Thyroid Cancer – Lymph Node Recurrences

šŸ‘‰Not all thyroid cancer recurrences require surgery.

šŸ‘‰Small lymph node recurrences in the neck can often be observed, however recurrent nodes greater than 0.8 cm in the central neck and greater than 1 cm in the lateral neck are typically removed.

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Anatomy of the Nasolacrimal System

  • The purpose of the nasolacrimal system is to:
    • Drain tears from the ocular surface to the lacrimal sac and, ultimately, the nasal cavity
    • Blockage of the nasolacrimal system:
      • Can cause tears to flow over the eyelid and down the cheek:
        • This condition is epiphora
  • Structure and Function:
    • Both the upper eyelid and the lower eyelid have a small opening on the surface of the eyelid margin near the medial canthus:
      • These are called puncta:
        • Each puncta leads to a drainage canal that eventually flows into the lacrimal sac and then the nasal cavity
    • The drainage canal connecting the ocular surface to the nasal cavity consists of multiple parts:
      • Within the lower eyelid:
        • The punctum leads to a 2 mm long ampulla:
          • Which runs perpendicular to the eyelid margin
        • The ampulla turns 90 degrees medially:
          • Becoming the inferior canaliculus and travels 8 to 10 mm before reaching the common canaliculus
        • The upper canaliculus travels 2 mm superiorly in the eyelid before turning 90 degrees medially and moving 8 to 10 mm before connecting to the common canaliculus
      • The common canaliculus:
        • Drains into the lacrimal sac
      • Within the junction between the common canaliculus and the lacrimal sac:
        • Is the valve of Rosenmuller:
          • This apparatus is a one-way valve that prevents reflux from the lacrimal sac to the puncta
    • The lacrimal sac drains:
      • Inferiorly to the nasolacrimal duct:
        • Which is bordered:
          • Medially by:
            • Palatine bone and the inferior turbinate in the nose
          • Laterally by:
            • Maxillary bone
      • The nasolacrimal duct:
        • Opens at the inferior meatus:
          • Located underneath the inferior nasal turbinate
      • The lacrimal sac is:
        • Approximately 10 to 15 mm in axial length and 13 to 20 mm in corneal length
      • The nasolacrimal duct is:
        • 12 to 18 mm long
      • The inferior nasal meatus is partially covered by a mucosal fold:
        • Known as the valve of Hasner
  • Embryology:
    • The nasolacrimal duct:
      • Starts forming around five weeks of gestation
      • It starts out as a linear thickening of ectoderm:
        • Located in a groove between the nasal and maxillary prominences
      • This thickening:
        • Eventually separates into a solid cord and sinks into the surrounding mesenchyme
        • Over time the cord canalizes:
          • Forming the lacrimal sac and the beginning of the nasolacrimal duct
      • The nasolacrimal duct extends:
        • Intranasally until it exits under the inferior turbinate
      • The lacrimal sac extends caudally:
        • To complete the canalicular system
      • The inside of the canal breaks down and forms a lumen:
        • So that the nasolacrimal system is patent:
          • This process is generally complete by the time of birth
  • Blood Supply and Lymphatics:
    • Blood supply to the nasolacrimal area of the face:
      • Is generally from the angular artery:
        • The angular artery is considered a branch of the facial artery:
          • However, some studies have shown that it can originate from the ophthalmic artery in some individuals
        • It terminates in anastomosis with the dorsal nasal branch of the ophthalmic artery
        • The angular artery and vein:
          • Appear alongside the nose near the medial orbit
        • A correlating angular vein drains this region
    • The medial and lateral portions of the eyelids have different lymphatic drainage systems:
      • The medial one-third of the upper eyelid and the medial two-thirds of the lower eyelid:
        • Drain to the submandibular lymph nodes
      • The lateral two-thirds of the upper eyelid and the lateral one-third of the lower eyelid:
        • Drain to the pre-auricular lymph nodes
  • Nerves:
    • Cranial nerve VII:
      • Supplies the motor innervation to the muscles of the face
    • The movement of these muscles:
      • Aid in proper drainage of the tears through the nasolacrimal system:
        • By what is known as the lacrimal pump mechanism
    • Cranial nerve III and cranial nerve VII:
      • Innervate the muscles that control the blinking of the eyelids:
        • This action is the primary driver of the lacrimal pump mechanism
    • Irritation of the ocular surface:
      • Stimulates the ophthalmic branch of cranial nerve five:
        • Which begins the reflex tear arc pathway:
          • The efferent pathway involves cranial nerve VII and parasympathetic fibers
        • The role of the sympathetic nervous system in tear production:
          • Is not well understood
  • Muscles:
    • The action of the orbicularis muscle and surrounding tissues:
      • Helps propel the flow of tears from the canaliculi to the nasolacrimal duct:
        • Via the lacrimal pump mechanism
  • References:
    • Computed tomography dimensions of the lacrimal gland in normal Caucasian orbits., Tamboli DA,Harris MA,Hogg JP,Realini T,Sivak-Callcott JA,, Ophthalmic plastic and reconstructive surgery, 2011 Nov-Dec.
    • An Unusual Case of Nasolacrimal Obstruction Caused by Foodstuffs., Matsumoto H,Matsumoto A,, Case reports in ophthalmology, 2015 Sep-Dec.
    • Lacrimal Gland Volume Changes in Unilateral Primary Acquired Nasolacrimal Obstruction., Yazici A,Bulbul E,Yazici H,Sari E,Tiskaoglu N,Yanik B,Ermis S,, Investigative ophthalmology & visual science, 2015 Jul.
    • Incidence of neoplasia in patients with unilateral epiphora., Bewes T,Sacks R,Sacks PL,Chin D,Mrad N,Wilcsek G,Tumuluri K,Harvey R,, The Journal of laryngology and otology, 2015 Jul.
    • Ducasse A,Arndt C,Brugniart C,Larre I, [Lacrimal traumatology]. Journal francais d’ophtalmologie. 2016 Feb.
    • Modified External Dacryocystorhinostomy in Primary Acquired Nasolacrimal Duct Obstruction., Sharma HR,Sharma AK,Sharma R,, Journal of clinical and diagnostic research : JCDR, 2015 Oct.

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Mucoepidermoid carcinoma (MEC)

  • Mucoepidermoid carcinoma (MEC):
    • Is the most common malignant neoplasm of the:
      • Mayor and minor salivary glands
  • Epidemiology:
    • They encompass between 2.8% to 15.5% of all salivary gland tumors
    • Among 12% to 35% of malignant salivary gland tumors
    • Among 6.5% to 41% of all minor salivary gland tumors:
      • Representing the most common type of malignant minor salivary gland tumor in most series
    • Approximately half the cases occur in the major salivary glands:
      • 65% to 80% of these occur in the parotid
      • 8% to 13% occur in the submandibular gland
      • 2% to 4% involve the sublingual gland
    • MEC of the minor salivary glands:
      • Ordinarily arises on the palate:
        • But a number may also be found in the:
          • Retro molar area
          • Floor of the mouth
          • Buccal mucosa
          • Lip
          • Tongue
    • Its prevalence is highest in:
      • The fourth to fifth decade of life (35 to 65 years of age):
        • With a female preponderance as high as 4:1
  • Grossly:
    • The tumor is poorly circumscribed and measures from 3 to 5 cm
  • Histologically:
    • They are characterized by a mixed population of cells, including:
      • Mucin-producing cells
      • Epidermoid cells with squamoid differentiation
      • Clear cells
      • Intermediate cells:
        • That may predominate in numbers
        • Are believed to be the progenitor of the other types of cells
      • No myoepithelial cells are present
  • The clinical behavior of MEC has proved to be difficult to predict:
    • But correlations to tumor grade and stage have been reported
    • The histologic features that are most useful in predicting the aggressive nature of these tumors are:
      • A minor cystic component (less than 20%)
      • Tumor necrosis
      • Neural invasion
      • Cellular anaplasia
      • Brisk mitotic activity
    • Based on the presence or absence of these features and the clinical behavior, MEC are classified as:
      • Low grade
      • Intermediate grade
      • High grade
    • Low-grade MEC are:
      • Well circumscribed, with pushing margins and dilated cystic areas containing mucin
      • Mucin producing, intermediate, or epidermoid cells make up the lining of these cystic structures
    • Intermediate-grade MEC:
      • As the grade worsens:
        • The tumors become more infiltrative, poorly circumscribed
        • Cystic formations are lost
        • Nests of tumor become more solid and irregular with intermediate or epidermoid cells dominating
    • High-grade MEC are characterized by:
      • The invasion of adjacent structures
      • Atypical mitoses
      • Necrosis
      • Perineural invasion
      • Lymph node metastasis:
        • 40% to 50%
      • Distant metastases
    • Differential diagnosis of these high-grade lesions are:
      • Primary of metastatic squamous cell carcinoma:
        • MEC is differentiated from metastatic SCC by:
          • The presence of intracellular mucin
      • Sebaceous carcinomas
      • Clear cell carcinomas
  • Histologic grade and tumor stage:
    • Appear to have profound effects on survival
    • Aro et al:
      • Found a statistically significant difference in disease free survival (DFS) by grade:
        • Between low-grade MEC and intermediate / high-grade MEC (P = 0.001)

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Cost of Contralateral Prophylactic Mastectomy (CPM) Versus Surveillance

  • There is robust literature to support the use of CPM as a cost-effective strategy:
    • In patients with hereditary breast cancer syndromes
  • Anderson et al. demonstrated that the most cost-effective strategy:
    • With and without quality adjustment:
      • For women with BRCA1 or BRCA2 mutations was:
        • Prophylactic bilateral salpingo-oophorectomy with bilateral mastectomy
  • Simulation models analyzing costs for CPM versus surveillance in patients with sporadic breast cancer reveal disparate findings:
    • An initial Markov model study found that CPM was cost effective compared with surveillance for:
      • Patients younger than 70 years:
        • But this finding was highly dependent on the quality of life assumptions
    • A second study that included operative complications and breast reconstruction costs used a decision-tree model and concluded that:
      • Although CPM resulted in a cost savings over surveillance for women younger than 50 years:
        • It also reduced quality of life years
      • When MRI was inserted in the model as the primary method of screening:
        • The cost-effectiveness of CPM increased
      • Loss of quality of life years was largely attributed to complications from reconstructive procedures
    • The two models differ in the assumptions regarding quality of life:
      • If we assume an improvement in quality of life after CPM:
        • Then CPM could be cost effective
      • Alternatively, if quality of life is decreased,:
        • CPM would not be a cost-effective strategy
  • The available data on cost effectiveness for CPM is limited
  • Summary:
    • CPM is a cost-effective strategy for women with BRCA mutations
    • At this time, there is insufficient evidence to support the concept of superior cost effectiveness for CPM in women with sporadic breast cancer and the cost effectiveness is highly dependent on the quality of life assumptions
  • Reference:
    • 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) 23:3106–3111

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  • Laboratory Evaluation:
    • Diagnosis is always established by the measurement of:
      • Sensitive TSHĀ andĀ thyroid hormone levelsĀ (free T3Ā andĀ free T4)
    • Thyrotoxicosis caused by TNG or Graves’ disease is usually characterized by:
      • AĀ suppressed TSH levelĀ with either:
        • Normal (subclinical) orĀ elevated (overt) free thyroid hormone levels
      • It isĀ insufficient to relyĀ on the measurement of TSH or free thyroid hormones:
        • Alone to diagnose TNG or Graves’ disease:
          • Because suppression of TSH or elevation of thyroid hormones can be associated with clinical conditions other than TNG and Graves’ disease
Low TSHHigh TSH
SecondaryĀ hypothyroidismTSH-secreting pituitary tumor
Non-thyroidal illnessThyroid hormone resistance
Glucocorticoid therapy
Amiodarone use
Excessive thyroid hormone therapy
  • Other serologic findings:
    • Such asĀ antithyroid antibodiesantithyroid peroxidaseĀ andĀ antithyroglobulin:
      • ThatĀ support the diagnosis of autoimmune thyroid disease:
        • May be detected in patients with Graves’ disease:
          • However,Ā serum TSHR-Ab:
            • Is occasionally helpful in the diagnosis of Graves’ disease:
              • Though there isĀ no consensusĀ regarding its routine measurement in Graves’ disease
  • Imaging:
    • Radionuclide Imaging:
      • Radionuclide scanningĀ andĀ radioactive iodine uptake (RAIU):
        • Are useful tests toĀ elucidate the cause of hyperthyroidism
      • InĀ toxic nodular goiter (TNG):
        • The radioactive iodine (RAI)Ā concentration is in the nodule(s), andĀ uptakeĀ is inhibited in the surrounding tissue:
          • GivingĀ the appearance of ā€œpatchyĀ uptakeā€
        • Consequently, the totalĀ RAIU may be either:
        • Slightly raised or at the upper limit of normal
      • InĀ Graves’ disease:
        • BecauseĀ of the diffuseĀ thyroid involvement:
          • TheĀ RAIUĀ is always intense and increased
      • Thyroid radionuclide imaging mayĀ not be necessary in every case:
        • WhenĀ the diagnosis is obvious:
          • But it is helpfulĀ in the differentiation of other clinical conditions associatedĀ with hyperthyroidismĀ but with low RAIU
Radionuclide scan of toxic nodular goiter demonstrating intense focal uptake of several hot nodules with different degrees of suppression of adjacent thyroid tissueĀ (A)Ā compared with the scan from a patient with non-toxic multi-nodular goiter, showing less intense patchy radioactive iodine uptakeĀ (B).
Radionuclide scan in Graves’ hyperthyroidism demonstrating the diffuse and homogeneous nature of increased uptake in both lobes of the thyroid.

Clinical Conditions Associated with LowĀ Radioactive Iodine Uptake and Hyperthyroidism

Thyroiditis
Iodine-induced thyrotoxicosis
Exogenous thyrotoxicosis (factitia)
Ectopic functional thyroid tissue
  • Computed tomography scan:
    • InĀ any patient with compressive or obstructive symptomsĀ andĀ an MNG:
      • Chest radiography and chest computed tomography (CT) are often informative
    • Chest CT is particularly valuable toĀ define the size and extent of the goiter:
      • Especially into the mediastinum
    • Care to avoid iodinated contrast:
      • Until the patient’s thyroid functional status must be taken into account or the significant iodine load CT contrast agent may acutely induce or worsen hyperthyroidism
A,Ā Chest radiography showing a huge solid goiterĀ (horizontal arrow)Ā displacing the trachea without compressionĀ (vertical arrow).Ā B,Ā Neck computed tomography of the same goiterĀ (arrows).Ā Thyroidectomy revealed a 290-g benign thyroid gland.
  • Associated metabolic abnormalities:
    • Altered glucose metabolism:
      • Reversible hyperglycemia
      • Elevated C-peptide
      • Elevated intact proinsulin
      • Insulin resistance
    • Increased bone turnover:
      • Elevated markers of bone formation and resorption
        • Are hallmarks of untreated hyperthyroidism
    • Untreated hyperthyroidismĀ is associated with anĀ elevated chromogranin A level:
      • That changes in parallel with thyroid status

Metabolic Abnormalities Associated with Hyperthyroidism

Mild hypercalcemia
Myopathy
Hypokalemic periodic paralysis
Pulmonary hypertension
Cholestatic jaundice

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Sentinel Lymph Node Surgery for Contralateral Prophylactic Mastectomy (CPM) – American Society of Breast Surgeons (ASBrS) Evidence-Based Recommendations

  • The benefit of performing sentinel lymph node (SLN) surgery at the time of CPM is:
    • That the lymph nodes have been evaluated in the event that an occult malignancy is found
  • The downside is:
    • Increased surgical morbidity such as lymphedema
  • By meta-analysis:
    • The risk of lymphedema after SLN alone is:
      • 5.6 % (95 % CI 6.1–7.9 %) and increases with longer follow-up
    • The chance of finding occult invasive disease in a prophylactic mastectomy is:
      • 1.8 %
    • An additional small percent of CPM specimens harbor noninvasive disease:
      • That would not require nodal evaluation
    • The rate of nodal positivity in patients with occult malignancy in CPM is:
      • Only 1.3 %
    • Considering these data:
      • Routine SLN surgery at time of CPM:
        • Places more patients at risk of lymphedema:
          • Than would be expected from the 1% to 2 % of patients with occult disease undergoing axillary dissection
        • Therefore the consensus group:
          • Does not recommend routine SLN for CPM
  • Patients at higher risk of contralateral occult malignancy are:
    • Postmenopausal patients
    • Those with triple-negative
    • Locally advanced
    • Inflammatory breast cancer
    • Invasive lobular disease
  • MRI at the time of breast cancer diagnosis:
    • Identifies occult contralateral disease:
      • 2% to 4 % of the time
    • Suspicious lesions in the contralateral breast should be biopsied:
      • But if a biopsy is not done:
        • SLN surgery should be considered for highly suspicious lesions
  • Summary:
    • Sentinel lymph node surgery on the CPM side should not be routinely performed
  • References:
    • 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) 23:3106–3111

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Lymph Node Staging in Breast Cancer in Patients Greater Than 70 Years of Age

  • Triple-negative breast cancer:
    • Is more responsive to preoperative chemotherapy compared to ER/PR+, HER2neu negative breast cancer:
      • Pathologic complete response is seen in approximately 30% to 40% of patients undergoing treatment with a third-generation regimen:
        • A pathologic complete response:
          • Is highly prognostic in this subset
  • While ER negative breast cancers:
    • Have a lower propensity for regional nodal metastasis compared to ER+ tumors:
      • The difference is relatively small (2% to 5%):
        • Therefore, nodal staging is still a standard practice recommendation
  • The Choosing Wisely guideline:
    • For omission of routine use of sentinel node biopsy in clinically node-negative women ≄ 70 years of age applies to hormone receptor positive breast cancer
  • Sentinel node biopsy may be successfully performed after neoadjuvant chemotherapy and should be performed patients with a clinically negative axilla
  • References
    • Cortazar P, Zhang L, Untch M, et al. Pathologic complete response and long term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-172.
    • Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25(28):4414-4422.
    • von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30(15):1796-1804.
    • Viale G, Zurrida S, Maiorano E, et al. Predicting the status of axillary sentinel lymph nodes in 4351 patients with invasive breast carcinoma treated in a single institution. Cancer. 2005;103(3):492-500.
    • Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31(19):2382-2387.

Bilateral Breast Cancer

  • Synchronous and metachronous bilateral breast cancers:
    • Appear in 1% to 20% of patients with breast cancer
  • Improvements in screening and the increased use of MRI:
    • Often diagnose more early-stage synchronous bilateral cancer
  • The role of MRI in the preoperative planning:
    • Is controversial and may be partly responsible for increasing mastectomy rates in the United States
  • MRI may identify additional lesions in both the ipsilateral and contralateral breast in many women diagnosed with unifocal breast cancer:
    • Many of these additional lesions are often found to be benign once additional diagnostic imaging is performed and biopsies are completed
    • Additional MRI findings should not prompt surgeons to recommend mastectomy:
      • Unless they are biopsy-proven to represent additional sites of malignancy not amenable to breast conservation, and/or the patient was inclined toward mastectomy prior to MRI findings
  • Retrospective studies evaluating the outcomes of synchronous bilateral breast cancer:
    • Are limited by small cohort sizes, differing definitions, and non-matched unilateral patients as controls
    • Most retrospective studies show no differences in local recurrence or survival for bilateral breast cancers:
      • Making bilateral breast-conserving treatment a safe option for early-stage synchronous cancers
  • References
    • Heron DE, Komarnicky LT, Hyslop T, Schwartz GF, Mansfield CM. Bilateral breast carcinoma: risk factors and outcomes for patients with synchronous and metachronous disease. Cancer. 2000;88(12):2739-2750.
    • Intra M, Rotmensz N, Viale G, et al. Clinicopathologic characteristics of 143 patients with synchronous bilateral invasive breast carcinomas treated in a single institution. Cancer. 2004;101(5):905-912.

Primary Lymphoma of the Breast

  • Current management strategies for primary breast lymphoma are largely based on:
    • Results published in small, single-institution series
  • Historically, primary breast lymphoma was treated with:
    • Modified radical mastectomy with or without adjuvant chemotherapy or radiotherapy:
      • Treatment strategies had focused on anthracycline-based chemotherapy with or without consolidative radiotherapy
  • Current treatment guidelines dictate:
    • That surgery should be reserved for
      • Obtaining adequate tissue for diagnosis, if needed, and:
        • Should not be regarded as a therapeutic modality in the treatment of this disease:
          • In several series, surgery has been associated with worse outcomes
      • Some histologies may be amenable to localized surgery so understanding the disease pathology is important in decision making
      • While axillary nodal status is an important prognosticator:
        • There are no definitive guidelines regarding how to stage the axilla:
          • In addition to CT scan, axillary ultrasound with percutaneous biopsy is frequently used
      • Sentinel lymph node biopsy has not been studied in this malignancy and currently has no role in its workup
  • References
    • Aviles A, Delgado S, Nambo MJ, Neri N, Murillo E, Cleto S. Primary breast lymphoma: results of a controlled clinical trial. Oncology. 2005;69(3):256-260.
    • Aviv A, Tadmor T, Polliack A. Primary diffuse large B-cell lymphoma of the breast: looking at pathogenesis, clinical issues and therapeutic options. Ann Oncol. 2013;24(9):2236-2244.
    • el-Ghazawy IM, Singletary SE. Surgical management of primary lymphoma of the breast. Ann Surg. 1991;214(6):724-726.
    • Jennings WC, Baker RS, Murray SS, et al. Primary breast lymphoma: the role of mastectomy and the importance of lymph node status. Ann Surg. 2007;245(5):784-789.

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Metaplastic Carcinoma of the Breast

  • Metaplastic carcinoma of the breast:
    • Tends to present in patients age 60 years and older
      • Is rare in young or premenopausal women
    • Compared to IDC:
      • It has been shown to present in a higher proportion of African Americans and Hispanics
  • Metaplastic breast cancer (MBC):
    • Is more likely to be high grade but axillary node negative at presentation
    • The mean tumor size:
      •  Is about 4 cm
    • Patients with this diagnosis are also more likely to receive chemotherapy and undergo mastectomy
    • Recurrence tends to be locoregional or pulmonary:
      • And is associated with a high mortality rate
  • Future directions may include immunotherapies:
    • As MBC has a unique histology, demonstrating increased PDL-1:
      • Which may make it a good candidate for targeted therapy:
        • More research is needed on this unique tumor phenotype
  • References
  • Pezzi CM, Patel-Parekh L, Cole K, Frank J, Klimberg VS, Bland K. Characteristics and treatment of metaplastic breast cancer: analysis of 892 cases from the National Cancer Data Base. Ann Surg Oncol. 2006;14(1):166-173.
  • Schwartz T, Mogal H, Papageorgiou C, Veerapong J, Hsueh EC. Metaplastic breast cancer: histologic characteristics, prognostic factors and systemic treatment strategies. Exp Hematol Oncol. 2013;(1)2:31.
  • Haque W, Teh BS. Current practice and future directions for metaplastic breast cancer. Ann Surg Oncol. 2018;25(Suppl 3):630-631.

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