Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Based on the classic paper by Norris and others:
  • The development of the parathyroid glands in humans can be divided into five stages:
    • Preprimordial stage
    • Early primordial stage
    • Branchial complex stage
    • Isolation stage
    • Definitive form stage

• The preprimordial stage:
  • Indicates the period between the formation of the pharynx and the earliest appearance of a recognizable parathyroid anlage:
    • During this stage, at 4 mm to 8 mm in length:
      • The third and fourth pharyngeal pouches show a slight dorsal extension.
    • The third pouch:
      • Which has the form of a tubelike lateral expansion of the primitive pharynx:
        • Makes contact with the ectoderm of the pharyngeal cleft and then continues its growth in a downward and ventral direction.
• The early primordial stage:
  • When the embryo is about 9 mm in length:
    • The parathyroid tissue can be recognized
  • Proliferation and differentiation of large, clear cells occur in the third and fourth pouches:
    • Resulting in:
      • A thickening of the third and fourth pouches
      • Formation of a budlike nodule of the fourth pouch
• The branchial complex stage:
  • The derivatives of the third and fourth pharyngeal pouches become separated from each other to reach independent positions. 
  • During the early phase of this stage:
    • The pharyngeal pouches are still joined to the primitive pharynx by pharyngobranchial ducts:
      • These latter, subsequently, narrow and finally divide:
        • Which determines the definitive separation of the third and caudal pharyngeal complexes from the primitive pharynx.
    • At the beginning of this stage:
      • The primordial thymus and PIII are intimately joined:
        • Subsequently, the thymus begins a period of rapid ventral growth:
          • Until the lower pole comes in contact with the pericardium.
        • On the other hand, the growth of the PIII is not as rapid, and it remains a budlike projection from the superior end of the thymus cord.
        • Finally, it takes a sphere shape, intimately attaching to the upper pole of the thymus cord.
      • The position of the caudal pharyngeal complex in relation to the median anlage of the thyroid depends on:
        • Changes in form, size, and position of the rapidly growing lateral lobe of the median thyroid.
        • During this stage, the PIV rudiment is still attached to lateral thyroid body. 
        • When the embryo is 13 mm to 14 mm long, the PIII and PIV migrate together with the thymus and ultimobranchial bodies, respectively.
        • Because of the extension of the cervical spine and the descent of the heart and great vessels:
          • The complex derived from the third branchial (parathymus) is drawn toward the superior mediastinum and, thus:
            • Migrates in a medial and caudal direction through the entire length of the embryonic neck to reach its final position, and separation of the PIII from the thymus begins.
        • The PIV follows the thyroid migration of the ultimobranchial bodies, which travel toward the lateral part of the main median thyroid rudiment:
          • Their descent in the neck is thus relatively limited. 
          • They remain in contact with the posterior part of the middle third of the thyroid lobes.
    • The complex branchial stage ends when the embryo is approximately 18 to 20 mm in length.

• The isolation stage:
  • Is characterized by the separation of the parathyroid rudiments (PIII and PIV) from the other elements of the third (the thymus) and of the caudal pharyngeal complexes (the ultimobranchial bodies), respectively.
  • The isolation of the parathyroid glands is usually accomplished when the embryo is 20 mm in length. 
  • After completing the descent through the neck:
    • The PIII increases in size and separation from the thymus occurs, because of cephalic regression of the last.
    • PIII is thus abandoned at the level of the anterior or posterolateral region of the inferior poles of the thyroid lobes, or at the level of the thyrothymic ligaments, vestigial structures indicative of their former connections.
  • The two elements of the caudal pharyngeal complex also grow separately and are conjoined by a connecting stalk:
    • The interruption of this stalk, determining the isolation of the PIV, occurs once the lateral and the median thyroid become incorporated. 
    • The final position of the PIV in relation to the thyroid gland is determined by the place at which the inclusion of the ultimobranchial body (lateral thyroid element) occurs.
• The definitive form stage:
  • Indicates the period from the end of the isolation to the time when the parathyroids assume their definitive form.

Rodrigo Arrangoiz MS, MD, FACS a head and neck surgeon / endocrine surgeon / surgical oncologist and is a member of Mount Sinai Medical Center:

• He is an expert in the management parathyroid diseases.

• Publication on parathyroid embryology and anatomy:

  • Parathyroid Embryology, Anatomy, and Pathophysiology of Primary Hyperparathyroidism:

    • Arrangoiz, R., Cordera, F., Caba, D., Juárez, M.M., More- no, E. and Luque, E. (2017) Parathyroid Em- bryology, Anatomy, and Pathophysiology of Primary Hyperparathyroidism. International Journal of Otolaryngology and Head & Neck Surgery, 6, 39-58.https://doi.org/10.4236/ijohns.2017.64007

      • https://file.scirp.org/pdf/IJOHNS_2018071317420392.pdf

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

#Arrangoiz

#Teacher

#Surgeon

#Cirujano

#ThyroidExpert

#ThyroidSurgeon

#CirujanodeTiroides

#ExpertoenTiroides

#ExpertoenParatiroides

#Paratiroides

#Hiperparatiroidismo

#PapillaryThyroidCancer

#SurgicalOncologist

#CirujanoOncologo

#CancerSurgeon

#CirujanodeCancer

#HeadandNeckSurgeon

#CirugiaEndocrina

#EndocrineSurgery

#CirujanodeCabezayCuello

• Clinical hallmarks of Paget’s disease of the breast include:
  • Scaling
  • Erythema
  • Ulceration of the nipple:
    • Sometimes extending to the areola
• Because the main differential diagnosis for this clinical presentation is eczema:
  • A short course of topical steroids was an appropriate initial step:
    • Failure to resolve should prompt tissue biopsy by punch or wedge technique and not additional steroid therapy
• Pathology:
  • Revealing adenocarcinoma cells within the epidermis (Paget cells):
    • Confirms the diagnosis
• HER2 amplification is found in 60% to 90% of cases of Paget’s disease of the breast:
  • But the patient should be fully evaluated prior to making decisions regarding the need for targeted therapy
• Appropriate diagnostic imaging includes:
  • Mammography
  • Ultrasound
  • Breast MRI (when indicated)
    • As Paget’s disease is associated with an underlying malignancy 85% of the time
• The appropriate surgical management of Paget’s disease is:
  • Breast conservation with central mastectomy (resection of the nipple-areolar complex) with resection of the primary tumor and irradiation or mastectomy, and not duct exploration
• References
  • Chen CY, Sun LM, Anderson BO. Paget disease of the breast: changing patterns of incidence, clinical presentation, and treatment in the U.S. Cancer. 2006;107(7):1448-1458.
  • Killelea BK, Chagpar AB, Horowitz NR, Lannin DR. Characteristics and treatment of human epidermal growth factor receptor 2 positive breast cancer: 43,485 cases from the National Cancer Database treated in 2010 and 2011. Am J Surg. 2017;213(2):426-432.
  • Caliskan M, Gatti G, Sosnovskikh I, et al. Paget’s disease of the breast: the experience of the European Institute of Oncology and review of the literature. Breast Cancer Res Treat. 2008;112(3):513-521.

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #MountSinaiMedicalCenter #MSMC #Miami #Mexico #BreastCancer

• The Society of Surgical Oncology-American Society for Radiation Oncology (SSO-ASTRO) 2014 Consensus Guidelines:
  • Regarding margins of resection for invasive carcinoma of the breast:
    • Recommend the use of “no ink on tumor” as the standard of care:
      • For patients with invasive cancer:
        • Even with associated ductal carcinoma in situ (DCIS), are treated according to these guidelines
• In a meta-analysis of 33 studies including 32,363 patients:
  • Odds of local recurrence were associated with margin status of positive vs. negative:
    • But not decreased with increasing margin distance for patients with invasive carcinoma
  • The study reported that rates of in-breast tumor recurrence are twice as high with positive margins:
    • Regardless of tumor biology, radiation boost, or endocrine therapy
      • There was no evidence that wide margins reduce recurrence:
        • Even in patients with extensive intraductal component
• The American Society of Clinical Oncology (ASCO) guidelines:
  • Recommend consideration of post-excision mammography to document adequate resection in patients with microcalcifications
• References
  • Moran MS, Schnitt SJ, Giuliano AE, et al. SSO-ASTRO consensus guideline on margins for breast-conserving surgery with whole breast irradiation in stage I and II invasive breast cancer. Int J Radiat Oncol Biol Phys. 2014;88(3):553-564.
  • Houssami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol. 2014;21(3):717-730.
  • Buchholz TA, Somerfield MR, Griggs JJ, et al. Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/American Society for Radiation Oncology consensus guideline. J Clin Oncol.2014;32(14):1502-1506.

• Key Points:
  • An updated analysis from RELATIVITY-047 trial:
    • After a median follow-up of 25.3 months continues to show a significant PFS benefit for the nivolumab / relatlimab combination over nivolumab alone in the first-line treatment of patients with unresectable or metastatic melanoma:
      • While no new safety findings were noted
  • Although investigators observed improvements in melanoma-specific survival and OS:
    • These did not meet the prespecified bar of significance
  • Analyses of outcomes with subsequent therapy suggested a continued benefit with nivolumab and relatlimab beyond initial treatment and first progression
• The dual-checkpoint inhibitor combination of nivolumab and relatlimab continues to provide a significant efficacy benefit over nivolumab alone in patients with previously untreated unresectable or metastatic melanoma:
  • According to an update from the randomized, double-blind, phase 2/3 RELATIVITY-047 trial presented during the 2023 ASCO Annual Meeting
  • After a median follow-up of 25.3 months:
    • Nivolumab and relatlimab continued to demonstrate a consistent, significant improvement over nivolumab in progression-free survival (PFS; HR 0.81, 95% CI [0.67, 0.97]) and a trend toward improved overall survival (OS; HR 0.82, 95% CI [0.67, 1.02])
  • An exploratory analysis found a numerical improvement in melanoma-specific survival with nivolumab and relatlimab versus nivolumab (HR 0.77, 95% CI [0.61, 0.97])
    • This updated analysis confirms previous efficacy and safety data reported in the trial

• Key Points:
  • In patients with stage IIB / IIC melanoma:
    • Adjuvant pembrolizumab continued to demonstrate significant improvements over placebo in DMFS and RFS:
      • After a median follow-up of 39.4 months
  • Whereas an earlier analysis suggested that there may be a lesser benefit with pembrolizumab in patients with stage IIC disease:
    • This was not observed with additional follow-up
  • The 3-year RFS rates were:
    • 76.2% with pembrolizumab and 63.4% with placebo
  • In patients with stage IIB / IIC melanoma, adjuvant pembrolizumab provides a:
    • 41% reduction in the risk of distant metastasis or death
    • 38% reduction in the risk of recurrence or death:
      • According to an update from the KEYNOTE-716 trial presented at the 2023 ASCO Annual Meeting
• KEYNOTE-716:
  • Was the first study to demonstrate a benefit for relapse-free survival [RFS] as well as distant metastasis-free survival [DMFS]:
    • Using anti–PD-1 immunotherapy (pembrolizumab) in patients with high-risk, non-nodal, stage IIB / IIC melanoma:
      • This updated analysis support[s] the durability of these findings over time
  • After a median follow-up of 39.4 months:
    • Adjuvant pembrolizumab continued to demonstrate significant improvements over placebo in DMFS (HR 0.59, 95% CI [0.44, 0.79]) and RFS (HR 0.62, 95% CI [0.49, 0.79]), consistent with prior reports
  • The investigators concluded that the results of this analysis support the use of pembrolizumab as adjuvant therapy in patients with resected stage IIB or IIC melanoma:
    • The effect of adjuvant anti–PD-1 antibodies is similar across stages of melanoma from stage IIB through stage IV resected disease
• Having therapeutic options now validated in this setting is a big step forward for our patients and that the results of this final DMFS analysis confirm the important benefit observed in the previous DMFS report and further consolidate the role of pembrolizumab in this setting

• In patients with melanoma:
  • Stage IIB / IIC disease is associated with a high risk of relapse
  • 5-year melanoma-specific survival outcomes are similar to those for patients with stage IIIB disease:
    • Highlighting a need for additional treatment strategies for these patients
• The randomized, phase 3 KEYNOTE-716 trial:
  • Was undertaken to evaluate the efficacy and safety of adjuvant pembrolizumab in patients with:
    • Newly diagnosed resected stage IIB / IIC melanoma with a negative sentinel lymph node biopsy
• A total of 967 patients were randomly assigned to pembrolizumab or placebo:
  • Administered every 3 weeks for up to 17 cycles
• In previous analyses, pembrolizumab demonstrated significant efficacy improvements in RFS and DMFS over placebo
  • In the last update, after a median follow-up of 27.4 months, median DMFS was not reached in either arm (HR 0.64, 95% CI [0.47, 0.88]; P = .0029)
• In the current update:
  • After a median follow-up of 39.4 months, median DMFS was still not reached in either arm, and there was a consistent benefit with pembrolizumab (HR 0.59, 95% CI [0.44, 0.79];)
• The RFS benefit with pembrolizumab was also maintained in the current follow-up:
  • The 3-year RFS rates were 76.2% with pembrolizumab and 63.4% with placebo, and median RFS was not reached in either arm (HR 0.62, 95% CI [0.49, 0.79])
• The DMFS and RFS benefit with pembrolizumab was observed in both stage IIB / IIC melanoma:
  • An earlier analysis suggested that there may be a lesser benefit with pembrolizumab in patients with stage IIC disease:
    • This was no longer observed with additional follow-up
  • We now see that this discrepancy has been resolved with longer follow-up:
    • The overall impact of pembrolizumab as adjuvant therapy appears to be similar across stages
• Safety outcomes were similar to those reported in the previous analyses
• Grade 3/4 treatment-related adverse events (AEs) occurred in 17.2% of patients receiving pembrolizumab and 5.1% of those receiving placebo; grade 3/4 immune-related AEs and infusion reactions occurred in 11.0% and 1.2% of patients, respectively.
• Treatment-related AEs led to discontinuation in 15.9% of patients receiving pembrolizumab and 2.5% receiving placebo
• Investigators noted that the overall survival analyses are forthcoming
• Next Steps
  • Looking ahead, one related area of discussion revolves around the role of sentinel lymph node biopsy for patients with melanoma:
    • If the patient has a deep primary melanoma, adjuvant pembrolizumab should be discussed with the patient whether the nodes are involved or not:
      • However, this remains an area of debate
• Patient selection beyond the current AJCC classification will be key for the future:
  • To identify patients with a particularly favorable prognosis for whom treatment could be spared and to identify those patients with a poor prognosis who would benefit from additional therapy:
    • Biomarker studies are underway to guide us in this important next step
• Another area of ongoing research is the potential use of combination immunotherapy regimens in the adjuvant setting:
  • Among the ongoing trials are:
    • KEYVIBE-010:
      • Evaluating pembrolizumab plus the anti-TIGIT antibody vibostolimab in patients with high-risk resected stage IIB, IIC, III, and IV melanoma
    • KEYNOTE-942:
      • Evaluating pembrolizumab plus a personalized neoantigen therapy (V940) for high-risk melanoma
• References
  • Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022;399(10336):1718-1729.
  • Long GV, Luke JJ, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2022;23(11):1378-1388.
  • Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-492.
  • Egger ME, Bhutiani N, Farmer RW, et al. Prognostic factors in melanoma patients with tumor-negative sentinel lymph nodes. Surgery. 2016;159(5):1412-1421.

• Based on initial results from the monarchE trial:
  • The FDA approved abemaciclib plus endocrine therapy (tamoxifen or an aromatase inhibitor) for adjuvant treatment of:
    • Hormone receptor–positive
    • HER2-negative (HER2-)
    • Node-positive
    • Early breast cancer in patients at high risk of recurrence and with a Ki-67 score of 20% or higher (as determined by an FDA-approved test)
• This marked the first approval of a CDK4/6 inhibitor:
  • For use as adjuvant treatment of breast cancer
• The limitation of the indication to a Ki-67 score of at least 20% has generated some confusion and controversy in the field:
  • Especially in light of the subsequent guidance from the American Society of Clinical Oncology and the National Comprehensive Cancer Network:
    • Which both recommend patient selection for adjuvant abemaciclib plus endocrine therapy in accordance with the trial design

• Patients diagnosed with estrogen receptor (ER)-positive breast cancer receive standard-of-care adjuvant treatment:
  • However, patients can experience disease recurrence:
    • With many recurrences occurring within the first 5 years
• When disease recurrence does occur, it is often at a more advanced stage when the disease may be incurable:
  • Therefore, it is critical to prevent recurrences to better reach the original curative intent of treatment
• Prior research demonstrated that ribociclib plus endocrine therapy:
  • Yielded significant improvements in overall and progression-free survival in patients with HR-positive / HER2-negative advanced breast cancer:
    • Based on that, NATALEE was designed to evaluate the combination in patients with early-stage disease
• Another CDK4/6 inhibitor, abemaciclib, is U.S. Food and Drug Administration (FDA) approved for adjuvant treatment of adult patients with HR-positive / HER2-negative, node-positive early breast cancer at high risk of recurrence
• What NATALEE now does:
  • If the FDA acknowledges the data for registration:
    • It enlarges the patient population who will have access to a CDK4/6 inhibitor

• 2023 ASCO ANNUAL MEETING – Key Points:
  • NATALEE was designed to evaluate the combination of ribociclib plus endocrine therapy in patients with early breast cancer
  • There was a trend toward improved OS with ribociclib plus endocrine therapy, and a 3-year treatment duration of ribociclib 400 mg showed a predictable safety profile that was more favorable than the 600 mg dose of ribociclib used in the metastatic setting
  • Follow-up data is still being collected, and further quality-of-life results will be provided later in the year
  • The combination of CDK 4 / 6 inhibitor ribociclib plus endocrine therapy significantly improved invasive disease-free survival (iDFS) compared with endocrine therapy alone in a broad population of patients with stage II or III HR-positive /HER2-negative early breast cancer:
    • According to results of the second interim efficacy analysis of the phase 3 NATALEE study
  • With a median follow-up for iDFS of 27.7 months:
    • The risk for invasive disease was reduced by 25.2% with ribociclib plus endocrine therapy compared with endocrine therapy alone (HR 0.748, 95% CI [0.618, 0.906]; P = .0014)
  • The 3-year iDFS rate was 90.4% for the combination therapy compared with 87.1% for endocrine therapy alone:
    • Which is an absolute difference of 3.3%
  • These results support ribociclib plus endocrine therapy as a new and effective treatment of choice for a broad population of at-risk patients with stage II or III HR-positive / HER2-negative early breast cancer, which is easy to identify in clinical practice

A 61-year-old woman presented to the hospital with dysphagia to solid foods and dyspnea on exertion that has been worsening over the last 1-2 months. Past medical history includes hypothyroidism from Hashimoto’s thyroiditis on levothyroxine, and T2DM on metformin (well-controlled). Physical exam is notable for significant diffuse thyroid enlargement, not rock hard or tender thyroid, positive Pemberton’s sign, hoarse voice (but she is able to speak in full sentences). Biochemical testing revealed normal CBC, CMP, and a TSH of 5.02 uIU/mL (normal 0.5-5.7). Thyroid ultrasound and neck CT are shown below.

What Is the Most Likely Cause for This Finding?

1. Anaplastic thyroid carcinoma
2. Fibrous thyroiditis
3. Subacute thyroiditis
4. Diffuse large B-cell lymphoma
5. Mucosa-associated lymphoid tissue (MALT) lymphoma

Correct Answer: Diffuse large B-cell lymphoma

This patient, with a history of Hashimoto’s thyroiditis, presents with a rapidly enlarging thyroid mass that has caused dysphagia and dyspnea on exertion. In that clinical context, the most likely etiology of her symptoms is thyroid lymphoma, and the most common type of primary thyroid lymphoma is diffuse large B-cell lymphoma (DLBCL). Thyroid lymphoma is a rare malignancy representing less than 5% of all thyroid cancers. Hashimoto’s thyroiditis is a well-established risk factor, as patients with Hashimoto’s thyroiditis have a 60 times higher risk of developing primary thyroid lymphoma, compared to the general population. On ultrasound, thyroid lymphoma will appear with diffuse enlargement of the thyroid in a uniform and very hypoechoic pattern, like the one presented here. Usually cross-sectional imaging will be needed, and in this case, there was the apparent narrowing of the upper trachea.

DLBCL usually appears malignant on cytology, while MALT lymphoma can be more subtle, which might result in an Atypia of Undetermined Significance (AUS) by the Bethesda classification. If lymphoma is clinically suspected, it is very important to obtain material for flow cytometry with the biopsy. Treatment of thyroid lymphomas depends on the subtype and staging of the tumor. Usually R-CHOP (rituximab- cyclophosphamide, doxorubicin, vincristine, prednisolone) is used, and no thyroidectomy is recommended.

This patient did not appear to demonstrate hyperthyroidism, nor had a tender thyroid gland, so subacute thyroiditis is unlikely. Fibrous thyroiditis (or Riedel’s thyroiditis) will present with a very hard, fixed goiter. Anaplastic thyroid carcinoma would usually present with asymmetric enlargement of the thyroid, as there is usually a dominant nodule that does not involve the thyroid gland in its entirety