.01 for all)
    • Analysis of clinical outcomes from 454 samples did not show differences in the frequency of vascular or capsular invasion, extrathyroidal extension, positive surgical margins, or lymph node metastases by cancer location
  • Conclusions:
    • Isthmus nodules were more likely to be malignant and to have increased rates of higher-risk molecular alterations compared to lobar nodules
    • IF-PTC from the isthmus was molecularly different than lobar IF-PTC
    • More investigation is needed to validate these findings before impacting the management of isthmus thyroid nodules
  • COMMENTARY:
    • The location of a nodule in the thyroid may provide a clue to the likelihood of malignancy and to the possibility of an aggressive type, but the current data supporting this are limited
    • Using the Afirma molecular test on validation and clinical data sets, this study found isthmus thyroid nodules to be more likely to have Bethesda V/VI cytology and higher rates of BRAF-like molecular signatures and other molecular markers associated with aggressive behavior than lobar nodules
    • When restricted to cancerous nodules, isthmus IF-PTC showed higher BRAF-like, ERK, and FMT expression scores consistent with aggressive molecular profiles than lobar IF-PTC
    • This study builds on prior work using The Cancer Genome Atlas demonstrating molecular differences between isthmus and lobar PTC, confirming previous literature demonstrating higher risk and histopathologic aggressiveness of PTC in isthmus nodules
    • The authors acknowledge study limitations, including its retrospective observational nature, making it prone to selection bias, low number of cancerous isthmus nodules, and lack of longterm outcome data, limiting their ability to potentially demonstrate histopathologic and clinical differences as compared to lobar nodules
    • While the molecular signatures associated with aggressive PTC behavior were statistically higher in isthmus nodules, their clinical significance needs further investigation
    • In summary, this study provides insights into different malignancy and aggressiveness risk of isthmus thyroid nodules based on molecular signatures
    • The findings should guide future investigations into the underlying reasons for these molecular differences and prospective analyses across different cohorts to improve the management of thyroid nodules