Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Risk stratification begins:
  • Immediately upon identification of a suspicious thyroid nodule
• In the absence of a validated peri-diagnostic risk-stratification system, I use a clinical framework that incorporates:
  • Tumor imaging characteristics, medical team characteristics, and patient preferences to risk stratify patients as:
    • Ideal
    • Appropriate
    • Inappropriate for minimalistic initial management options:
      • Such as active surveillance or thyroid lobectomy
      • This clinical framework address the key factors that differentiate actionable from non-actionable disease

#Arrangoiz #ThyroidSurgeon #ThyroidExpert #ThyroidCancer #DynamicRiskStartification #HeadandNeckSurgeon #CancerSurgeon #MountSinaiMedicalCenter #MSMC

• The administration of neoadjuvant chemotherapy (NAC):
  • Offers several advantages in locally advanced breast cancer:
    • It allows for downstaging the disease:
    • Which can potentially allow for less extensive surgery in the breast and axilla
  • It also provides information regarding the responsiveness of the cancer to systemic therapy while the tumor remains in vivo:
    • Which can guide the course of therapy
• Administering chemotherapy in the neoadjuvant vs. adjuvant setting:
  • Does not change overall survival:
    • As demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and NSABP B-27 trials
• The patient’s response to chemotherapy:
  • However, does offer prognostic information:
    • Particularly in patients with hormone receptor negative (HR-) disease
• Patients who achieve pathologic complete response (pCR):
  • Which is typically defined as no residual invasive disease in the breast or axilla:
    • Appear to have improved event-free survival (EFS) and overall survival (OS) compared with patients with residual disease
    • This finding was demonstrated by a recent meta-analysis that included 36 studies including 5,768 patients with HER2 positive breast cancer:
      • This correlation was strongest in patients with HR- disease
    • Further, among patients with HER2 positive disease that do not have a pCR:
      • The degree of residual cancer burden appears to correlate with outcomes
• Patients with HER2 positive tumors:
  • May complete up to 1 year of HER2-targeted therapy with trastuzamab ± pertuzamab
• When planning surgery:
  • The pre-treatment volume does not need to be excised if the tumor has responded to chemotherapy:
    • However if multifocal disease is present, the satellite lesion(s) should be localized and excised with the index lesion
  • When considering the appropriateness for breast conservation following NAC, the distance between the lesions, location, and breast size must be considered
  • Placement of clips in the index lesion and any satellite lesions prior to initiation of NAC is critical for appropriate surgical planning post-NAC
• References:
  • Rastogi P, Anderson SJ, Bear HD. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008; 10;26(5):778-785.
  • Broglio KR, Quintana M, Foster M, et al. Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis. JAMA Oncol. 2016;2(6):751-760.
  • Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049-1060.
  • Boughey JC, Peintinger F, Meric-Bernstam F, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg.2006;244(3):464-470.

• Adenoid cystic carcinoma (ACC) of the breast:
  • Is a very rare special histological type of breast cancer:
    • Accounting for approximately 0.1% of all breast tumors
  • It is usually triple negative
  • It is much less likely to have nodal involvement
  • Is more common in postmenopausal women:
    • Most cases are in females
    • The median age of onset is:
      • Between 50 and 60 years
    • With a mean age of 66
  • The typical clinical feature is:
    • A single breast tumor / mass:
      • Multiple nodules are rare
    • Most ACCs are located:
      • Under the areola or in the upper outer quadrants
  • ACC of the breast has no characteristic imaging findings:
    • Ultrasound features are those of:
      • A hypoechoic solid or heterogeneous mass
    • On mammography:
      • The case may present as a lobulated mass with sharp or un sharp margins
    • Nevertheless, these clinical and radiographic features may be similar to any breast cancer:
      • Thus making their precise diagnosis difficult for radiologists
  • Histologically:
    • ACC of the breast typically consists of a dual-cell population of:
      • Luminal and myoepithelial-basal cells:
        • Which are generally negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)
    • In addition, some studies have also reported some HR-positive ACC cases:
      • The significance of a positive hormone receptor status is not known:
        • Compared with ACC with negative HR expression, the clinical characteristics and prognosis of this type of ACC are also unknown
  • Distant metastases are rare:
    • However, the lung is the most common site
  • It has a better prognosis than infiltrating ductal triple negative breast cancer:
    • With a 5-year overall survival rate of 88%
    • As prognosis is good:
      • Accurate preoperative diagnosis is important in the determination of suitable treatment

• References
• Treitl D, Radkani P, Rizer M, El Hussein S, Paramo JC, Mesko TW. Adenoid cystic carcinoma of the breast, 20 years of experience in a single center with review of literature. Breast Cancer. 2018;25(1)28-33.
• Welsh JL, Keeney MG, Hoskin TL, et al. Is axillary surgery beneficial for patients with adenoid cystic carcinoma of the breast? J Surg Oncol. 2017;116(6):690-695.
• Kulkarni N, Pezzi CM, Greif JM, et al. Rare breast cancer: 933 adenoid cystic carcinomas from the National Cancer Data Base. Ann Surg Oncol. 2013;20(7):2236-2241.
• Kshirsagar AY, Wader JV, Langade YB, Jadhav KP, Zaware SU, Shekhar N. Adenoid cystic carcinoma of the male breast. Int Surg (2006) 91(4):234–6.
• Pang W, Wang Z, Jin X, Zhang Q. Adenoid cystic carcinoma of the breast in a male: A case report. Med (Baltimore) (2019) 98(32):e16760. doi: 10.1097/MD.0000000000016760
• Tang W, Peng WJ, Gu YJ, Zhu H, Jiang TT, Li C. Imaging Manifestation of Adenoid Cystic Carcinoma of the Breast. J Comput Assist Tomogr (2015) 39(4):523–30. doi: 10.1097/RCT.
• Torrao MM, da Costa JM, Ferreira E, da Silva MV, Paiva I, Lopes C. Adenoid cystic carcinoma of the breast. Breast J (2007) 13(2):206.
• Marchio C, Weigelt B, Reis-Filho JS. Adenoid cystic carcinomas of the breast and salivary glands (or ‘The strange case of Dr Jekyll and Mr Hyde’ of exocrine gland carcinomas). J Clin Pathol (2010) 63(3):220–8. doi: 10.1136/jcp.2009.073908

#Arrangoiz @BreastSurgeon #BreastCancer #AdenocysticCarcinomaoftheBreast #ACC #SurgicalOncologist #CASO #CenterforAdvancedSurgicalOncology #Miami

• National Comprehensive Cancer Network (NCCN) guidelines:
  • Recommend surgical management:
    • For local control for women with early stage invasive breast cancer
  • Several studies have shown an equivalence in overall and / or breast cancer-specific survival rates:
    • For breast conservation with radiation compared to mastectomy among early stage breast cancer patients
  • For patients with ER positive disease:
    • Endocrine therapy with tamoxifen or aromatase inhibitors is prescribed after surgery:
      • A systematic review evaluated the efficacy of primary endocrine therapy alone versus surgery in women over 70 years old with operable tumors:
        • The review reported similar survival between the two groups, but women treated with surgery had lower rates of local failure when compared to endocrine therapy alone
        • The authors concluded that primary endocrine therapy should be reserved for women who are unfit for surgery or decline surgery
  • Sentinel node biopsy:
    • Has become the standard method for staging the axilla in women with early stage breast cancer:
      • Who are clinically node negative
    • Axillary dissection is only performed in women with:
      • Documented nodal involvement
      • Inflammatory breast cancers
      • Those who fail lymphatic mapping
• References:
  • National Comprehensive Cancer Network. Breast Cancer. 2014; https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 8/28/2024, 2024
  • Fisher B, Anderson S, Bryant J, et al. Twenty-year followup of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. New Engl J Med. 2002;347(16):1233-1241.
  • Litiere S, Werutsky G, Fentiman IS, et al. Breast-conserving therapy versus mastectomy for stage I-II breast cancer: 20 year followup of the EORTC 10801 phase 3 randomized trial. Lancet Oncol. 2012;13(4):412-419.
  • Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. New Engl J Med. 2002;347(16):1227-1232.
  • Morgan J, Wyld L, Collins KA, Reed MW. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev. 2014(5). https://www.cochrane.org/CD004272/BREASTCA_surgery-versus-primary-endocrine-therapy-for-elderly-women-with-operable-primary-breast-cancer Accessed August 25, 2019.

• Pathologic nipple discharge:
  • Is characteristically spontaneous, unilateral, or bloody
• Physiologic discharge:
  • Is non-spontaneous, bilateral, and milk
• The most common causes for pathologic nipple discharge:
  • Are benign:
    • Intraductal papillomas
    • Duct ectasia
• The presence of abnormal clinical findings on imaging or physical exam:
  • Is associated with increased risk of malignancy:
    • 38% vs. 2%
• Contemporary workup for nipple discharge includes:
  • Mammography
  • Evaluation of the retroareolar region with ultrasound
• Patients with normal findings on mammography, ultrasound, and physical exam:
  • Can be further evaluated with breast MRI:
    • As it is highly sensitive and specific for cancer
• Surgical management of nipple discharge includes:
  • Excision of a single duct or central duct apparatus:
    • Depending on the number of ducts involved
• References:
  • Li GZ, Wong SM, Lester S, Nakhlis F. Evaluating the risk of underlying malignancy in patients with pathologic nipple discharge. Breast J. 2018;24(4):624-627.
  • de Paula IB, Campos AM. Breast imaging in patients with nipple discharge. Radiol. Bras. 2017;50(6):383-388.
  • Yilmaz R, Bender O, Celik Yabul F, Dursun M, Tunaci M, Acunas G. Diagnosis of nipple discharge: value of magnetic resonance imaging and ultrasonography in comparison with ductoscopy. Balkan Med J. 2017;34(2):119-126.

• Three important areas form the foundation for the evolving use of altered fractionation:
  • Tissue response
  • Duration of treatment
  • Fraction size and number
• Acutely responding tissues:
  • Are rather active in ongoing cellular proliferation
  • Most tumors (except perhaps prostate cancer, breast cancers, and melanoma) and some normal tissues such as skin, mucous membranes, and gastrointestinal epithelium:
    • Share this characteristic:
      • These tissues are most affected by the overall treatment duration rather than by the size or number of fractions used
• Late-responding tissues:
  • Have a low proliferative rate and include the spinal cord, brain, bone, and cartilage
  • These tissues are most affected by the:
    • Size and number of fractions rather than by treatment duration:
      • Therefore are spared by decreasing the dose per fraction of radiation delivered
• Because most tumors consist of rapidly dividing cells:
  • Local tumor control is strongly dependent on the overall treatment duration rather than on the size or number of fractions
• When squamous cell carcinoma of the head and neck is exposed to radiation:
  • The less radiosensitive cells within the lesion:
    • Can undergo rapid proliferation:
      • Approximately 3 to 5 weeks after treatment commences
      • This accelerated repopulation can overwhelm the ongoing treatment effects of radiation:
        • Which ultimately can lead to local failure
      • The clinical significance of this phenomenon is that even with significant regression of the primary tumor mass:
        • Local failure still ultimately could result from proliferation of these resistant clones
      • Therefore it is essential to complete treatment in as short a time as possible so that accelerated repopulation is minimized:
        • Increasing the chance for local control
    • For this reason, split-course radiation:
      • Which incorporates a treatment break during the course of radiotherapy is not recommended
• Based on the aforementioned principles:
  • The goal of altered fractionation schemes:
    • Is to improve the therapeutic ratio by maximizing the tumoricidal effect and minimizing acute and late toxicities while using readily available low-LET radiation
• Two major categories of altered fractionation schemes exist:
  • Hyperfractionation
  • Accelerated fractionation
• They share basic radiobiological principles yet have their own particular features (Table)
• Accelerated fractionation:
  • Is the strategy of choice for rapidly proliferative tumors
  • Accelerated fractionation is based on the concept that the shortened overall treatment time:
    • Would reduce the opportunity for accelerated repopulation effectively
• Hyperfractionation:
  • Is preferred for slowly proliferating tumors
  • Hyperfractionation improves the therapeutic ratio primarily through:
    • Redistribution of tumor cells into more radiosensitive phases as a result of multiple fractions
    • Differential sparing of late-responding normal tissues because of a decrease in the size of the dose per fraction

• Current consensus guidelines from the American Society of Breast Surgeons:
  • Do not recommend CPM for women with sporadic breast cancers
• A Cochrane review of 8 studies evaluating patients who underwent CPM:
  • Concluded that while CPM reduces risk of contralateral breast cancer:
    • It is not associated with improved survival
• Reasons for not recommending CPM include:
  • A low estimated risk of cancer in the contralateral breast (2% to 6% over 10 years)
  • Increased complication rates
  • Studies showing that CPM does not improve survival or recurrence from the index cancer
• References:
  • Lostumbo L, Carbine N, Wallace J, Ko H. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 2004(4):CD002748.
  • Boughey JC, Attai DJ, Chen SL, et al. Contralateral prophylactic mastectomy consensus statement from the american society of breast surgeons: additional considerations and a framework for shared decision making. Ann Surg Oncol. 2016;23(10):3106-3111

• Inflammatory breast cancer (IBC):
  • Is a clinical syndrome in women with invasive breast cancer that is characterized by:
    • Erythema and edema (peau d’orange) of a third or more of the skin of the breast
  • The differential diagnosis includes:
    • Cellulitis of the breast or mastitis
  • Because most IBC cases are first seen by healthcare providers not necessarily familiar with IBC:
    • The absence of complete response to a trial of antibiotic therapy should heighten suspicion of IBC and prompt further investigation:
      • Further trial of antibiotics is not warranted in the absence of clinical signs of infection and previous adequate antibiotic therapy
  • Workup includes physical exam and imaging:
    • Imaging may not reveal a mass:
      • But thickening of the skin is frequently seen
    • The most common signs of IBC on mammography include:
      • Thickening of the skin (84%)
      • Trabecular thickening (81%)
      • Asymmetric focal density (61%)
      • Microcalcifications (56%)
    • Mammography is the least sensitive diagnostic tool available for IBC:
      • Whereas ultrasound and MRI are more sensitive:
        • In a series published by Yang, et al., sonography demonstrated a mass or architectural distortion in 95% of patients with associated global skin and subcutaneous thickening and dilated lymphatics
        • MRI can also show skin thickening and is more sensitive than mammography in detecting an underlying mass:
          • The same series by Yang and colleagues found that a primary breast lesion was present in every MRI obtained in patients with IBC as either nonmass or mass-like enhancement
  • IBC is a clinical diagnosis:
    • Dermal biopsy confirmation is not mandatory:
      • Dermal lymphatic invasion is seen only in approximately 60% of IBC cases:
        • It is neither required, nor sufficient by itself for a diagnosis of inflammatory breast cancer
  • Treatment is multidisciplinary trimodality therapy consisting of neoadjuvant chemotherapy, modified radical mastectomy, and local regional radiation:
    • Yet, the median survival at 5 years for patients presenting with primary IBC is still only approximately 55%
• References
  • Yang WT, Le-Petross HT, Macapinlac H, et al: Inflammatory breast cancer: PET/CT, MRI, mammography, and sonography findings. Breast Cancer Res Treat. 2008;109(3):417-426.
  • Somio G, Jones V. Inflammatory breast cancer. In: Klimberg S, Bland K, eds. The Breast: Comprehensive Management of Benign and Malignant Disease. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011:832-838.

• Hypofractionation:
  • Larger fraction size (600 to 800 cGy) compared with conventional fractionation (180 to 200 cGy)
    
  • Fractions delivered several days apart
  • Lower total dosage (2100 to 3200 cGy) than
    conventional fractionation (7000 cGy)
  • Shortened overall treatment duration
    compared with conventional fractionation
• Hypofractionation:
  • Is the administration of high-dose-per-fraction (HDPF) radiation:
    • In which only one or two fractions are given per week
  • This technique has evolved for the treatment of malignant melanoma:
    • Which generally is perceived as being radioresistant
• Conventional fractions of 200 cGy delivered 5 days a week:
  • Allow normal tissues and tumor cells to recover during the intervals between fractions
• Experimental in vitro data have shown that malignant melanoma cells are better at repairing radiation-induced sublethal damage compared with other cells:
  • This finding may explain the long-standing notion that melanoma is intrinsically “radioresistant”
• HDPF regimens:
  • Deliver higher doses of radiation per fraction (600 cGy twice a week or 800 cGy once weekly):
    • With the aim of overcoming the reparative capacity of the tumor cells by increasing the damage per fraction
• In retrospective analyses, response rates have been shown to correlate with dose per fraction but not with the total dose delivered:
  • However, a prospective randomized trial (RTOG 83–05) found no therapeutic advantage in a comparison of HDPF (800 cGy once a week up to a total dose of 3200 cGy) and conventional fractionation (250 cGy daily, 5 days a week, for a total of 5000 cGy):
    • Although no therapeutic advantage was seen, the shorter delivery time of HDPF radiation allows earlier initiation of systemic therapies if applicable
• Moderately hypofractionated radiation (225 cGy per fraction):
  • Has demonstrated superior results for early-stage larynx cancers treated with radiotherapy alone:
    • This is currently considered the standard of care in this setting
• Additionally, a regimen commonly referred to as quad shot:
  • Which was originally developed for advanced pelvic tumors:
    • Is sometimes applied for palliation of tumors in the head and neck
  • This involves cycles of a 1480 cGy course of radiotherapy delivered in four fractions over the course of 2 days:
    • Which can be repeated multiple times over a period of weeks or months depending on the treatment response
    • Aside from the demonstrated efficacy of this regimen, it also allows significant advantages in terms of patient convenience in the palliative setting

• Breast cancer-related lymphedema (BCRL):
  • Has been a significant concern for breast cancer patients undergoing axillary surgery
• The development of BCRL is associated with:
  • Significantly lower physical and psychosocial well-being and increased health care utilization
• The risk of BCRL:
  • Is a function of the extent of axillary intervention:
    • Ranging from about 12% following a sentinel node biopsy to about 30% after an axillary lymph node dissection (ALND)
• The highest risk of BCRL (51%) has been reported in patients with inflammatory breast cancer:
  • Who receive trimodality therapy (neoadjuvant taxane-containing chemotherapy, modified radical mastectomy, and adjuvant radiation):
    • Therefore, adjuvant radiotherapy is associated with an increased risk of BCRL
• The value of routine screening for BCRL in patients at risk is controversial
• There is growing evidence that subclinical lymphedema:
  • Defined as relative volume change of the affected arm of 5% to 10% compared to the baseline measurement:
    • Is strongly associated with the development of more symptomatic BCRL:
      • Which correlates with a relative volume change of greater than 10%
• Consequently, identifying patients with subclinical lymphedema is a potential opportunity for early intervention and long-term improvement in quality of life
• Furlan et al prospectively evaluated 85 breast cancer patients (n=40 had an ALND and n=45 had a sentinel node biopsy) by obtaining serial circumferential arm measurements preoperatively, then 1 month, 3, 6, 12, and 24 months after surgery:
  • Study results showed that the earliest signs of subclinical lymphedema were detected no sooner than the 6-month assessment, and those with subclinical lymphedema were promptly referred for decongestive therapy
• An international randomized trial comparing bioimpedance spectroscopy (BIS) and tape measurement to detect subclinical lymphedema:
  • Showed that BIS had a higher sensitivity and was associated with an earlier referral for decongestive therapy
  • In the same study, earlier administration of decongestive therapy was associated with a lower risk of progression to symptomatic BCRL
  • The practical aspects of implementing BCRL screening with BIS versus tape measurements and other techniques warrant further study
• References
  • Coriddi M, Kim LN, Haglich K, et al. The impact of lymphedema on patient-reported outcomes after breast reconstruction: a preliminary propensity score-matched analysis. Ann Surg Oncol. 2023;30(5):3061-3071. doi: 10.1245/s10434-022-12994-z
  • Cheville A, Lee M, Moynihan T, et al. The impact of arm lymphedema on healthcare utilization during long-term breast cancer survivorship: a population-based cohort study. J Cancer Surviv. 2020;14(3):347-355. doi: 10.1007/s11764-019-00851-0
  • Bucci LK, Brunelle CL, Bernstein MC, et al. Subclinical lymphedema after treatment for breast cancer: risk of progression and considerations for early intervention. Ann Surg Oncol. 2021;28(13):8624-8633. doi: 10.1245/s10434-021-10173-0
  • Farley CR, Irwin S, Adesoye T, et al. Lymphedema in inflammatory breast cancer patients following trimodal treatment. Ann Surg Oncol. 2022;29(10):6370-6378. doi: 10.1245/s10434-022-12142-7
  • Furlan C, Matheus CN, Jales RM, Derchain SFM, Bennini JR Jr, Sarian LO. Longitudinal, long-term comparison of single-versus multipoint upper limb circumference periodical measurements as a tool to predict persistent lymphedema in women treated surgically for breast cancer: an optimized strategy to early diagnose lymphedema and avoid permanent sequelae in breast cancer survivors. Ann Surg Oncol. 2021;28(13):8665-8676. doi: 10.1245/s10434-021-10290-w
  • Ridner SH, Dietrich MS, Boyages J, et al. A comparison of bioimpedance spectroscopy or tape measure triggered compression intervention in chronic breast cancer lymphedema prevention. Lymphat Res Biol. 2022;20(6):618-628. doi: 10.1089/lrb.2021.0084