Pathology of BRCA1- and BRCA2-associated Breast Cancers: Known and Less Known Connections.

INTRODUCTION: BRCA1/BRCA2 mutation carriers indefinitely comprise a distinct group of patients with breast cancer (BC), with their tumors displaying specific pathologic characteristics. Although these connections are known, they are not fully elucidated. We therefore sought to investigate the clinicopathologic characteristics and overall survival of Greek patients with BC carrying BRCA1/BRCA2 mutations. PATIENTS AND METHODS: Greek patients with BC diagnosed between 1999 and 2016, fulfilling the National Comprehensive Cancer Network criteria for genetic testing, were analyzed for BRCA1/BRCA2 mutations by Sanger sequencing or by a 94-gene panel. Medical records and pathology reports were retrospectively reviewed to retrieve patient and tumor baseline characteristics. Potential associations with mutation status were assessed using the Fisher exact, Pearson χ2, and Mann-Whitney tests. RESULTS: Of 2096 selected patients with BC, we identified 297 (14.2%) BRCA1 and 88 (4.2%) BRCA2 carriers. The mean age at BC diagnosis was 40 and 42.6 years, respectively (P = .02). Tumor histologic subtypes in BRCA1 and BRCA2 carriers were predominantly ductal (79%) followed by medullary (10%), and ductal (72%) followed by lobular (15%), respectively. A significantly higher percentage of BRCA2 tumors were human epidermal growth factor receptor 2-positive, compared with BRCA1 tumors (21.7% vs. 5.8%; P < .001). Second primary cancer diagnosis was more frequent in BRCA1 compared with BRCA2 mutation carriers (36.2% vs. 10.7%; P < .001), whereas there was no difference in 15-year overall survival (hazard ratio, 0.92; 95% confidence interval, 0.48-1.83; P = .804) between the 2 groups. CONCLUSIONS: These data confirm established observations in the pathology of BRCA-related tumors and provide further insight on the association of rare histologic entities with mutations in these genes, which can be clinically beneficial.

[Radiation therapy in thyroid cancer]. / Place de la radiothérapie externe dans les cancers de la thyroïde.

Anaplastic thyroid cancers represent 1-2% of all thyroid tumours and are of very poor prognosis even with multimodality treatment including external beam radiation therapy. Conversely, differentiated thyroid carcinomas (at least 80% of thyroid cancers) hamper good prognosis with surgery with or without radioiodine and there is hardly any room for external beam radiation therapy. Insular and medullar carcinomas have intermediary prognosis and are rarely irradiated. We aimed to update recommendations for external beam irradiation in these different clinical situations and put in light the benefits of new irradiations techniques. A search of the French and English literature was performed using the following keywords: thyroid carcinoma, anaplastic, chemoradiation, radiation therapy, surgery, histology and prognostic. Non-mutilating surgery (often limited to debulking) followed by systematic external beam radiation therapy is the standard of care in anaplastic thyroid cancers (hyperfractionated-accelerated radiation therapy with low-dose weekly doxorubicin with or without cisplatin if possible). Given anaplastic thyroid cancers' median survival of 10 months or less, neoadjuvant and adjuvant chemotherapy may also be discussed. Ten-year survival rates for patients with papillary, follicular and Hürthle-cell carcinomas are 93%, 85%, and 76%, respectively. Massive primary incompletely resected iodine-negative disease indicates external beam radiation therapy. Older age (45 or 60-year-old), poor-prognosis histological variants (including tall cell cancers) and insular cancers are increasingly reported as criteria for external beam radiation therapy. Massive extracapsular incompletely resected nodal medullary disease suggests external beam radiation therapy. Radiation therapy morbidity has been an important limitation. However, intensity modulated radiation therapy (IMRT) offers clear dosimetric advantages on tumour coverage and organ sparing, reducing late toxicities to less than 5%. The role of radiation therapy is evolving for anaplastic thyroid cancers using multimodal strategies and new chemotherapy molecules, and for differentiated cancers using minor criteria, such as histological variants, with IMRT becoming a standard of care.

[Differentiated thyroid cancer -- 2009]. / Differenciált pajzsmirigyrák -- 2009.

Three years ago continental guidelines were published referring management and follow-up of low risk thyroid cancer patients. The aim of this paper is to summarize the changes and new directions in this field. High risk patients require another protocol. Neck ultrasound plays important role in differential diagnosis and in detecting recurrences. Some new ultrasound techniques are discussed, too. FDG-PET can help to solve the problem of patients having negative scan and increased thyroglobulin level. In recent years there was an expansion of our knowledge about the pathomechanism of thyroid cancer. It appears that genetic alterations frequently play a key role in carcinogenesis. There are molecular methods that allow the detection of these genetic events in thyroid fine needle aspirations samples providing important information for diagnosis, management and prognosis. Instead of diagnostic whole body scanning the posttherapeutic scan became preferable but in high risk cases the diagnostic whole body scintigrams serve useful data. Primary therapy of thyroid cancer is an adequate surgery: total thyreoidectomy and, if necessary, lymph node dissection or limited surgery in selected cases. Nowadays radioguided surgery can help to improve the results. Radioiodine therapy (e.g. rest ablation) proved to be a safe and effective method to complete surgery. It can prevent relapses and results in longer survival. Thyroid hormone withdrawal or recombinant human thyrotropin stimulation can increase thyrotropin level before radioiodine treatment. These two methods have similar success rate of rest ablation but irradiation burden of blood is lower in the case of exogenous stimulation which avoids hypothyroid state and preserves quality of life. Since tumor cells fail to maintain the ability to perform physiological functions they undergo dedifferentiation. Therefore, an important aim is to reactivate some function of differentiated cells, e.g. iodine uptake, production of thyroperoxydase and thyroglobulin. Opportunities for this therapeutic effort are also mentioned. Restoration of iodine uptake enables radioisotope treatment. Until now there has been little interest in the development of new drugs for the treatment of thyroid cancer. However, advances in our understanding of tumor cell biology will lead to a paradigm shift in the therapy that is likely to benefit patients who have high risk disease and who do not almost have any therapeutic option. There are new drugs in clinical trials that appear to be more effective than earlier cytotoxic agents. Probably modern chemotherapy of advanced thyroid cancer will have significant results in the near future.

New therapeutic advances in the management of progressive thyroid cancer.

The spectrum of thyroid cancers ranges from one of the most indolent to one of the most aggressive solid tumors identified. Conventional therapies for thyroid cancers are based on the histologic type of thyroid cancers such as papillary or follicular thyroid cancer (differentiated thyroid cancer (DTC)), medullary thyroid cancer (MTC), or anaplastic thyroid cancer (ATC). While surgery is one of the key treatments for all such types of thyroid cancers, additional therapies vary. Effective targeted therapy for DTC is a decades-old practice with systemic therapies of thyroid stimulating hormone suppression and radioactive iodine therapy. However, for the iodine-refractory DTC, MTC, and ATC there is no effective systemic standard of care treatment. Recent advances in understanding pathogenesis of DTC and development of molecular targeted therapy have dramatically transformed the field of clinical research in thyroid cancer. Over the last five years, incredible progress has been made and phases I-III clinical trials have been conducted in various types of thyroid cancers with some remarkable results that has made an impact on lives of patients with thyroid cancer. Such history-making events have boosted enthusiasm and interest among researchers, clinicians, patients, and sponsors and we anticipate ongoing efforts to develop more effective and safe therapies for thyroid cancer.

Heat shock treatment of tumor lysate-pulsed dendritic cells enhances their capacity to elicit antitumor T cell responses against medullary thyroid carcinoma.

BACKGROUND: In vitro and in vivo studies have shown that dendritic cells (DCs) can stimulate antitumor T cell responses against medullary thyroid carcinoma (MTC). However, despite promising results in selected cases, the clinical efficacy of DC immunotherapy in patients with MTC has been limited. Recently, it has been demonstrated in mice that heat shock enhances the capacity of bone-marrow-derived DCs to stimulate antigen-specific T cells. The aim of our investigations was to evaluate whether heat shock also increases the capacity of human monocyte-derived DCs to stimulate antitumor T cell responses against MTC tumor cells. METHODS: DCs from six patients with metastatic MTC were pulsed with tumor lysate derived from allogeneic MTC tumor cells and were heat shocked for 12 h at 40 C or kept at 37 C. Thereafter, the DCs were matured and cocultured with T cells. Finally, the cytotoxic activity of T cells against MTC tumor cells was measured in vitro. RESULTS: In all patient samples, cytotoxic T cell responses against MTC tumor cells could be induced. Notably, heat-shocked DCs were more potent stimulators of cytotoxic T cell responses than control DCs, with T cells stimulated with heat-shocked DCs displaying a significantly increased cytotoxic activity against MTC tumor cells as compared with T cells stimulated with control DCs. In none of the experiments was a cytotoxic T cell response against unrelated pancreatic tumor cells (PANC-1) observed, using both control and heat-shocked DCs. CONCLUSIONS: Our study shows that heat-shocking DCs may be a valuable strategy to increase the immunostimulatory capacity of DCs used for immunotherapy of MTC.

Radioactive iodine treatment in medullary thyroid carcinoma.

BACKGROUND: Elevated levels of basal and stimulated calcitonin are commonly seen in hereditary and sporadic medullary thyroid cancer (MTC) following total thyroidectomy. The cause of these high levels can be residual thyroid tissue, possibly with C-cell hyperplasia, and/or residual micro-MTC foci. MTC does not have the ability to concentrate radioactive iodine. However, radioactive iodine trapped by thyroid follicular cells may affect the neighbouring parafollicular cells. AIM: To investigate the effect of radioactive iodine treatment as adjuvant therapy to surgery in seven patients with persistent elevation of basal and stimulated calcitonin levels. METHODS: Pentagastrin testing was performed in each case immediately before surgery and at intervals of 6 months over a maximum period of 5 years (range, 44-60 months) after surgery. RESULTS: A significant decrease in basal and stimulated calcitonin levels was observed in three patients whose disease was localized to the thyroid gland at the final visit. In the remaining four patients, who initially had lymph node involvement at surgery, basal and stimulated calcitonin levels were decreased significantly in only one. At follow-up, of the three patients who showed no decrease in basal and stimulated calcitonin levels, two developed further regional lymph node and distant metastases. CONCLUSIONS: In patients with persistently elevated basal and stimulated calcitonin levels, radioactive iodine treatment may be the therapy of choice for C-cell hyperplasia and/or micro-MTC after optimal thyroid surgery, especially if the disease has not spread beyond the thyroid gland.

Treatment of "locally advanced" well-differentiated thyroid carcinomas.

PURPOSE: To analyse thyroid carcinomas having an extrathyroid extension in order to identify the principal prognostic factors and outline an effective therapeutic strategy. METHODS: We selected a sample of 160 patients suffering from locally advanced "well differentiated thyroid carcinoma (T4) who had undergone surgery at the Department of Surgery of University of Rome "La Sapienza". The sample was subdivided into three groups: T4, limited type I, and extensive type II, T4 microcarcinomas. RESULTS: We obtained excellent results with the T4 microcarcinomas, above all in patients under the age of 45, with a 94.5% survival rate, compared with 88% in patients aged over 45. In the extensive type II T4 carcinoma we obtained a survival rate of 29.4% in patients aged over 45 years. CONCLUSIONS: Age, combined with an aggressive histological variant (Sclerosing and tall-cell papillary carcinoma), is an important factor in prognosis. The radicality of surgical excision is considered an important prognostic factor, although the results reported in the literature are contradictory. Aggressive surgery can free from the disease a high percentage of patients over the age of 50 even with T4. We deem it fundamental to perform total thyroidectomy in all advanced cases of thyroid neoplasm and to extend neoplasm excision to the adjacent tissues, even involving justified surgical demolition.

[Treatment of a thyroid neoplasm infiltrating the respiratory-digestive tracts]. / Leczenie raka tarczycy naciekajacego droge oddechowo-pokarmowa.

From 1992 to 1999, 58 thyroid gland operations (41 female and 17 male) were performed in ENT Department of the District Hospital in Rzeszów. In 14 (21.4%) cases (9 female and 5 male) thyroid surgery was done for malignant disorders: papillary carcinoma in 11 (79%) patients, follicular carcinoma in 2 patients and medullary carcinoma in 1 patient. There were neck metastases in 9/14 (64.4%) patients. In 3 cases with papillary carcinoma (all with neck metastases) aerodigestive tract was invaded. One patient had neoplasmatic invasion of the larynx and trachea, one patient had invasion of larynx et pharynx and in one patient tumour invaded the esophageal wall. In those patients radical surgery was done: total thyroidectomy with total laryngectomy and radical neck dissection (2 patients) and subtotal thyroidectomy with conservative neck dissection (1 patient). External beam irradiation and radioactive iodine 131 treatment followed surgery. Two patients are still alive 6 years after the treatment free of disease, and 1 patient died of unrelated causes 3 months after the surgery. Symptoms, diagnostic evaluation and treatment of thyroid papillary carcinoma invading the aerodigestive tract are detailed in paper.

Drug therapy alternatives in the treatment of thyroid cancer.

Therapy of thyroid cancers is based on the removal of the primary disease by surgery, replacement of the hormonal deficiencies and subsequent therapy of the recurrent and metastatic disease. The metabolic characteristics of many thyroid tumors mean that radionuclide techniques have been used in the identification of sites of tumour and their subsequent therapy. Differentiated thyroid cancers, papillary, follicular and mixed papillary follicular, are treated by surgery--usually a total or subtotal thyroidectomy. Postoperatively, patients have thyroxine as a replacement therapy and to suppress thyroid-stimulating hormone production. Radioiodine therapy is often given to ablate the thyroid remnant. This allows (a) adequate follow-up of patients using thyroglobulin measurements and assessment scans as necessary, and (b) further therapy with radioiodine for metastatic disease. Patients with a short effective half-life of radioiodide may require higher activities or pharmacological methods of prolonging the retention half-times of iodine. The use of chemotherapy in this group of tumors is limited and at best provides palliation. The overall prognosis is good for differentiated thyroid cancer; papillary carcinomas have an 80 to 90% 10-year survival, whereas follicular tumors are associated with a 65 to 75% 10-year survival. Medullary carcinomas may be sporadic or familial, and some of the latter form part of a multiple endocrine neoplasia syndrome (MEN). Primary treatment is surgery, and total thyroidectomy is usually recommended since tumours are often multifocal. The use of radiolabelled metaiodobenzylguanidine (MIBG) and 111In octreotide as potential therapeutic agents has been explored and may be potentially useful in palliative care. Chemotherapy is of limited benefit. The 10-year survival for medullary carcinomas is 60 to 70%. Anaplastic tumours of the thyroid are usually aggressive, with a high mortality. Treatment is palliative by surgical debulking; some patients may benefit from local radiotherapy or occasionally chemotherapy. The use of therapeutic doses of radionuclides is well tolerated, although it may be associated with a variety of mostly transient adverse effects, including gastritis, thyroiditis and sialadenitis. Therapy with high activities of radioiodine require radiation protection precautions. Despite retreatment with radioiodine there appear to be no long term effects on the fertility of patients, and healthy children are born to women receiving this treatment. 131I remains perhaps the most specific cancer therapy available today and has few adverse effects. It is difficult to see any marked improvement being developed for differentiated thyroid cancer, with the possible exception of targeted gene therapy.