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• Diabetic mastopathy, or lymphocytic lobulitis:
  • Is a benign condition found in premenopausal women:
    • With long-standing type 1 diabetes mellitus
  • Patients usually present with:
    • A firm, painless, irregular, suspicious mass in one or both breasts
  • Mammograms often show:
    • Dense fibroglandular tissue but no discrete mass
  • Ultrasound usually shows:
    • An ill-defined hypoehoic area with shadowing
  • Core needle biopsy:
    • Is the preferred technique to make the diagnosis
  • The pathologic findings are typically:
    • Glandular atrophy
    • Lymphocytic / mononuclear perivascular inflammation:
      • Which is predominantly B-cell
    • Dense, often keloid-like fibrosis:
      • With or without epithelioid-like fibroblasts
  • If the lesion is well-sampled and the pathology is concordant with the imaging:
    • There is no need for excision because it is not a premalignant lesion
  • In fact, up to 60% of diabetic mastopathy recurs after excision:
    • Therefore, surgical excision is not recommended
  • The etiology may be:
    • An autoimmune reaction:
      • To accumulated matrix related to hyperglycemia
  • Once diagnosed:
    • Patients should be aware of changes in their breasts and have any new lumps evaluated
  • Well-controlled blood sugar:
    • Is advocated as diabetic mastopathy often presents in patients with other complications of diabetes such as:
      • Retinopathy
      • Neuropathy
      • Nephropathy
    • Otherwise, there is no known treatment
• References:
  • Camuto PM, Zetrenne E, Ponn T. Diabetic mastopathy: a report of 5 cases and a review of the literature. Arch Surg. 2000;135(1):1190-1193.
  • Neetu G, Pathmanathan R, Weng NK. Diabetic mastopathy: a case report and literature review. Case Rep Oncol. 2010;3(2):245-251.
  • Thorncroft K, Forsyth L, Desmond S, Audisio RA. The diagnosis and management of diabetic mastopathy. Breast J. 2007;13(6):607-613.

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• Histologic section shows non-atypical breast ducts and lobules scattered amongst fibrofatty stroma:
  • With a circumscribed border (arrow shows thin capsule):
    • These features are characteristic of mammary hamartoma:
      • Alternately termed:
      • Fibroadenolipoma
        • Adenolipoma)
• Hamartomas:
  • Are characterized by normal breast elements in disordered distribution:
    • May harbor other benign findings such as:
      • Pseudoangiomatous stromal hyperplasia (PASH)
      • Apocrine metaplasia
  • The so-called “myoid hamartoma” includes”:
    • Smooth muscle
  • It may be very difficult to recognize and diagnose mammary hamartomas on core biopsy, given the normal constituents:
    • Yet the radiologic appearance of hamartoma is characteristic and is said to resemble “breast within breast”

• Hamartomas are benign breast lesions
• References:
  • Schnitt SJ, Collins L. Biopsy Interpretation of the Breast. 3^rd edition. Philadelphia, PA: Wolters Kluwer, 2018:196-198.
  • Tan PH, Tse G, Lee A, et al. Fibroepithelial tumours. In: Lakhani SR, Ellis IO, Schnit SJ, Tan PH, van de Vijver MJ. eds. WHO Classification of Tumours of the Breast. Lyon: IARC Press, 2012: 147.
  • Tse GM, Tan PH, Lui PC, Putti TC. Spindle cell lesions of the breast–the pathologic differential diagnosis. Breast Cancer Res Treat. 2008;109(2):199-207.
  • Amir RA, Sheikh SS. Breast hamartoma: a report of 14 cases of an under-recognized and under-reported entity. Int J Surg Case Rep. 2016;22:1-4.

• Breast fibromatosis:
  • May occur sporadically or:
    • Less commonly, in patients with a germline syndrome
  • Mutations in the beta-catenin gene (CTNNB1):
    • Are found in about 45% of fibromatosis:
      • Whereas mutations in other components of the same pathway, such as in:
        • The adenomatous polyposis coli gene (APC) or 5q loss occur in about 30%:
          • The APC mutation is associated with Gardner syndrome:
            • Desmoid tumors
            • Osteomas
            • Colon adenomas, and other tumors
          • Familial adenomatous polyposis (FAP1) syndromes

• References
  • Lee A, Gobbi H. Desmoid type fibromatosis In: Lakhani SR, Ellis IO, Schnit SJ, Tan PH, van de Vijver MJ. eds. WHO Classification of Tumours of the Breast. Lyon: IARC Press, 2012:131-132.
  • Schnitt SJ, Collins L. Biopsy Interpretation of the Breast. 3^rd edition. Philadelphia, PA: Wolters Kluwer, 2018: 412-416.
  • Kuba MG, Lester SC, Giess CS, Bertagnolli MM, Wieczorek TJ, Brock JE. Fibromatosis of the breast: diagnostic accuracy of core needle biopsy. Am J Clin Pathol. 2017;148(3):243-250.
  • Kim T, Jung EA, Song JY, Roh JH, Choi JS, Kwon JE, et al. Prevalence of the CTNNB1 mutation genotype in surgically resected fibromatosis of the breast. Histopathology. 2012;60(2):347-56.

• Is a fibroepithelial lesion with rapid growth in an adolescent:
  • The histologic features of:
    • Increased stromal cellularity with pericanalicular architecture:
      • Nodular stroma around non-compressed open duct-like structures)
    • So-called gynecomastoid hyperplasia:
      • Are characteristic of juvenile fibroadenomas
  • Gynecomastoid hyperplasia:
    • Refers to non-atypical epithelial proliferation with tufted architecture
• Phyllodes tumors:
  • Comprise only about 5% of pediatric fibroepithelial neoplasms:
    • Can be difficult to distinguish from juvenile fibroadenomas
  • In the pediatric population:
    • Both juvenile fibroadenomas and phyllodes tumors:
      • May have increased stromal cellularity and rudimentary or focal leaf-like architecture
    • Tan et al:
      • Did not find that focal leaf-like architecture or stromal hypercellularity:
        • Correlated with recurrence in pediatric fibroepithelial lesions
    • Yet other studies suggested that:
      • Tumors with greater than two mitotic figures per 10 high power fields:
        • Have a greater recurrence rate

• Some have used the terms “juvenile” and “giant” fibroadenoma synonymously:
  • While others have used “giant”:
    • To describe particularly large fibroadenomas (> 5 cm)

• References:
  • Tan PH, Tse G, Lee A, et al. Fibroepithelial tumours. In: Lakhani SR, Ellis IO, Schnit SJ, Tan PH, van de Vijver MJ,. eds. WHO Classification of Tumours of the Breast. Lyon: IARC Press, 2012:142-143.
  • Schnitt SJ, Collins L. Biopsy Interpretation of the Breast. 3^rd edition. Philadelphia, PA: Wolters Kluwer, 2018: 180-193.
  • Tay TK, Chang KT, Thike AA, Tan PH. Paediatric fibroepithelial lesions revisited: pathological insights. J Clin Pathol. 2015;68(8):633-641.
  • Krings G, Bean GR, Chen YY. Fibroepithelial lesions; The WHO spectrum. Semin Diagn Pathol. 2017;34(5):438-452.

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• Iliopectineal Arch:
  • This is a medial thickening of the iliopsoas fascia:
    • Deep to the inguinal ligament
• The surgeon does not directly use this arch:
  • But it is important as the junction of a number of structures of the groin
• These structures are:
  • The insertion of fibers of the external oblique aponeurosis
  • The insertion of fibers of the inguinal ligament
  • The origin of part of the internal oblique muscle
  • The origin of part of the transversus abdominis muscle
  • Part of the lateral attachment of the iliopubic tract
  • It contributes also to the lateral wall of the femoral sheath

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• Background:
  • Papillary thyroid micro-carcinomas (PTMCs):
    • Are well-differentiated tumors with an indolent nature and excellent outcome
  • The American Thyroid Association (ATA) guidelines:
    • Have endorsed active surveillance as a safe alternative to surgery for the management of PTMC
  • Data from the Kuma Hospital, Japan:
    • Have reported 5- and 10-year cumulative rates of:
      • Tumor enlargement:
        • Defined as a maximal tumor diameter increase of greater than 3 mm:
          • At 4.9% and 8.0%, respectively
      • Lymph node (LN) metastasis rates were:
        • 1.7% and 3.8%
    • Based on these findings, clinicians have used an:
      • Increase of greater than 3 mm in maximal tumor diameter or the presence of new cervical LN metastasis:
        • As a threshold for surgical intervention
      • However, there are limited data on clinical features that can reliably differentiate which PTMC patients will go on to develop clinically significant disease progression:
        • This would allow better risk stratification and tailoring of PTMC management
• Methods:
  • Clin Thyroidol 2021;33:490–492:
    • Is multicenter, retrospective cohort study of patients with PTMCs undergoing active surveillance from three tertiary medical centers in Korea
  • All patients had uni-focal tumors measuring less than 10 mm, cytologically diagnosed as suspicious for malignancy or confirmed malignant
  • Physical exam and ultrasound follow-up were done every 6 to 12 months
  • Fine-needle aspiration and thyroglobulin needle washout:
    • Was performed on new suspicious LNs found during active surveillance
  • Exclusion criteria included:
    • Undergoing surgery instead of active surveillance and a follow-up duration of less than 3 years
  • The primary outcome of the study was disease progression during active surveillance:
    • Which was defined as:
      • An increase in maximal tumor diameter greater than 3 mm
      • Tumor volume (TV) increase of greater than 50%
      • Tumor volume doubling time (TVDT) < 5 years
      • Development of cervical LN metastasis
  • A Cox proportion-al-hazards model was used to evaluate risk factors for disease progression
• Results:
  • The 326 patients included had a median follow-up of 4.9 years (IQR, 3.4–6.3)
  • Disease progression was confirmed in 26 patients (8.0%; 95% CI, 5.0–10.9):
    • 17 of whom (5.2%; 95% CI, 2.7–7.6) had a maximal tumor diameter increase of greater 3 mm after a median of 4.0 years of follow-up
      • Nine of whom (2.8%; 95% CI, 1.0–4.5) developed new LN metastasis after a median of 2.2 years of follow-up:
      • Lateral neck metastasis developed in two of the 9 patients who developed new LN metastasis
      • Seven had central neck LN metastasis
    • All patients with LN metastasis had an increase of tumor diameter greater than 3 mm
    • TV greater 50% was seen in:
      • 94 patients, with 3 (3.2%) developing new LN metastasis
        • The rate of new LN metastasis in TVDT less than 5 years:
          • Was 7.4%
  • Univariate and multi-variate analyses showed that TVDT less than 5 years was:
    • An independent risk factor for LN metastasis:
      • HR, 6.51; 95% CI, 1.73–24.50; P = 0.002
• Conclusions:
  • TVDT less than 5 years:
    • Was an independent risk factor:
      • For PTMC tumor growth and development of new LN metastasis
• Active surveillance for PTMC in appropriately selected patients is a safe and viable treatment method
• The development of cervical LN metastasis:
  • Is an important clinical outcome that:
    • Requires conversion from an active surveillance approach to a surgical one
• In this study Clin Thyroidol 2021;33:490–492:
  • The authors investigate several tumor kinetic parameters as markers to predict disease progression in PTMC
  • The authors concluded that TVDT less than 5 years:
    • May be a useful predictor for identifying patients who may be at risk for developing clinically significant disease progression
  • However, the application of these results in practice may require a better understanding of estimates of prediction
  • Using the study’s data about the association between TVDT and LN metastasis:
    • We can calculate that the accuracy of TVDT less than 5 years to predict LN metastasis:
      • Is low – sensitivity 56% / specificity 80%:
        • Which corresponds to a positive predictive value of 8%:
          • Of 100 patients followed with active surveillance for PTMC who experience TVDT < 5 years, only 8 will have LN metastasis
      • In practice, this means that for most patients who experience TVDT < 5 years:
        • The probability of finding LN metastasis is still low
  • Nevertheless, this information about the association of tumor kinetics with disease progression could help:
    • Recalibrate expectations, follow-up times, and informed decision-making with patients:
      • For instance, a patient considered ideal for active surveillance may be considered not ideal or appropriate if TVDT < 5 years occurs during the initial years of follow-up
  • This and other studies highlight the need for future research on the role of tumor kinetic parameters in active surveillance risk stratification
• References:
  • Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumber M, et al. 2016 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26:1–131.
  • Jin M, Kim HI, Ha J, Min JJ, Kim WG, Lim DJ, Kim TY, Chung JH, Shong YK, Kim TH, Kim WB 2021 Tumor volume doubling time in active surveillance of papillary thyroid microcarcinoma: A multicenter cohort study in Korea. Thyroid. Epub 2021 Aug 3.
  • Ito Y, Uruno T, Nakano L, Takamura Y, Miya A, Kobayashi K, Yokozawa T, Matsukuza F, Kuma S, Kuma K, Miyauchi A 2003 An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid 13:381–387.
  • Tuttle RM, Fagin JA, Minkowitz G, Wong RJ, Roman B, Patel S, Untch B, Ganly I, Shaha AR, Shah JP, et al. 2017 Natural history and tumor volume kinetics of papillary thyroid cancers during active surveillance. JAMA Otolaryngol Head Neck Surg 143:1015–1020.
  • Brito JP, Ito Y, Miyauchi A, Tuttle RM 2016 A clinical framework to facilitate risk stratification when considering an active surveillance alternative to immediate biopsy and surgery in papillary microcarcinoma. Thyroid 26:144–149.

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• MERAIODE:
  • Dr. Sophie Leboulleux presented the results of MERAIODE:
    • A single-group, phase 2 study examining:
    • Re-differentiation with the MEK inhibitor trametinib followed by radioactive iodine:
      • For metastatic RAS-mutant radioactive iodine-refractory differentiated thyroid cancer
  • Attempts to recruit the sodium iodine symporter (NIS) to the cell surface:
    • Through MEK inhibition and render thyroid cancer cells susceptible to radioactive iodine have shown promise in the past:
      • Particularly in RAS-mutant cases:
        • Where significant uptake can be induced by this approach and tumors regress along with drops in serum thyroglobulin levels and/or radiographic responses]
  • The RAS mutations (NRAS, KRAS, and HRAS):
    • Are the second most frequent mutations in thyroid cancer after BRAF
  • In this part of the study, patients with RAS-mutant radioactive iodine (RAI)–refractory thyroid cancer:
    • Received trametinib 2 mg daily for 42 days after a diagnostic RAI scan
    • Patients then received 150 mCi RAI with rhTSH stimulation
  • Eleven patients were enrolled, of whom 10 received RAI
  • At 6 months after treatment, two patients had partial responses (PRs) by RECIST criteria (the primary end point), but no complete responses (CRs) were observed
  • RAI uptake increased from 30% of this cohort to 60% at 35 days after treatment
  • It may be fair to say, however, that the radiographic response rate was unexpectedly low in this selected cohort:
    • For example, BRAF V600E–mutant cases were also part of the same study, for which the results were presented earlier this year:
      • In that part of the trial, among 24 patients, the radiographic response rate was 38%
  • Although this study helps to further shed light on the use of MEK inhibition followed by RAI therapy in iodine-refractory disease:
    • This strategy remains experimental until more robust data from larger trials become available
• COSMIC 311:
  • The final analysis of COSMIC-311, a randomized, phase 3 study of cabozantinib after failure of at least one tyrosine kinase inhibitor (TKI) in RAI-refractory thyroid cancer was presented by Dr. Jaume Capdevila
  • As reported in the preliminary analysis presented at the ASCO meeting this year:
    • 170 patients were randomly assigned to cabozantinib 60 mg daily and 88 to placebo
    • Progression-free survival (PFS):
      • Was again significantly better in the treatment group:
        • HR, 0.2; 95% CI, 0.15–0.32; P = 0.0001
    • Overall survival, however, was not significantly different:
      • Although no difference had been expected in this trial that allowed crossover at disease progression
    • The response rate was 18% for cabozantinib and 0% for placebo
    • Based on these data, cabozantinib was granted approval by the Food and Drug Administration (FDA) for patients with:
      • RAI-refractory thyroid cancer who have previously had no success with one or more multi-TKI drugs
    • While the results were hardly surprising, the data are important:
      • Since they establish cabozantinib:
        • As an appropriate second-line treatment in RAI-refractory thyroid cancer
      • This FDA approval will affect insurance coverage of the drug
  • The difficult question is what to do with patients with NTREK or RET fusions for whom more specific FDA-approved TKIs are available
  • Given the toxicity of cabozantinib:
    • Which was intense (62% of patients suffered grade 3 or 4 toxicity despite the use of a lower dose of 60 mg daily, as compared with the full 140-mg dose):
      • It is likely that most clinicians would prefer NTREK or RET inhibitors for such cases
• STUDY 211:
  • Study 211, presented by Dr. Matthew Taylor,:
    • Examined whether or not a lower starting dose of lenvatinib (18 mg daily):
      • Would be associated with a better safety profile, while being no less effective than the full-dose regimen (24 mg daily)
  • In the pivotal phase 3 study (SELECT), in which lenvatinib had been used at 24 mg daily:
    • Dose interruptions occurred in 82.4%, and 67.8% of patients required dose reductions owing to side effects
  • Previously presented results of Study 211:
    • Had shown similar response rates at 24 weeks of treatment:
      • 57.3% for the 24-mg dose group and 40.3% in the lower-dose group
  • The data presented at this meeting were an update examining whether or not quality of life (QOL) measures, as assessed by standard questionnaires, were different between the lower and full doses:
    • Surprisingly, this was not the case:
      • QOL deteriorated similarly in both the 24- and 18-mg groups
  • The authors, therefore, drew the conclusion that lenvatinib 18 mg daily should not be recommended as a starting dose:
    • Although the study was carefully conducted and the results appear pretty clear, one could question whether the primary end point for this study (the response rate at 24 weeks) was ideal, since response rate and survival are not necessarily linked
  • While QOL measures may not be so different between the 18-mg and the 24-mg groups:
    • Some might argue that lower doses (such as 10 mg or 14 mg) seem to be much better tolerated and that starting at these levels may actually be a reasonable strategy:
      • With the option to escalate the dose regimen as tolerated
  • Nonetheless, this study adds to the current body of knowledge and is a laudable attempt at reducing the intense toxicities associated with this drug
• While no major breakthroughs were on the docket this year at ESMO, important data were presented that help on the quest to find more and better-tolerated treatment options for advanced thyroid cancers
• References:
  • Leboulleux S, Benisvy D, Taieb D, Attard M, Bournaud C, Terroir M, Al Ghuzlan A, Lamartina L, Schlumberger MJ, Godvert Y Borget I 2021 MERAIODE: A redifferentiation phase II trial with trametinib followed by radioactive iodine for metastatic radioactive iodine refractory differentiated thyroid cancer patients with a RAS mutation. Ann Oncol 32(suppl_5): S1205–S1210.
  • Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, Pentlow KS, Zanzonico PB, Haque S, Gavane S, et al. 2013 Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 368:623–632.
  • Leboulleux S, Do Cao C, Zerdoud S, Attard M, Bournaud C, Benisvy D, Taieb D, Bardet S, Terroir-Cassou-Mounat M, Betrian S, et al. 2021 MERAIODE: A redifferentiation phase II trial with trametinib and dabrafenib followed by radioactive iodine administration for metastatic radioactive iodine refractory differentiated thyroid cancer patients with a BRAFV600E mutation (NCT 03244956). J Endocr Soc 5(Suppl 1):A876.
  • Capdevila J, Robinson B, Sherman SI, Jarzab B, Lin C, Vaisman F, Hoff AO, Hitre E, Bowles DW, Sen S, et al. 2021 Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: Updated results from the phase III COSMIC-311 trial and prespecified subgroup analyses by prior therapy. Ann Oncol 32(suppl_5):S1283–S1346.
  • Taylor MH, Leboulleux S, Panaseykin S, Konda B, de La Fouchardiere C, Hughes BGM, Gianoukakis AG, Park YJ, Romanov I, Krzyzanowska MK, et al. 2021 Health-related quality-of-life (HRQoL) analyses from study 211: A phase 2 study in patients (pts) with radioiodine-refractory differentiated thyroid cancer (RR-DTC) treated with 2 starting doses of lenvatinib (LEN). Ann Oncol 32(suppl_5):S1205–S1210.
  • Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, et al. 2015 Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621–630.

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• Optimize Imaging:
  • Use high-quality imaging equipment
• Initial Steps and Objectives:
  • Before starting the dissection:
    • Use the triangle of Calot for orientation
  • Find the cystic duct starting at the triangle of Calot
  • Pull the gallbladder infundibulum laterally to open the triangle of Calot
  • Clear the medial wall of the gallbladder infundibulum
  • Make sure the cystic duct can be traced uninterrupted into the base of the gallbladder
  • Open any subtle tissue plane between the gallbladder and the presumed cystic duct:
    • The real cystic duct may be hidden in there
• Factors that Suggest One may be dissecting the Common Duct instead of the Cystic Duct :
  • The duct when clipped is not fully encompassed by a standard M/L clip (9 mm)
  • Any duct that can be traced without interruption to course behind the duodenum is probably the common bile duct
  • Another unexpected ductal structure is present
  • A large artery is behind the duct:
    • The right hepatic artery runs posterior to the common bile duct
  • Extralymphatic and vascular structures are encountered in the dissection
  • The proximal hepatic ducts fail to opacify on operative cholangiograms

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• Excision is recommended:
  • Because approximately 8% to 17% of radial scars:
    • Will be found to be associated with an adjacent malignant lesion:
      • The risk may be higher with abnormal mammogram findings
• There is no indication for annual breast magnetic resonance screening in a patient with a radial scar
• As a radial scar does not confer an increased risk of developing breast cancer:
  • Chemoprevention with tamoxifen is not indicated
• References:
  • Linda A, Zuiani C, Furlan A, Londero V, Girometti R, Machin P, et al. Radial scars without atypia diagnosed at imaging-guided needle biopsy: how often is associated malignancy found at subsequent surgical excision, and do mammography and sonography predict which lesions are malignant? AJR Am J Roentgenol. 2010;194(4):1146-1151.
  • Hayes BD, O’Doherty A, Quinn CM. Correlation of needle core biopsy with excision histology in screen-detected B3 lesions: the Merrion Breast Screening Unit experience. J Clin Pathol. 2009;62(12):1136-1140.
  • Kennedy M, Masterson AV, Kerin M, Flanagan F. Pathology and clinical relevance of radial scars: a review. J Clin Pathol. 2003;56(10):721-724.
  • Patterson JA, Scott M, Anderson N, Kirk SJ. Radial scar, complex sclerosing lesion and risk of breast cancer. Analysis of 175 cases in Northern Ireland. Eur J Surg Oncol. 2004;30(10):1065-1068.

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