Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Thyroid gland imaging studies with radionuclides:
  • Provide both structural and functional information and can be very useful in determining the etiology of biochemical hyperthyroidism:
    • In contrast, thyroidal nuclear imaging is not recommended in the evaluation of a patient with hypothyroidism
• For nuclear imaging, scans using radioactive iodine isotopes are most preferred:
  • Because these directly reflect the active accumulation (trapping) of iodine by the thyroid follicular cell and covalent attachment (organification) of iodine to thyroglobulin
• The preferred radionuclide for diagnostic nonthyroid cancer imaging:
  • Is 123I, because this isotope emits only gamma rays that pass through tissue without significant cellular damage:
    • In contrast, 131I emits both gamma rays for imaging, as well as damaging beta particles:
      • So it can be used for the treatment of hyperthyroidism and thyroid cancer:
        • To destroy iodine-avid thyroid tissue
  • For diagnostic imaging:
    • 123I is administered orally:
      • With the measurement of iodine uptake and gamma scintigraphy images:
        • Obtained 4 hours and / or 24 hours later
    • Measured thyroidal uptake depends on the activity of NIS and overall iodine status as determined by the amount of circulating nonradioactive iodine:
      • When there is an excess of nonradioactive iodine:
        • The measured radioactive iodine uptake is reduced due to the competition between radioactive and nonradioactive iodine uptake by the thyroid follicular cells:
          • Sources of excess nonradioactive iodine include kelp, seaweed, seafood, iodine-rich medications and agents (amiodarone, saturated solution of potassium iodide [SSKI], Lugol’s solution, povidone iodine, tincture of iodine, iodoform gauze), and radiographic contrast media used commonly in computed tomography (CT) scans and gallbladder studies
• An alternate radionuclide is technetium99m pertechnetate (99mTc):
  • Which is administered intravenously
  • Images are obtained much more rapidly than 123I:
    • Usually on the order of 30 to 60 minutes after the administration of the radionuclide tracer
    • Although 99mTc will be trapped by the thyroid follicular cells:
      • There is no iodine moiety for attachment to thyroglobulin, and therefore does not as accurately mimic the thyroidal uptake of iodine as radioiodine nuclides:
        • Thus 123I thyroid scans have 5% to 8% fewer false negative results than 99mTc scans:
          • However, because 99mTc scans are easier, faster, more readily available and less expensive to perform, they have largely replaced 123I scans at some institutions
• Studies of direct comparison of radioiodine and 99mTc thyroid scans have been highly concordant in patients without nodules and in those with cold nodules:
  • One study reported that of 273 patients with thyroid nodules, only two had increased uptake with pertechnetate and no uptake with radioiodine:
    • However, if the results of the 99mTc scan are not in agreement with the clinical picture, an 123I scan should be performed
• Although nuclear scans are useful in the differential diagnosis of biochemical hyperthyroidism:
  • Other radiologic modalities (e.g., ultrasonography, CT, and magnetic resonance imaging [MRI]) provide information regarding structural anatomy of the thyroid and provide no functional data
• The primary role of thyroid ultrasound is in the initial evaluation of thyroid nodules:
  • As recommended by the American Thyroid Association and the American Association of Clinical Endocrinologists
  • Although thyroid ultrasound does not have a role in the initial evaluation of biochemical thyroid dysfunction:
    • It may demonstrate changes that are consistent but are not necessarily diagnostic of chronic lymphocytic thyroiditis, subacute granulomatous thyroiditis, and postpartum thyroiditis
  • Some individuals with subclinical hypothyroidism and sonographic features suggestive of chronic thyroiditis:
    • Are at significant risk for developing overt hypothyroidism requiring thyroid hormone replacement therapy

• Clinical Presentation:
  • Before the implementation of routine screening mammography:
    • Most patients with DCIS presented with a:
      • Palpable mass
      • Nipple thickening
      • Nipple discharge
      • Paget disease of the nipple
    • Occasionally, DCIS was an incidental finding:
      • In an otherwise benign breast biopsy specimen
    • In patients with palpable lesions:
      • Up to 25% demonstrated foci of invasive disease
  • Now that screening mammography is more prevalent:
    • The incidence of DCIS has increased dramatically and currently comprises:
      • Approximately 20% of all breast cancers
    • Most cases of DCIS are diagnosed:
      • When the tumor is still clinically occult
    • Patients with abnormalities detected by screening mammography:
      • Should always undergo diagnostic imaging of the contralateral breast:
        • Because 0.5% to 3.0% of patients have:
          • Synchronous occult abnormalities or cancers in the contralateral breast
      • Mammographic images should be compared with previous images, if available, to establish interval changes
• Mammographic features:
  • On a mammogram, DCIS can present as:
    • Microcalcifications:
      • 80% to 90% of mammographic manifestations
    • A soft-tissue density
    • Both
  • Microcalcifications:
    • Are the most common (80% to 90%) mammographic manifestation of DCIS:
      • Which, in turn, accounts for 80% of all breast carcinomas:
        • Presenting with calcifications
  • Any interval change from a previous mammogram:
    • Is associated with malignancy in 15% to 20% of cases:
      • Most often indicates in situ disease
  • Holland et al. (1990):
    • Described two different classes of microcalcifications:
      • Linear branching-type microcalcifications:
        • Which are more often associated with:
          • High–nuclear-grade lesions
          • Comedo-type lesions
      • Fine, granular calcifications:
        • Which are primarily associated with:
          • Micropapillary or cribriform lesions:
            • Of lower nuclear grade and that do not show necrosis
    • Although the morphology of microcalcifications:
      • Suggests the architectural type of DCIS:
        • It is not always reliable
  • Holland et al:
    • Also demonstrated that the mammographic findings:
      • Significantly underestimated the pathologic extent of disease:
        • Particularly in cases of:
          • Micropapillary DCIS:
            • Lesions were more than 2 cm larger by histologic examination than by mammographic estimation:
              • In 44% of cases of micropapillary lesions, compared with only 12% of cases of the pure comedo subtype
      • However, when magnification views were used in diagnostic mammographic examination:
        • The extent of disease was underestimated in only 14% of cases of micropapillary tumors
      • Hence, magnification views increase the image resolution and are better able to delineate the shape, number, and extent of microcalcifications when compared with mammography alone:
        • And should be used routinely in the evaluation of suspicious mammographic findings

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• TP53 is a tumor suppressor gene:
  • That plays a crucial role in:
    • Maintaining genomic stability and regulating cell cycle checkpoints
• Carriers of a TP53 pathogenic variant:
  • Would be expected to be unable to repair tissue damage from DNA-damaging radiotherapy and be at risk for significant radiotherapy-associated sequelae
• Outcomes reported in published case reports:
  • Support this recommendation against radiotherapy in women with breast cancer who are carriers of a TP53 pathogenic variants:
    • Due to increased risk of radiation-induced secondary malignancies
• Mutations in TP53 are considered:
  • An absolute contraindication of radiotherapy:
    • Except in those with a significantly high risk of locoregional recurrence
  • Mastectomy is the recommended therapeutic surgical option
• The radiotherapy-induced toxicity spectrum in patients with breast cancer carrying ATM pathogenic variants is controversial:
  • Seven studies identified in a systematic review addressed radiotherapy after breast-conserving surgery among women with breast cancer who harbor ATM pathogenic variants:
    • Meyer et al found no significant differences in local relapse-free survival in a cohort of 138 patients with early stage breast cancer treated with breast-conserving surgery, followed by radiotherapy, of whom 20 were found to carry either an ATM truncating or missense variant:
      • They concluded that the results do not support the hypothesis that patients with breast cancer carrying a sequence variant in the ATM gene differentially benefit from postoperative radiotherapy
• According to the ASCO-ASTRO-SSO Consensus recommendations for carriers of BRCA 1/2 and other germline pathogenic variants,:
  • Women with breast cancer may safely be offered radiotherapy when clinically indicated
  • Data on toxicity rates comparing carriers of ATM pathogenic variants and noncarriers:
    • Do not favor avoiding radiotherapy:
      • Potential absolute risks do not appear to be significant:
        • However, more research is needed
  • A discussion with ATM carriers interested in breast-conserving therapy is encouraged
  • There is no evidence of increased toxicity or contralateral breast cancer events from radiation exposure in BRCA 1/2, CHEK2, CDH1 carriers
• References:
  • Trombetta MG, Dragun A, Mayr NA, Pierce LJ. ASTRO Radiation Therapy Summary of the ASCO-ASTRO-SSO Guideline on Management of Hereditary Breast Cancer. Pract Radiat Oncol. 2020;10:235-242.
  • Lazzari G, Buono G, Zannino B, Silvano G. Breast cancer adjuvant radiotherapy in BRCA1/2, TP53, ATM genes mutations: Are there solved issues? Breast Cancer (Dove Med Press). 2021;13:299-310.
  • Ferrarini A, Auteri-Kaczmarek A, Pica A, et al. Early occurrence of lung adenocarcinoma and breast cancer after radiotherapy of a chest wall sarcoma in a patient with a de novo germline mutation in TP53. Fam Cancer. 2011;10:187-192.
  • Heymann S, Delaloge S, Rahal A, et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li- Fraumeni syndrome. Radiat Oncol. 2010;5:104.
  • Meyer A, John E, Dörk T, Sohn C, Karstens JH, Bremer M. Breast cancer in female carriers of ATM gene alterations: outcome of adjuvant radiotherapy. Radiother Oncol. 2004;72: 319-323.

• Bioactive free T4 concentrations:
  • Can be estimated using a variety of indirect (analog, immunometric, and two-step labeled hormone assays) or direct methods (equilibrium dialysis, ultrafiltration), and are the most commonly used measurements of circulating thyroid hormone levels
• Generally, most laboratories estimate free T4 by either the analog immunoassay or a calculated FT4I corrected to thyroid hormone binding capacity:
  • The former is readily available and provides quick results; it does not directly measure the free T4 concentration but is a reliable estimate of FT4 levels in most patients, based on one-step, two-step, or labeled antibody approaches
• This type of free T4 estimate is especially sensitive to abnormal serum albumin levels and should not be used with conditions such as:
  • Familial dysalbuminemic hyperthyroxinemia, pregnancy, or severe nonthyroidal illness:
    • For example, it is common to have a free T4 lower than the reference range in a euthyroid pregnant woman:
      • Due to the high estrogen state of pregnancy greatly increasing serum TBG concentrations, thus resulting in inaccurate FT4 measurements
• The serum FT4I measurement is a calculated value that is the product of the total T4 concentrations and a correction factor related to the number of available thyroid hormone binding sites:
  • This correction factor may be called:
    • A thyroid hormone binding ratio (THBR), T3 resin uptake (T3RU), or T3 uptake (T3U)
    • The T3RU is inversely related to the free thyroid hormone binding sites but is now used in only a few laboratories
• Free T4 by equilibrium dialysis:
  • Is the gold standard and measures the 0.03% of T4 that is biologically active and unbound to protein
  • This assay is available only at reference laboratories and is useful to directly determine free T4 levels when other testing does not provide a clear result
• Although a TSH-first testing algorithm is suffcient for general screening:
  • Both FT4 and TSH assays are needed for:
    • Diagnosing subclinical thyroid dysfunction, central hypothyroidism, and in the assessment of elderly and hospitalized patients, as well as for accurate assessment of treatment effects
• Guidelines from multiple thyroid and endocrine societies:
  • Have also endorsed a TSH-first strategy in most clinical scenarios with FT4 testing when clinically indicated or TSH is found to be abnormal
  • Work by Henze et al. goes even further suggesting that a TSH-first strategy can be further perfected by:
    • Widening the TSH reference range from 0.4 to 4.0 mIU/L to 0.2–6.0 mIU/L with minimal impact on case detection
    • They found that only 4.2% of TSH values between 0.2 mIU/L and 0.4 mIU/L would not have led to detection of a high FT4 and equally, only 2.5% of TSH values between 4.0 mIU/L and 6.0 mIU/L were associated with low FT4 level
    • It is likely that this small additional group of patients outside the wider range with abnormal FT4 is clinically unimportant in most cases

• Serum total T4 (TT4) and total T3 (TT3) concentrations:
  • Are a measure of both the bound and free hormone levels of these two hormones
• TT4 or TT3 levels should be interpreted in the context of the clinical situation:
  • Because many clinical conditions and medications alter the concentrations of thyroid hormone binding proteins and / or compete with the binding of thyroid hormones to the binding proteins:
    • As such, measured TT4 and TT3 levels may be affected, even though the bioactive free levels and thus, the thyroidal status, remain unchanged
• T3 is the active thyroid hormone:
  • It is primarily useful in the diagnosis and management of patients with hyperthyroidism
  • It occasionally can be used to differentiate stimulation induced thyrotoxicosis / Graves’ disease (TT3 / TT4 ratio > 20) from destruction induced thyrotoxicosis / subacute thyroiditis (TT3 / TT4 ratio < 12):
    • This assessment can be further augmented when TSH is considered as serum levels of TSH are generally suppressed in most untreated Graves’ patients, whereas they usually were not completely suppressed in patients with painless thyroiditis or subacute thyroiditis
  • Measurement of serum TT3 is not usually helpful if hypothyroidism is suspected:
    • Because the activity of 5’deiodinas type 2 enzyme (Dio2):
      • Which converts T4 to the biologically active T3:
        • Increases while serum T4 falls:
          • Thus maintaining normal T3 levels until the overall thyroid hormone levels are very low
• rT3, which may be elevated during nonthyroidal illness:
  • Is not biologically active:
    • As such, the utility of measuring it and other forms of inactive iodothyronine are limited during the evaluation of thyroid status
• Finally, the human anti-mouse antibodies (HAMAs) that interfere with TSH testing:
  • Can also interfere with the thyroid hormone assays
  • HAMA positivity:
    • May result in artificially elevated or reduced TT4, TT3, FT4, and FT3 levels
  • Patients who have received therapeutic monoclonal antibody treatment may be at increased risk of develop interfering positive HAMA titers

• Thyroid Stimulating Hormone (TSH):
  • Is produced from the anterior pituitary gland:
    • After stimulation by thyrotropin-releasing hormone (TRH)
• Thyrotropin-releasing hormone (TRH):
  • Is a modified three-amino acid peptide:
    • Produced by neurons of the paraventricular nucleus:
      • In the hypothalamus
  • TRH signaling from the hypothalamus:
    • Is achieved through a portal venous system:
      • Located in the infundibulum of the pituitary stalk:
        • Which allows communication to the pituitary gland
• Both TRH and TSH gene expression:
  • Are decreased by excess thyroid hormone levels:
    • Via negative feedback mechanisms (Figure)
  • Both the hypothalamus and pituitary:
    • Have high levels of 5′deiodinases Type 2 enzyme (Dio2):
      • Catalyzes the removal of the 5′ iodine from the outer ring of thyroxine (T4):
        • To create the metabolically active triiodothyronine (T3)
      • So T4 levels are the primary feedback:
        • T4 is converted locally to T3:
          • Which suppresses TRH and TSH gene expression

• Pituitary TSH is secreted in a pulsatile manner:
  • Higher levels at night and lower levels during the day:
    • The inverse of the cortisol cycle
  • Although pulse frequency is increased nocturnally to result in a diurnal variation of TSH concentrations:
    • Levels remain within the reference range
  • Generally, laboratory testing of serum TSH concentrations during daylight hours:
    • Is not substantially affected by the diurnal variation of TSH secretion:
      • But results outside the reference range may occur in euthyroid individuals when drawn outside of these times
• TSH stimulates the synthesis and release of thyroid hormone from the thyroid gland:
  • TSH production from the anterior pituitary gland is inverse log-linearly regulated by serum thyroid hormone concentrations:
    • When there are small decreases in thyroid hormone levels in circulation:
      • Large increases in serum TSH stimulate thyroid hormone production by the thyroid gland
    • This negative feedback loop between serum TSH and the serum-free thyroid hormones:
      • Is able to maintain circulating thyroid levels within a tight range
• Serum TSH is the preferred screening test:
  • In the evaluation of thyroid function in the ambulatory patient:
    • Regardless of whether the patient is taking thyroid hormone replacement medication
• For the healthy patient in an ambulatory setting:
• The diagnosis of hypothyroidism or hyperthyroidism:
  • May be determined with approximately 98% sensitivity and 92% specificity using serum TSH
  • In addition, TSH has a narrow intraindividual variability of ± 0.5 mIU/L:
    • Such that thyroid dysfunction may be present if there are significant changes in TSH values over time in an individual, even if they remain within the reference range
• In certain situations, however, such as known or suspected pituitary or hypothalamic dysfunction, recent hyperthyroidism, critical illness, starvation, use of certain medications (dopamine or high-dose glucocorticoids), interference with serum thyroid autoantibodies, and thyroid hormone resistance syndromes:
  • The TSH level is inaccurate for the thyroidal status and should not be used in isolation to determine thyroid function
• In addition, the presence of interfering heterophile antibodies (antibodies against the animal-derived antibodies used in the immunometric assay):
  • May rarely cause abnormally high or low TSH levels:
    • These conditions should be suspected when the pattern of the TSH levels does not correlate to the clinical presentation or when the peripheral serum hormone levels do not change as expected with elevated or suppressed serum TSH concentrations
• Serum TSH assays:
  • Have evolved considerably since measurements were first described in the 1960s:
    • When the functional sensitivity was between 1 and 2 mIU/L
  • The commonly used second-generation TSH assays have an improved functional lower limit of 0.10 to 0.20 mIU/L:
    • Which is able to differentiate between euthyroid and hyperthyroid states but does not indicate the degree of hyperthyroidism
  • In contrast, a third-generation TSH assay can detect levels as low as 0.01 to 0.02 mIU/L:
    • This is helpful when there is a challenging pattern of serum thyroid function tests that include an extremely suppressed TSH
  • In the rare instance they are needed, fourth-generation immunochemiluminometric assays are capable of detecting TSH levels in the range of 0.01 to 0.001 mIU/L
• A serum TSH level measured in an ambulatory population that lies within the reference range:
  • Is generally considered evidence of normal thyroid function and requires no additional testing
  • Reference ranges for serum TSH can vary slightly from one commercial laboratory to another:
    • It should be noted that normal ranges, which are based on the epidemiologic distribution of serum TSH concentrations in healthy populations:
      • From which serum thyroid autoantibody positivity and iodine status (both of which can affect TSH), may be variable
  • If an abnormal screening TSH result is encountered:
    • The circulating thyroid hormone levels should be assessed
      • The specific pattern of tests will allow further insight into whether clinical thyroid dysfunction should be suspected

• Hyperthyroidism and hypothyroidism:
  • Are often the result of autoimmune diseases:
    • In which immunoglobulin G (IgG) antibodies:
      • Such as thyroid peroxidase (TPO Ab, previously known as antimicrosomal antibodies), thyroglobulin (Tg Ab), and the TSH receptor (TSHR Ab):
        • Are formed against thyroid proteins
  • The presence of TPOab is commonly associated with patients with hypothyroidism:
    • But can be present in normal individuals who do not display any obvious symptoms of clinical thyroid disease
  • TPOabs are present in approximately 10% of normal individuals:
    • While it was detected in almost 100% of samples of patients with autoimmune hypothyroidism
• More than 90% of patients with autoimmune thyroid disease (Hashimoto’s thyroiditis and Graves’ disease):
  • Will have elevated titers of second-generation assays for TPO Ab and Tg Ab
• When biochemical hypothyroidism is found:
  • Measuring TPO Ab can be helpful:
    • Because its result can provide additional information regarding the etiology of the thyroid dysfunction
• Median serum TSH concentrations are increased within the reference range:
  • Among those with serum TPO Ab and Tg Ab positivity:
    • Compared with those without TPO Ab titers, and are a predictor for the development of biochemical thyroid dysfunction in euthyroid individuals
• In individuals with subclinical hypothyroidism:
  • Both serum TPO Ab positivity and sonographic characteristics suggestive of chronic thyroiditis:
    • Are associated with an increased likelihood of progression to overt hypothyroidism
• The TSHR Abs are a group of immunoglobulins:
  • That produce Graves’ hyperthyroidism
  • Measured as:
    • TSH receptor binding, TRAB (TSH-receptor antibody) or in a functional bioassay, thyroid stimulating immunoglobulin (TSI)
  • TSH receptor antibodies:
    • Are being increasingly recommended for monitoring activity of disease to assess response to therapy in Graves’ patients
  • Less commonly, TSH receptor binding antibodies:
    • Can block the TSH receptor and produce hypothyroidism
• In the setting of normal serum thyroid function:
  • Thyroid antibodies should generally not be measured except in special circumstances:
    • Such as a history of hyperthyroidism during pregnancy or recurrent miscarriages:
      • In these situations, both the stimulating and inhibiting TSHR Abs can cross the placenta to affect fetal thyroid function and potentially induce fetal goiter
    • Although serum thyroid antibody positivity during pregnancy:
      • Is associated with a higher risk of postpartum subacute thyroiditis:
        • Antibody screening in pregnant women is not currently recommended

• The evaluation of a chronically ill or hospitalized patient with abnormal serum thyroid function tests:
  • Can often be challenging
• Nonthyroidal illness is not considered a primary thyroid disorder:
  • Its pathophysiology is not completely understood:
    • Although it is known that the elevation of cytokines and hypoxia plays a significant role
  • It is generally recommended to avoid measuring serum thyroid function tests during acute illness:
    • Unless thyroid dysfunction is thought to be a significant contributor to the illness
• Severe nonthyroidal illness:
  • Is accompanied by significant alterations in thyroid physiology
• Due to the decreased availability in all of the thyroid binding proteins (thyroxine bindings globulin, transthyretin, albumin):
  • Serum total T4 and total T3 levels are reduced:
    • Whereas free levels are usually normal or slightly low (Figure)
  • Total T3 levels are further decreased:
    • Due to reduced Dio1 activity:
      • Which converts T4 to T3
  • A relatively greater amount of T4 is metabolized to the inactive metabolite:
    • Reverse T3 (rT3):
      • By Dio3
    • Although measurement of rT3 does not reliably distinguish nonthyroidal illness from primary hypothyroidism
    • The degree of serum rT3 elevation, depressed T3 / rT3 ratio, and decreased FT3 and FT4 concentrations:
      • Have been associated with higher mortality among patients in the intensive care unit (ICU):
        • Treatment with T4 or T3, however, does not consistently improve outcome
    • Whether other T4 metabolites, including 3,3′-diiodothyronine (3,3′-T2); 3,5-diiodothyronine (3,5-T2); and 3-iodothyronamine (3-T1AM):
      • Have functional roles in nonthyroidal illness remains unclear

• It is important that the diagnosis of primary thyroid dysfunction:
  • Is not established during severe illness based solely on an abnormal serum TSH
• In nonthyroidal illness:
  • Serum TSH concentrations may be low, normal, or high:
    • Due to the TSH-lowering effects of commonly used medications (glucocorticoids, ipodate, amiodarone, dopamine) in patients managed for a nonthyroidal illness or from a reversible form of acquired central hypothyroidism in severe nonthyroidal illness
• During the recovery phase of nonthyroidal illness:
  • The TSH may briefly rise above the upper reference range, as suppression of TSH lessens, before it normalizes
  • When possible, thyroid evaluation after recovery from an acute illness is recommended in patients suspected of having intrinsic thyroid disease

• 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