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• Fine linear or branching calcifications:
  • In a group or segmental distribution:
    • Are often associated with high-grade DCIS
• Amorphous calcifications:
  • Are often associated with low-grade DCIS
• Mammography relies on the presence of calcifications for the detection of DCIS:
  • Thus, lesions without calcifications are generally occult on mammography
• Extensive DCIS:
  • Can present as a palpable mass
• Nipple discharge:
  • Can also be a sign of either DCIS or invasive breast cancer
• Paget disease:
  • Is a rare presentation:
    • Occurring in only 1% to 4% of women with breast cancer
  • It is characterized histologically by:
    • Intraepithelial tumor cells
    • It presents as a chronic ulceration or eczema of the nipple:
      • That can involve the surrounding areolar skin
  • It may be associated with invasion but, in the absence of invasion:
    • Is treated as DCIS

#Arrangoiz #CancerSurgeon #BreastSurgeon #SurgicalOncologist #BreastCancer #LCIS #DCIS #DuctalCarcinomaInsitu #LobularNeoplasia #LobularCarcinomaInsitu #Surgeon #Teacher #Miami #Mexico #MSMC #MountSinaiMedicalCenter

• Pure ductal carcinoma in situ (DCIS):
  • Is by definition non-invasive:
    • Thus lacks the ability to metastasize to axillary nodes and distant sites:
    • For this reason, surgical axillary staging is not recommended in the management of most patients with DCIS undergoing breast conserving surgery
• Approximately 20% of patients with DCIS on core needle biopsy:
  • Will upstage to invasive cancer:
    • And may ultimately require surgical axillary staging
• Factors associated with upstaging to invasive disease include:
  • A palpable mass at the time of diagnosis
  • Intermediate- or high-grade lesions
  • Comedonecrosis
  • ER negative (-) subtype
  • A large span of disease:
    • Typically cited as > 5cm
• The location of the lesion (eg. upper outer quadrant):
  • Is not predictive of upgrade or spread to regional / distant sites
• While some authors cite multifocality as a risk factor for upstaging:
  • It is more predictive of recurrence than upstage
• One exception to the recommendation of omission of SLNB is:
  • For DCIS patients undergoing mastectomy:
    • First, most patients undergoing mastectomy for DCIS have a larger burden of disease:
      • Therefore have a higher likelihood of upstaging to invasive cancer:
        • For which surgical axillary staging is warranted
    • Second, while axillary mapping and sentinel lymphadenectomy may be feasible after mastectomy (with injection of radiocolloid and / or blue dye into the remaining skin):
      • The accuracy of this strategy has not been fully evaluated and is therefore not the recommended approach
    • However, since the rate of nodal positivity is low in these patients, newer strategies (such as injection of superparamagnetic iron oxide nanoparticles at time of mastectomy as a tracer for delayed sentinel lymph node dissection):
      • Are under investigation and may serve to decrease the number of patients with DCIS undergoing surgical axillary staging
• References:
  • American Society of Breast Surgeons. Consensus Statement on Axillary Management for Patients With In-Situ and Invasive Breast Cancer: A Concise Overview.
  • Lee, S.K., et al. Nomogram for predicting invasion in patients with a preoperative diagnosis of ductal carcinoma in situ of the breast. British J Surg. 2013;100: 1756-1763.
  • Tanaka, K., et al. Clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with ductal carcinoma in situ (DCIS): a multi-institutional retrospective cohort study. Breast Cancer. 2021;28: 896–903.
  • Salvatorelli, L., et al. Ductal Carcinoma In Situ of the Breast: An Update with Emphasis on Radiological and Morphological Features as Predictive Prognostic Factors. Cancers. 2020; 12(3), 609.
  • Port, E.R., et al. Reoperative sentinel lymph node biopsy: a new frontier in the management of ipsilateral breast tumor recurrence. Ann Surg Oncol. 2007;14(8):2209–14.
  • Karakatsanis, A., et al. Delayed Sentinel Lymph Node Dissection in Patients with a Preoperative Diagnosis of Ductal Cancer In Situ by Preoperative Injection with Superparamagnetic Iron Oxide (SPIO) Nanoparticles: The SentiNot Study. Ann Surg Oncol. 2023;30:4064-4072
• Due to the non-invasive nature of ductal carcinoma in situ (DCIS):
  • Assessment of the axilla is not indicated regardless of receptor status or grade with pure DCIS in the setting of breast conserving surgery
• It may be considered if the patient is undergoing a mastectomy or the tumor is located in a position where excision may compromise future performance of a sentinel lymph node biopsy
• Microinvasive DCIS:
  • Comprises 5% to 10% of all cases of DCIS
  • In a review of the literature, the reported incidence of axillary metastases in microinvasive DCIS:
    • Has ranged from 0% to 28%
  • Axillary staging is appropriate and sentinel node biopsy should be performed in the setting of microinvasive DCIS
• References
  • NCCN Guidelines 2023.  breast.pdf (nccn.org)  Last accessed 9/24/23.
  • Consensus Statement on Axillary Management for Patients with In-Situ and Invasive:  A Concise Overview.  Official Statements | ASBrS (breastsurgeons.org)  Last accessed 10/9/23
  • Adamovich TL, Simmons RM. Ductal carcinoma in situ with microinvasion. Am J Surg 2003; 186: 112–6.
  • Guth AA, Mercado C.  Microinvasive breast cancer and the role of sentinel node biopsy:  an institutional experience and review of the literature.  Breast J.  2008; 14 (4); 335-9.

• 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:
    • It is classified as stage 0 cancer
• DCIS with microinvasion:
  • Is considered T1mi:
    • It upstages DCIS from stage 0 to stage I disease
• By definition, DCIS without microinvasion:
  • Does not have the ability to metastasize to axillary lymph nodes or distant sites:
    • Whereas DCIS with microinvasion does
• Axillary metastases:
  • Have been reported in 0% to 20% 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. reported:
  • A 2% incidence of microinvasion in patients with DCIS measuring less than 25 mm in diameter:
    • Compared with a 29% incidence of microinvasion in those with lesions larger 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 or nipple discharge
• There is conflicting data in the literature on the prognosis of DCIS with microinvasion compared to DCIS without microinvasion:
  • Historically, studies have shown that patients with DCIS with microinvasion have a worse prognosis compared with those who have DCIS alone
  • In a retrospective study of 1,248 serially sectioned DCIS tumors, de Mascarel et al:
    • Reported a 10.1% incidence of axillary metastases in cases of DCIS with microinvasion
    • Patients with DCIS alone 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 alone:
      • 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
  • In a retrospective review of the SEER database from Champion et al., 134,569 women with DCIS alone, DCIS with microinvasion, and T1a intraductal carcinoma were compared:
    • They found that the disease-specific survival of DCIS with microinvasion was significantly different from the other two groups (DCIS alone: hazard ratio [HR] 0.59, confidence interval [CI] 0.43–0.80; invasive: HR 1.43, CI 1.04–1.96) but the overall survival of DCIS with microinvasion was similar to early invasive disease
    • Patients with DCIS alone had an improved overall survival compared to DCIS with microinvasion (HR 0.83, CI 0.75–0.93)
    • These results suggest that DCIS with microinvasion should be characterized as an early invasive tumor with a good outcome and that the therapeutic approach for these patients should be similar to that for patients with invasive cancer
  • However, some studies have pointed toward DCIS with microinvasion as having a more similar natural history to DCIS alone than to early-stage invasive disease:
    • In a review of 393 patients treated at Yale between 1973 and 2004, there was no significant difference between patients with DCIS alone 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
  • In a more recent study from Zheng et al., 308 cases of DCIS alone were compared to 92 cases of DCIS with microinvasion and 111 cases of T1a tumors:
    • With a 25-month median follow-up, their analysis demonstrated no difference in disease-free survival and overall survival among the three groups

• Nipple-sparing mastectomy:
  • Has been a highly debated topic since first described by Hinton et al in 1984
• There is consensus regarding some contraindications to nipple-sparing mastectomies, such as:
  • Direct involvement of the nipple or areola by tumor
• However, many relative contraindications, such as:
  • Tumor size greater than 2 cm
  • Tumor location within 1 cm to 2 cm of the nipple-areolar complex:
    • Are still debated
• Additional relative contraindication considerations are:
  • Perioperative smoking (or smoking within 4 weeks of surgery):
    • Which increases the risk of complication significantly:
      • As much as 2 to 10 times the risk, depending on the study
  • Obesity (BMI of ≥30):
    • Which doubles the risk
  • Older women:
    • Have not shown to have higher rates of nipple or skin necrosis in a large single institutional study
• Despite early concerns:
  • There is no decreased survival by maintaining the nipple-areolar complex with mastectomy procedures, including in pathologic mutation carriers
• Nipple-sparing mastectomies:
  • Are almost always performed in conjunction with some form of immediate reconstruction
• The type of planned reconstruction influences the incision choice and outcomes:
  • Salibian et al. looked at immediate microvascular autologous reconstructions:
    • He found that vertical incisions had only a 5.8% rate of ischemic complications:
      • Whereas inframammary incisions had a 25% rate and lateral radial a 7.8% rate of ischemic complications
  • This has been shown in systematic reviews as well
• References:
  • Galimberti V, Vicini E, Corso G, et al. Nipple-sparing and skin-sparing mastectomy: review of aims, oncological safety and contraindications. Breast. 2017;34 Suppl 1(Suppl 1):S82-S84. doi: 10.1016/j.breast.2017.06.034
  • McCarthy CM, Mehrara BJ, Riedel E, et al. Predicting complications following expander/implant breast reconstruction: an outcomes analysis based on preoperative clinical risk. Plast Reconstr Surg. 2008;121(6):1886-1892. doi: 10.1097/PRS.0b013e31817151c4
  • Parmeshwar N, Dugan CL, Barnes LL, et al. Nipple-sparing mastectomies in patients over the age of 60 years: factors associated with surgical outcomes. Ann Surg Oncol. 2023;30(13):8428-8435. doi: 10.1245/s10434-023-14278-6
  • Metere A, Fabiani E, Lonardo MT, Giannotti D, Pace D, Giacomelli L. Nipple-sparing mastectomy long-term outcomes: early and late complications. Medicina (Kaunas). 2020;56(4):166. doi: 10.3390/medicina56040166
    Salibian AA, Bekisz JM, Frey JD, et al. Comparing incision choices in immediate microvascular breast reconstruction after nipple-sparing mastectomy: unique considerations to optimize outcomes. Plast Reconstr Surg. 2021;148(6):1173-1185. doi: 10.1097/PRS.0000000000008282
  • Chicco M, Ahmadi AR, Cheng H-T. Systematic review and meta-analysis of complications following mastectomy and prosthetic reconstruction in patients with and without prior breast augmentation. Aesthet Surg J. 2021;41(7):NP763-NP770. doi: 10.1093/asj/sjab028

• The adult transgender population in the US:
  • Is estimated to be 0.6% of the population:
    • At least 1.4 million people
• Cross sex hormonal therapy:
  • Is estrogen based for people transitioning male to female:
    • This results in stimulation of breast glandular tissue:
      • The breast tissue will develop with muted Tanner stage development:
        • Subareolar breast buds typically develop at 3 to 6 months of treatment and maximum development is achieved after 2 to 3 years of treatment
  • The addition of progesterone:
    • Has not been shown to increase breast size or add to feminization:
      • Thus, the risk of adding progesterone appears to outweigh the benefits
• Breast enhancement / augmentation is a safe procedure:
  • Providers should educate their patients about the associated risk of various implant illnesses, including large cell lymphoma
• Guidelines regarding imaging for transgender women:
  • May follow established guidelines for cis gendered males, the number of years of estrogen therapy, breast development, and known risk factors
• The American College of Radiology guidelines:
  • Support digital breast  tomosynthesis or routine mammography for:
    • Transgender women 40 years old or more with more than 5 years of hormone use
  • For transgender women older than 25 to 30 years of age with more than 5 years of current or prior hormone therapy use or for individuals with genetic predisposition to breast cancer:
    • ACR also supports digital breast tomosynthesis or routine mammography as appropriate
  • In transgender women deemed at average risk with no hormone use or less than 5 years of use:
    • Routine breast screening imaging is not appropriate or necessary:
      • There is no longitudinal data, however
• The risk of breast cancer for transgender women:
  • Does not appear to be significantly greater than that of natal males
• Cross sex hormone therapy:
  • Does not appear to alter breast cancer risk
• References:
  • Hayward J. Updates in Transgender Breast Imaging. Seminars in Ultrasound CT and MRI. Published online November 2022. doi:https://doi.org/10.1053/j.sult.2022.10.002
  • Guerrero DL, Sowinski J, Patel KM. (Apr 26, 2022). Effects of Gender-affirming Medical and Surgical Therapy on Breast Imaging Findings and Breast Cancer Risk. Appl Radiol. 2022; 51(3):24-32.
  • Legato MJ. PLASTICITY of SEX : The Molecular Biology and Clinical Features of Genomic Sex, Gender … Identity and Sexual Behavior.;  pages 187-205; 2020.
  • Lockhart, Ryan, and Aya Kamaya. “Patient-Friendly Summary of the ACR Appropriateness Criteria: Transgender Breast Cancer Screening.” Journal of the American College of Radiology , Jan. 2022, doi:https://doi.org/10.1016/j.jacr.2021.10.015.
  • Pivo S, Montes J, Schwartz S, et al. Breast Cancer Risk Assessment and Screening in Transgender Patients. Clinical Breast Cancer. 2017;17(5):e225-e227. doi:https://doi.org/10.1016/j.clbc.2016.08.003
  • Brown A, Lourenco AP, Niell BL, et al. ACR Appropriateness Criteria® Transgender Breast Cancer Screening. Journal of the American College of Radiology. 2021;18(11):S502-S515. doi:https://doi.org/10.1016/j.jacr.2021.09.005
  • Meggetto O, Peirson L, Yakubu M, et al. Breast cancer risk and breast screening for trans people: an integration of 3 systematic reviews. CMAJ Open. 2019;7(3):E598-E609. doi:https://doi.org/10.9778/cmajo.20180028
  • Hartley RL, Stone JP, Temple-Oberle C. Breast cancer in transgender patients: A systematic review. Part 1: Male to female. European Journal of Surgical Oncology: The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2018;44(10):1455-1462. doi:https://doi.org/10.1016/j.ejso.2018.06.035

• Significant changes in thyroid physiology occur during pregnancy:
  • This can make the interpretation of serum thyroid function tests challenging
• During the first trimester of pregnancy:
  • Serum thyroxine binding globulin (TBG) concentrations increase by up to 50%:
    • As a result of altered estrogen induced glycosylation:
      • Which prolongs TBG half-life
  • The elevated TBG levels increase the quantities of protein-bound T4 and T3:
    • Which results in an increase in total serum T4 and T3 concentrations:
      • However, in euthyroid individuals:
        • The active or free levels of T4 and T3 remain normal
• In addition, during the first trimester of pregnancy:
  • Levels of placental human chorionic gonadotropin (hCG) steadily increase:
    • Because hCG is a weak TSH receptor agonist:
      • This results in a small increase of free T4 (although still within the normal range) and a concomitant decrease in TSH:
        • Below the lower reference range in up to 15% of normal women in the first trimester
• Serum TSH concentrations:
  • Should thus be assessed using trimester-specific ranges during pregnancy
• The changes of reduced TSH and elevated FT4 are more pronounced:
  • In pregnancies associated with higher levels of hCG:
    • Such as multiple gestations and hyperemesis gravidarum, and are most extreme in hydatidiform moles
  • The physiologic suppression of TSH does not require medical intervention and usually normalizes after the first trimester of pregnancy

• Tumor grade ≤ 2
• Luminal-like subtypes
• Small tumor (≤ 3 cm)
• Negative lymphovascular space invasion
• Low- to moderate-grade ductal carcinoma in situ (DCIS)
• Age at diagnosis ≥ 50 years
• Unicentric or unifocal disease
• Clear surgical margins (> 5 mm)
• Node negative (including isolated tumor cells)
• No use of primary systemic therapy

• Fibrocystic breast disease:
  • Is the most common benign type of breast disease:
    • Diagnosed in millions of women worldwide
  • Certain hormonal factors underpin the function, evaluation, and treatment of this disease
• Benign breast disease:
  • Is an umbrella term for various non-malignant lesions, such as:
    • Tumors, trauma, mastalgia, and nipple discharge
• The above-mentioned benign lesions are not associated with an increased risk for malignancy:
  • However, it associates with an up to 50% risk of developing breast cancer under certain histopathological and clinical circumstances
• A palpable mass upon clinical evaluation:
  • Is evident in both benign and malignant breast conditions
• The clinical findings include symptoms such as dimpling of the skin (peau d’orange), thickening, pain, and nipple discharge
• The most common investigative tools to assess for these clinical findings are:
  • Mammograms and ultrasound
• The main components of the breast are prone to fibrocystic changes during:
  • Hormonal fluctuations
• These components include the:
  • Stroma, ducts, and lobules of the breast
• During the reproductive age:
  • Glandular breast tissue has a direct relation to cyclical surges of plasma levels of estradiol and progesterone
• Etiology:
  • The etiology of benign breast disease has demonstrated a strong clinical association:
    • With women receiving estrogen and anti-estrogen treatment
  • The prevalence of benign breast lesions in postmenopausal women receiving estrogens and progestins for over eight years:
    • Is increased by 1.7 fold
  • During the Women’s Health Initiative study (WHI):
    • The combined use of estrogen and progestin correlated with a:
      • 74% risk of benign breast disease
  • The use of anti-estrogens:
    • Led to a 28% reduction in the prevalence of benign proliferative breast disease
• Epidemiology:
  • Fibrocystic breast disease incidence is varies:
    • Ranging from 30% to 60% of all women
  • It is most common in women:
    • Between the ages of 30 to 50 years
  • One of the most common forms of benign breast disease is:
    • Fibroadenomas:
      • Characterized by localized proliferation of breast ducts and stroma
      • This subtype accounts for 70% to 95% of all benign breast tumors
      • The incidence is mostly seen in the 17 to 20 year age group:
        • Extending to 2 years premenarche to 35
• Pathophysiology:
  • Mammary gland development, maturation, and differentiation:
    • Act upon the hormonal and growth factor changes:
      • Affecting the stromal and epithelial cells
  • During the late proliferative phase:
    • Glandular breast tissue evolves to hyperplastic stages such as:
      • Sclerosing adenosis or lobular hyperplasia:
        • This state of hyperplasia, if associated with a 2% prevalence of Ki67 cell activity has a twofold increased incidence for the development of breast cancer
  • Various types of benign breast disease exist, such as:
    • Hyperplasia, cysts, fibroadenomas, sclerosing adenosis, and mastitis
• Histopathology:
  • There is a limited pathological consensus regarding the histopathological appearance of benign breast disease
  • The main features are an extracellular matrix of collagen, peri canalicular patterns of stromal cells with the presence of florid epithelial hyperplasia
  • During the menopausal phase:
    • Fibroadenomas involute, which affects dense collagen stroma and atrophic glands
  • Cystic changes derive from the terminal duct lobular unit (TDLU):
    • Due to the expansion of the efferent ductules of the TDLU:
      • Cysts form as a result of fluid accumulation in these structures
    • The lining appears flat with a myoepithelial layer present
• History and Physical:
  • Benign cysts are typically mobile within the glandular breast tissue, chest wall, and skin and are rubber-like in texture:
    • Except for inflammatory type cysts, discomfort and tenderness experienced by a patient are either absent or mild
  • Most patients present with multiple cysts upon further clinical and diagnostic evaluation
  • Various subtypes of cysts are known, including hyperplastic fibrous cysts, adenosis, and papillomatosis
  • These types of cysts are usually found in the:
    • Upper outer quadrants of the breast, as well as in the central margins
  • The texture upon evaluation ranges from a firm texture to multiple subcentimeter cysts
  • Fibroadenomas present in varied sizes:
    • With a common oval-shaped, well-defined margin
    • As with cysts, fibroadenomas are mobile upon evaluation and are often multiple, occurring either simultaneously or over a specified period
  • Nipple discharge is associated with:
    • Ductal ectasia, intraductal papilloma, or in rare instances, carcinoma
  • The finding of an intraductal papilloma:
    • Is associated with a single duct presenting a bloody, sudden discharge with a small palpable nodule in the retro areolar region
  • Multiple ducts presenting with nonspontaneous, green, yellow, clear discharges:
    • Are a common feature with duct ectasia
• Evaluation:
  • Triple testing is a combination consisting of clinical examination, imaging, and excision biopsy
  • This is essential for all women with a clinical finding, such as a discrete palpable mass
  • Nodularity in young women less than 30 years of age:
    • May have management with clinical surveillance and short-term follow-up examination in 2 to 3 months
  • An investigation may be necessary if the lump has changed on review or if, at the initial presentation, there is a new change in her breasts
  • Nodularity or thickening that is asymmetric in women over the age of 30 years;
    • Further investigation utilizing mammography and ultrasound, is warranted
  • Short-term follow-up is an important part of the management of nodularity so that the progression in size of a mass of nodularity or other associated findings (e.g., skin or nipple changes) is detected
  • Mammography with ultrasound examination is required:
    • For all discrete palpable lesions in women over 35 to distinguish cysts from solid lesions
  • Complex cysts containing both fluid and solid matter require biopsy:
    • Aspiration and the solid component persists core biopsy is performed
  • For solid lesions, radiographically or ultrasonically directed core biopsy provides further information regarding the presence or absence of malignancy
  • Core excision biopsy involves a cutting needle with a spring-loaded, automated biopsy instrument that allows sufficient specimen of tissue for histologic analysis
  • FNA allows a cytopathologist to evaluate cellular material:
    • However, the amount of material retrieved during FNA procedures being sufficient for diagnosis is non-successful in 35% to 47% of non-palpable lesions:
      • A core biopsy is then the recommendation
  • Cytology of nipple discharge has limited specificity and sensitivity to detect malignancy (35 to 47%)
  • If the results of both clinical and diagnostic evaluations are benign:
    • A 6 to 12-month clinical breast examination, ultrasound, and mammography are the suggested follow-up to confirm a stable appearance
  • A study of 156 patients in Japan who had a benign breast biopsy showed that 13% required a subsequent biopsy within two years of having routine FNA procedures performed
  • In a retrospective study, 150 patients with benign histology after ultrasound-guided vacuum-assisted biopsy for complex cystic breast lesions (BI-RADS 4) were assessed:
    • This subset of patients underwent evaluation in 6 monthly intervals
    • Of the 104 lesions, none led to the development of malignancy
  • Routine ultrasound screening in Japan was used with 10,519 women to evaluate recall criteria:
    • Researchers noted a cystic-type breast pattern in 6512 cases
    • Only one of the patients reported malignancy the following year, related to a solid tumor with a cystic component, proven to be a micro-invasive cancer of less than 1 mm
• Treatment / Management:
  • Due to the role of estrogen and progesterone treatments, promoting fibrocystic changes in the breast:
    • Metformin has been suggested as a treatment method to reduce the excessive cell proliferation caused by associated hormones
  • For patients presenting with mastalgia:
    • The first-line options are lifestyle changes
    • Other suggestions are the use of a supportive bra, as well as altering the dose of hormone replacement therapy regimen
    • There is no evidence that reducing caffeine improves fibrocystic breast disease or mastalgia
    • Analgesics such as aspirin and ibuprofen are options
    • Researchers have proposed that a deficiency in prostaglandin E and its precursor gamma-linolenic acid (GLA) increase the sensitivity of breasts during the luteal phase of the menstrual cycle:
      • GLA is subsequently also the active component of evening primrose oil
      • Despite not having proven efficacy in previous studies, the use of evening primrose oil is warranted as supportive measures if pain persists despite treatment and advice
      • A 3 to 6 month period is the suggested timeframe to observe the desired effect
      • If breast pain is severe for more than six months and disrupts daily activities, other therapies such as tamoxifen, bromocriptine, or danazol can be options
      • Due to the recurrent nature and long duration of these symptoms, several months of treatment is necessary
  • Fluid from cysts aspirated for symptomatic relief does not require cytological assessment
  • This evaluation is reserved for clinically evident lumps that resolve following the FNA procedure or where the cyst fluid appears macroscopically bloodstained
  • Fluid from atypical cysts should have a cytological assessment
  • Surgery is indicated for cysts that repetitively, despite frequent FNA, which have an intra-cystic solid appearance on ultrasound or have atypical cells present upon cytopathological evaluation
• Differential Diagnosis:
  • Breast lump
  • Breast abscess
  • Fibrocystic changes
  • Fibroadenomas
  • Infections
  • Trauma
  • Fat necrosis
  • Papilloma
  • Phyllodes tumor
  • Breast ectasia

• A full appreciation of thyroid function and its testing:
  • Is dependent on a thorough understanding of its axis of regulation
• Thyroid stimulating hormone (TSH):
  • The major regulator of thyroid hormone production and secretion:
    • Is synthesized and secreted by the thyrotroph cells of the anterior pituitary
  • The main stimulator of TSH production by the anterior pituitary is:
    • Thyrotropin-releasing hormone (TRH):
      • Via the hypothalamic-pituitary portal system
  • Conversely, exposure to the thyrotrophs by circulating T4 and T3:
    • Inhibits the secretion of TSH and TRH via a negative feedback loop:
      • Decreasing gene expression of these hormones:
        • Therefore decreasing its activity
  • As with other pituitary hormones:
    • TSH secretion is pulsatile in nature:
      • With higher levels seen at night than during the day
    • However, despite this diurnal variation:
      • Serum TSH concentrations generally remain in the reference range when drawn during the day:
        • But may be elevated if  drawn at night
  • Among TRH and thyroid hormone itself:
    • TSH secretion is also affected by:
      • Glucocorticoids
      • Retinoids
      • Somatostatin
      • Dopamine
    • Consequently, several disease states and medications can affect TSH levels such as:
      • Pituitary or hypothalamic dysfunction
      • Recent hyperthyroidism
      • Critical illness
      • Starvation
      • Use of certain medications:
        • Beta Blockers
        • Ipodate
        • Amiodarone
        • Dexamethasone
        • Prophylthiouracil
      • Interference with serum thyroid autoantibodies
      • Thyroid hormone resistance syndromes
    • During starvation and acute illness:
      • Expression of the 5 deiodinase type 3 (Dio3) is increased:
        • Converting the bioactive T4 and T3 to two biologically inactive molecules:
          • Reverse T3 (rT3) and 3,3′-diiodothyronine (T2)
• Given this, thyroid physiology can be affected in nonthyroidal illness (euthyroid sick syndrome) and it is important that the diagnosis of primary thyroid dysfunction not be established during severe illness based solely on an abnormal serum TSH:
  • In these conditions, serum TSH concentrations may be low, normal, or high, due to the TSH-lowering effects of medications or from an acquired central hypothyroidism and therefore, when possible, assessment of thyroid function should be done after recovery from an acute illness

• The basic functional unit of the thyroid gland:
  • Is the thyroid follicle:
    • The thyroid follicle contains a single layer of thyroid follicular cells (epithelial cells):
      • That form a sphere with a follicular lumen:
        • Which is filled with a colloid protein aggregate
    • Thyroid follicular cells are polar:
      • The apical membrane is adjacent to the follicular lumen
      • The basolateral membrane is the one in contact with capillaries and the circulatory system (Figure)

• Thyroid hormone synthesis:
  • Is activated by the binding of thyroid-stimulating hormone (TSH) to the TSH receptor on the basolateral membrane:
    • Which activates adenylate (adenylyl) cyclase and increases intracellular cyclic adenosine monophosphate (cAMP):
    • Leading to phosphorylation of protein kinase A and activation of targets in the cytosol and nucleus of the thryoid cell:
      • Through this cAMP pathway, TSH stimulates the accumulation of iodide in the thyroid
      • This initiates the cascade that results in thyroid hormone synthesis and secretion:
        • Which includes iodide transport, synthesis of thyroglobulin, iodination of thyroglobulin, and secretion of the thyroid hormones (Figure)

• After the binding of TSH:
  • The initial step in the thyroid hormone synthesis pathway:
    • Is iodide transport across the basolateral membrane of the thryoid follicular cell:
      • Mediated by the Na+/I (NIS) symporter
• NIS is a sodium-dependent transporter:
  • So iodine is only transported with an inward sodium gradient:
    • Which is in turn maintained by the action of the Na-K-ATPase
• The intracellularly accumulated iodide ion is then passively translocated across the apical membrane into the colloid protein aggregate:
  • Via pendrin proteins and Cl- channels
• The transported (effluxed) iodide ion becomes covalently attached to the precursor thyroid hormone glycoprotein:
  • Thyroglobulin:
    • At the interface between the apical membrane and the follicular lumen by the enzyme:
      • Thyroperoxidase (TPO)
• Further iodinization (organification) of tyrosine molecules on the thyroglobulin glycoprotein:
  • Then occurs via TPO facilitating the further incorporation of iodide onto the tyrosine residues:
    • Tyrosine molecules (thyrosyl residues) in the thyroglobulin molecule:
      • Are then iodinated to form:
        • Monoiodotyrosines (MITs) and diiodotyrosines (DITs) (Figure)
      • Incorporation of iodide into protein is referred to as:
        • Organification
• It should be noted that this process of oxidation of iodide, organification, and coupling is dependent on:
  • The presence of hydrogen peroxide present intralumenally and truly occurs simultaneously
• The bioactive thyroid hormones:
  • L-thyroxine / tetraiodothyronine (T4) and triiodothyronine (T3):
    • Are formed by the coupling of two DITs or one DIT with one MIT, respectively:
      • By TPO (Figure)
• T4 and T3 remain attached to thyroglobulin and are stored as colloid within the follicular lumen:
  • Where they remain available for release through TSH stimulation
• In healthy and iodine-sufficient individuals:
  • The majority of thyroid hormone in colloid is stored as:
    • T4 with a small amount (~ 20%) stored as T3
• Upon stimulation of the TSH receptor:
  • A cytoplasmic vesicle is formed for uptake of colloid into the follicular cell through pinocytosis (micropinocytosis) (Figure)
• The cytoplasmic vesicles fuse with lysosomes:
  • Forming phagolysosomes (intracellularly):
    • In which Tg is broken down by proteolysis:
      • Proteases hydrolyze the peptide bonds of thyroglobulin:
        • To release T4 and T3 into the cytoplasm
    • The thyroid hormone transporter:
      • Monocarboxylate transporter 8 (MCT8):
        • Located in the basolateral membrane of the thyroid follicular cell:
          • Is expressed in the thyroid gland and is important for transport of T4 and T3 out of the thyroid gland and into the circulation
      • Production of thyroid hormone varies widely between:
        • 75 and 250 mcg daily
• In the blood:
  • Approximately 99.97% of T4 and 99.7% of T3 are bound to the binding proteins:
    • Thyroxine binding globulin (TBG), transthyretin (also known as prealbumin), and albumin:
      • Of these, TBG has the highest affinity to bind thyroid hormone:
        • Binding approximately 75% of both T4 and T3 in circulation) and is the most clinically relevant among the binding proteins
      • Transthyretin, previously referred to as prealbumin:
        • Binds approximately 20% of the circulating T4 and < 5% of T3
      • Albumin has the lowest affinity for thyroid hormone, but is the most abundant of the proteins:
        • Binds 5% of the T4 and 20% of the T3
• In total, most of the thyroid hormones in circulation are in the bound state and biologically inactive:
  • The unbound thyroid hormones:
    • Free T4 (0.03%) and free T3 (0.3%):
      • Enter the target cells
  • In some tissues, such as those from the brain and pituitary:
    • Specific thyroid hormone membrane transporters are required for thyroid hormone uptake:
      • Principally monocarboxylate transporter 8 (MCT8)
• Triiodothyronine / T3:
  • Binds with a much greater affinity to the thyroid hormone receptors and for a longer period of time:
    • Compared with T4
  • T3 is regarded as the primary active thyroid hormone
• Tetraiodothyronine / T4:
  • Is synthesized exclusively by the thyroid gland:
    • Whereas T3 is produced primarily in peripheral tissues:
      • From the deiodination of circulating T4
    • Only about 20% of the daily T3 requirement:
      • Is synthesized directly by the thyroid gland
• The activation of T4 to T3 requires the 5’-deiodinase enzymes type 1 (Dio1) and type 2 (Dio2):
  • These enzymes are differentially expressed:
    • Dio1 predominantly in the liver
    • Dio2 in tissues that require local T3 production, such as:
      • The brain, pituitary, muscle, and brown fat
• In the setting of fluctuating T4 levels:
  • Deiodinase activity is modulated to maintain normal circulating and target tissue T3 levels (Figure)

• When serum T4 levels fall, as in hypothyroidism:
  • Dio2 is activated locally by a deubiquitination process:
    • That reduces Dio2 degradation:
      • Increases Dio2 activity, and promotes greater conversion of T4 to the bioactive T3:
        • Normal serum T3 levels are maintained until the serum T4 becomes very low
• Thyroid metabolism is influenced by illness and drugs:
  • The activity of Dio1 and the resulting T3 level is reduced in:
    • Malnutrition
    • Critical illness
    • By the action of certain medications:
      • Beta-blockers
      • Ipodate
      • Amiodarone
      • Dexamethasone
      • Propylthiouracil
• During starvation and acute illness:
  • Expression of the 5 deiodinase type 3 (Dio3) is increased and converts the bioactive T4 and T3:
    • To two biologically inactive molecules:
      • Reverse T3 (rT3) and 3,3’diiodothyronine (T2)
• The available free T3:
  • Binds to a nuclear thyroid hormone receptor at the target tissue:
    • Alters gene expression, and regulates cellular function (Figure)

• The thyroid hormone nuclear receptor (THR) is a protein within a superfamily of receptors:
  • That bind steroid and steroid-like hormones such as retinoic acid, vitamin D, and estrogen
• The THRs mediate the majority of biologic activities of T3:
  • Two THR genes, alpha and beta:
    • Encode four THR isoforms:
      • Alpha 1, beta 1, beta 2, and beta 3
  • The transcriptional activity of THRs is regulated by the binding of T3:
    • The thyroid hormone response elements located on the promoters of the T3 regulated gene, by the developmental- and tissue-dependent expression of THR isoforms and by nuclear cofactors or coregulatory proteins
  • There are also nongenomic actions of iodothyronine (T4) that are not mediated by intranuclear THR:
    • Action at the plasma membrane is mediated by the integrin alpha-v beta 3 receptor that binds T4, and activates ERK1/2, which leads to changes in membrane ion transport, such as the Na(+)/H(+) exchanger, and is also involved in other important cellular events such as cell proliferation