I find this question a bit more difficult since you have to have clear concepts of pathologic anatomy. In any case, it is possible to exclude by exclusion and by the way the answers are expressed: Answer 2: prophylactic emptying is indicated in the medullary. Answer 4: simply by the way of expressing it, it should already have been ruled out. Answer 5: you already know that calcitonin is used in medullary carcinoma and not in differentiated carcinoma. Answers 1 and 3 are contrary, one recommends completing thyroidectomy and the other does not. The only ones in which complete thyroidectomy is not recommended are microcarcinomas measuring less than 1 cm.

I find this question a bit more difficult since you have to have clear concepts of pathologic anatomy. In any case, it is possible to exclude by exclusion and by the way the answers are expressed: Answer 2: prophylactic emptying is indicated in the medullary. Answer 4: simply by the way of expressing it, [HIDDEN]. Answer 5: you already know that calcitonin is used in medullary carcinoma and not in differentiated carcinoma. Answers 1 and 3 are contrary, one recommends completing thyroidectomy and the other does not. The only ones in which complete thyroidectomy is not recommended are microcarcinomas measuring less than 1 cm.

Ten days after performing a hemithyroidectomy on a patient with a 1.5 cm thyroid nodule you receive the following definitive report from the pathologist: "very cellular follicular pattern without capsular invasion invading adjacent blood vessels and nerves". Point out the correct answer:

As there is no capsular invasion it is not convenient to perform further surgery.

The follicular pattern is an indication for prophylactic cervical lymph node emptying.

It is a follicular carcinoma and requires completion of thyroidectomy.

The report allows to rule out papillary carcinoma with total certainty in the remaining thyroid.

Measurement of plasma calcitonin will allow us to differentiate between papillary and follicular carcinoma.

Medullary thyroid cancer

Prognosis Depending on source, the overall 5-year survival rate for medullary thyroid cancer is 80%, 83% or 86%, and the 10-year survival rate is 75%. By overall cancer staging into stages I to IV, the 5-year survival rate is 100% at stage I, 98% at stage II, 81% at stage III and 28% at stage IV. The prognosis of MTC is poorer than that of follicular and papillary thyroid cancer when it has metastasized (spread) beyond the thyroid gland. The prognostic value of measuring calcitonin and carcinoembryonic antigen (CEA) concentrations in the blood was studied in 65 MTC patients who had abnormal calcitonin levels after surgery (total thyroidectomy and lymph node dissection). The prognosis correlated with the rate at which the postoperative calcitonin concentration doubles, termed the calcitonin doubling time (CDT), rather than the pre- or postoperative absolute calcitonin level:

[The lymph node dissection in thyroid carcinoma].

Rule and indications of lymph node dissection (LD) in thyroid carcinoma is still under debate because of the biological variety of different histological types and the difficulty to have an accurate preoperative diagnosis of metastatic lymph nodes; moreover prognostic factors of metastatic lymph nodes are still unclear. The AA. have separately analyzed different thyroid carcinomas and different clinical situations requiring thyroid LD. Metastatic lymph nodes from differentiated carcinomas, including papillary and follicular type, range from 12 to 90% and apparently do not worsen the prognosis. Level II-VI LD is indicated in presence of metastatic lymph nodes or macroscopic nodal recurrence after a previous LD. No prognostic advantages have been demonstrated when LD is performed without clinical or instrumental evidence of metastatic disease, including suspected recurrence characterised only by plasma Thyreoglobulin increased values. Lymph node metastases from medullary carcinoma range from 25 to 63%. Level II-VI LD is indicated if node metastases are present, whereas prophylactic LD, confined to level VI, is always recommended. Controversies still remain about: 1) LD extension whether it is prophylactic (level VI vs. II- VI) or in case of nodal involvement (levels II- VI monolateral or bilateral), 2) LD indications in case of an increased plasma Calcitonin levels during the follow-up after total thyroidectomy, without clinical or instrumental evidence of nodes involvement. Anaplastic carcinoma represents 5% of all thyroid carcinomas; it is the most aggressive type with an early tendency to invade surrounding organs and to give metastases; prognosis is very poor. LD is indicated only for a palliation in cases with compression syndromes.

Selective treatment of differentiated thyroid carcinoma.

Over a period of 20 years 84 papillary and 82 follicular carcinomas operated on by one surgeon and examined by one pathologist were documented prospectively, treated selectively, and followed for 1 to 20 years (median 7 years). Tumors with a low risk of recurrence or incurable disease-i.e., papillary carcinoma pT1-3 N0 M0 (n = 56) and minimally invasive follicular carcinoma (n = 37)-were treated by a limited-radicality hemithyroidectomy or total thyroidectomy without radioiodine in 79 of the 93 cases (85%). No unfavorable course was observed, and only one curable recurrence (1.3%) developed contralaterally after hemithyroidectomy for papillary cancer. Of the remaining 73 patients, including 100% of those with nodal involvement, 65 (89%) underwent total thyroidectomy with radioiodine. Total thyroidectomy was achieved in 34% of the cases by completion thyroidectomy, based on definitive histologic examination. No instance of a serious, potentially incurable recurrence and no tumor-related death was observed in patients with a papillary TNM stage I+II or with a minimally invasive follicular carcinoma. Five of the patients (6%) with papillary carcinoma, all with TNM stage III or IV, and seven of the patients (8.5%) with follicular carcinoma, all grossly invasive and pT3 or pT4, had tumor-related deaths following total thyroidectomy in all and with remnant ablation in 10 cases. A potentially curable node recurrence occurred in two patients 1 and 10 years, respectively, after primary treatment. Permanent hypoparathyroidism (n = 4) (2.4%) and permanent recurrent laryngeal nerve palsy (n = 2) (1.2%) were observed only in patients with a grossly invasive follicular carcinoma and concomitant benign recurrent goiter. We conclude that (1) hemithyroidectomy or total thyroidectomy without radioiodine is adequate for papillary carcinoma pT1-3 N0 and minimally invasive follicular carcinoma; (2) there were no nodal recurrences in tumors recognized as node-negative; and (3) extracapsular excision of one or both lobes can be carried out technically with low morbidity. The study confirms the prognostic value of age-related TNM classification for papillary carcinoma; classification of follicular thyroid carcinoma as minimally invasive or grossly invasive proved to be useful.

Follicular Adenoma -- Evaluation

FNA is performed to provide a cytological examination of the nodule, and it remains the mainstay for assessing these lesions, although it may not provide a diagnosis in all cases. [7] The success rate of FNA is improved when the procedure is done under ultrasound guidance. The cytopathological findings are reported using one of the three major international nomenclatures: the British Thyroid Association and Royal College of Pathologists (Thy), the Italian Consensus (TIR) and the Bethesda System for Reporting Thyroid Cytopathology [40] [28] . Thyroid nodule fine-needle aspiration (FNA) washout may be examined for calcitonin in the preoperative evaluation in patients with elevated serum calcitonin (20–100 pg/mL). In patients with follicular adenoma the cytological sample has abundant follicular epithelial cells organized in sheets with crowding and overlapping of cells, microfollicle formation with scant or absent colloid. Some patients have follicular cells with abnormal architecture with atypia that is more significant than usually seen with benign lesions but not sufficient enough to call it a neoplasm. According to the Bethesda classification system, these patients are characterized as having "atypia of undetermined significance" or "follicular lesion of undetermined significance". Molecular assessment of indeterminate cytology can be helpful [28] . A final diagnosis of follicular adenoma is made only after ruling out capsular and vessel invasion by standard nodulectomy or thyroidectomy with subsequent histological examination. Frozen section should not be requested in clinically benign nodules but is a common practice in cases of suspect papillary thyroid carcinoma hence its evaluation intraoperatively can guide in performing lymphadenectomy.

Thyroid cancer

The follicular and papillary types together can be classified as "differentiated thyroid cancer". These types have a more favorable prognosis than the medullary and undifferentiated types. Papillary microcarcinoma is a subset of papillary thyroid cancer defined as a nodule measuring less than or equal to 1 cm. 43% of all thyroid cancers and 50% of new cases of papillary thyroid carcinoma are papillary microcarcinoma. Management strategies for incidental papillary microcarcinoma on ultrasound (and confirmed on FNAB) range from total thyroidectomy with radioactive iodine ablation to lobectomy or observation alone. Harach et al. suggest using the term "occult papillary tumor" to avoid giving patients distress over having cancer. Woolner et al. first arbitrarily coined the term "occult papillary carcinoma", in 1960, to describe papillary carcinomas ≤ 1.5 cm in diameter.

Thyroidectomy

Hemithyroidectomy — Entire isthmus is removed along with 1 lobe. Done in benign diseases of only 1 lobe. Subtotal thyroidectomy — Removal of majority of both lobes leaving behind 4-5 grams (equivalent to the size of a normal thyroid gland) of thyroid tissue on one or both sides—this used to be the most common operation for multinodular goitre. Partial thyroidectomy —Removal of gland in front of trachea after mobilization. Done in nontoxic MNG. Its role is controversial. Near total thyroidectomy — Both lobes are removed except for a small amount of thyroid tissue (on one or both sides) in the vicinity of the recurrent laryngeal nerve entry point and the superior parathyroid gland. Total thyroidectomy — Entire gland is removed. Done in cases of papillary or follicular carcinoma of thyroid, medullary carcinoma of thyroid. This is now also the most common operation for multinodular goitre.

Follicular thyroid cancer

Hurthle cell variant Hurthle cell thyroid cancer is often considered a variant of follicular cell carcinoma. Hurthle cell forms are more likely than follicular carcinomas to be bilateral and multifocal and to metastasize to lymph nodes. Like follicular carcinoma, unilateral hemithyroidectomy is performed for non-invasive disease, and total thyroidectomy for invasive disease. Diagnosis It is difficult to correctly diagnose follicular neoplasms (FNs) on fine-needle aspiration cytology (FNAC) because it shares many cytological features with other mimicking lesions.

[Papillary and follicular thyroid carcinoma].

Papillary and follicular carcinomas of the thyroid are differentiated carcinomas developed from the follicular epithelium, that keep some of its morphological and functional characteristics. Their increased incidence is related to an improved screening. Thyroid carcinoma usually presents as a thyroid nodule. Only 5% of nodules are malignant and fine needle biopsy is the most accurate tool for their diagnosis. Initial treatment is standardized and includes a total thyroidectomy with central lymph node dissection in case of papillary carcinoma, that is followed by the administration of a large activity of radioiodine in case of incomplete surgery, distant metastases or high risk factors. Papillary carcinomas of less than 1 cm in diameter, when unifocal and intra-thyroid are treated with surgery only, and radioiodine is not indicated. Thyroxine treatment is given to all patients. The majority of patients are cured, as demonstrated by the work-up performed at 1 year (undetectable serum thyroglobulin following stimulation with recombinant human TSH and normal neck ultrasonography). Subsequent follow-up is yearly with serum Tg and TSH determinations that is maintained within the normal range. In the other patients, other tests may be indicated, starting with the administration of a large activity of radioiodine. In these patients, serum TSH should be decreased to a low level.

Follicular thyroid cancer

Diagnosis It is difficult to correctly diagnose follicular neoplasms (FNs) on fine-needle aspiration cytology (FNAC) because it shares many cytological features with other mimicking lesions. Classification It is impossible to distinguish between follicular adenoma and carcinoma on cytological grounds. If fine needle aspiration cytology (FNAC) suggests follicular neoplasm, thyroid lobectomy should be performed to establish the histopathological diagnosis. Features sine qua non for the diagnosis of follicular carcinoma are capsular invasion and vascular invasion by tumor cells. Still, focuses of the capsular invasion should be carefully evaluated and discriminated from the capsular rupture due to FNA penetration resulting in WHAFFT (worrisome histologic alterations following FNA of thyroid). Follicular carcinoma tends to metastasize to lung and bone via the bloodstream. Papillary thyroid carcinoma commonly metastasizes to cervical lymph nodes.

[Critical reflections on differentiated carcinoma of the thyroid: difficulties, doubts and differential-diagnosis problems].

This work reviews the problems associated with the diagnosis of well differentiated carcinomas of the thyroid (follicular and papillary), which anatomically and clinically can show characteristics not readily distinguishable from those found in thyroid hyperplasia and adenomas. Some features of atypical adenomas and Hurthle cell tumors are detailed, in particular the borderline malignancy of the latter. We have examined the histological parameters useful in diagnosis of follicular carcinoma (cellular polymorphism and size variability with increased and atypical mitoses, invasion of the capsule and vessels, metastasis to lymph nodes and distant organs) and of papillary carcinoma (true papillae, large and crowded nuclei displaying a "ground glass" appearance with grooves and cytoplasmic inclusions and psammoma bodies). The limitations of these parameters are discussed with emphasis on frozen section examination when the lack of time limits examination to few and small tissue fragments. Invasion of the capsule and vessels is not easily detected and the "ground glass" nucleus and presence of grooves are not evident. The biological behavior of well differentiated carcinomas is discussed and, although unpredictable and variable in the single case, is generally that of a slow growing tumor. It is partially influenced by the age of the patient, size and stage of the tumor, invasion of the capsule and vessels and metastatic spread. We have observed that the biological behavior, apparently different in the follicular and papillary forms, appears identical for both tumors when a large number of cases are analyzed. Mention is made of the various surgical choices (total thyroidectomy, subtotal thyroidectomy, lobectomy, different surgical procedures which take into account the various risk factors). No statistically significant differences in recurrences and metastatic spread are obtained by electing more or less aggressive surgery with or without extensive dissection of cervical lymph nodes.

Utility of frozen section analysis on follicular lesions of the thyroid.

The experience of one surgeon (R.H.) with intraoperative frozen sections (FS) performed on thyroid nodules over a 10-year period was studied to assess the utility of FS in follicular thyroid lesions. One hundred and ten patients with dominant or solitary nodules demonstrating a follicular growth pattern were evaluated. The FS slides and subsequently the permanent sections of the nodules were reviewed by the pathologists in the study (M.P.B., VAL.) without knowledge of the original diagnoses. Our results indicate: (1) if the FS was definitively benign (58 patients), the final diagnosis was benign [these lesions consisted of adenomatous nodule, nodular goiter, follicular adenoma, and Hürthle cell adenoma); (2) if an FS diagnosis of malignancy was rendered (4 patients), it was confirmed on permanent sections (follicular variant of papillary carcinoma in all 4); and (3) if the FS diagnosis was deferred (48 patients), the final diagnosis was benign in all but 10 (21 %) (of these 10, 6 had minimally invasive follicular carcinoma [2 of the Hürthle cell type], and 4 had follicular variants of papillary carcinoma). Overall, sensitivity, specificity, and accuracy rates for FS diagnoses were 29, 100, and 91%. Because unilateral lobectomy may be acceptable therapy for well-differentiated thyroid cancers, and because the efficiency of FS evaluation in diagnosing malignancy is low (only 4 malignancies of 110 total patients were diagnosed at FS, or 3.6% overall), we conclude that in this era of cost-containment, FS is not useful in the evaluation of follicular thyroid nodules identified preoperatively as follicular lesions by fine-needle aspiration cytology. Several recommendations concerning the 3 categories of FS diagnosis (i.e., definitively benign, definitively malignant-especially the follicular variant of papillary carcinoma-and deferred) are also put forward.

History Patients in the distant past with this lesion would have been regarded as showing signs of having a benign lesion, a follicular adenoma. However, over time and with additional evaluation and molecular testing, these lesions came to be regarded as showing features of a papillary thyroid carcinoma because of their papillary carcinoma type nuclei. Thus, the "follicular variant" of a tumor that normally shows a papillary architecture and papillary nuclear features was named. Over the years, those cases that do not show invasion of either the capsule of the tumor or the vessels in the capsule, have been shown to behave in an indolent fashion, with only rare reported cases of metastatic disease.

Follicular thyroid cancer

Initial treatment If follicular cells are found on cytological testing, it is common to carry out hemithyroidectomy to distinguish between follicular adenoma and follicular carcinoma on histopathological examination, proceeding to completion thyroidectomy and postoperative radioiodine ablation where carcinoma is confirmed. This way total thyroidectomy is not carried out unnecessarily. Thyroidectomy is invariably followed by radioiodine treatment at levels from 50 to 200 millicuries following two weeks of a low iodine diet (LID). Occasionally treatment must be repeated if annual scans indicate remaining cancerous tissue. Some physicians favor administering the maximum safe dose (calculated based on a number of factors), while others favor administering smaller doses, which may still be effective in ablating all thyroid tissue. I-131 is used for ablation of the thyroid tissue. Minimally invasive thyroidectomy has been used in recent years in cases where the nodules are small.

Completion thyroidectomy: a critical appraisal.

Completion thyroidectomy can most accurately be described as reexploration of the neck to remove the contralateral thyroid lobe. This procedure has commonly been performed when the histopathologic condition of the ipsilateral thyroid lobe reveals papillary or follicular carcinoma of the thyroid. Because of a definitely increased risk of complications with completion thyroidectomy, avoiding its routine use is important. The purpose of this paper is to define the specific indications for completion thyroidectomy. Over the past 9 years, we have performed 400 thyroidectomies; the patients ranged in age from 18 to 88 years. Although we have routinely used preoperative needle biopsy and intraoperative frozen section, decisions regarding the extent of thyroidectomy have been based on the gross findings at operation, taking into consideration such prognostic factors as patient age, tumor grade and size, the presence of extracapsular spread or distant metastasis, and associated risk factors. The minimal procedure for solitary thyroid nodule has been lobectomy with isthmusectomy. If the contralateral lobe is grossly normal, lobectomy with isthmusectomy has also been the maximal operation in most of patients. Very few specific indications exist for removal of the opposite lobe. Only three patients underwent completion thyroidectomy. All three patients had aggressive follicular carcinoma requiring radioactive iodine ablation, and all were referred after the initial surgery. We have not performed completion thyroidectomy on any of the patients on whom we initially operated. The most common indication considered for completion thyroidectomy is a frozen section diagnosis of a benign follicular adenoma that is subsequently changed on permanent pathologic condition to follicular carcinoma based on the presence of capsular and/or vascular invasion. However, if minimal invasion has occurred, no difference exists in survival related to the extent of the thyroidectomy. Local recurrence in the contralateral lobe occurs in less than 10% of the time. Because completion thyroidectomy carries more risks, it should be avoided in most patients when possible. The definitive decision should be made during the initial operation based on gross findings, prognostic factors, and frozen section, and this plan should only be changed to mandate completion thyroidectomy in select circumstances.

Computed tomography of the thyroid

Thyroid cancers Epidemiology Primary thyroid carcinomas include papillary, follicular, medullary, and anaplastic carcinomas. Lymphoma and metastasis of other primary malignancies to the thyroid gland represent a minority of thyroid carcinomas. Differentiated thyroid carcinomas (DTCs) originate from follicular epithelial cells and encompass PTCs and follicular thyroid carcinomas, including the Hurthle cell variant of follicular carcinoma. DTCs have an excellent prognosis and fortunately represent the majority of thyroid carcinomas. PTCs and follicular thyroid carcinomas represent 88 % and 8 %, respectively, of all thyroid malignancies. Medullary thyroid carcinoma arises from neuroendocrine C-cells and has a good prognosis. Anaplastic carcinoma is an aggressive undifferentiated tumour that usually affects the elderly and tends to have a worse prognosis. Role of imaging

Over a multiyear time frame, an international consensus project was undertaken to re-define the pathological criteria for the encapsulated follicular variant of papillary thyroid carcinoma. Based on a rigorous review of the literature and a multicentre review of many cases with long-term follow-up (a minimum of 10 years) together with molecular analysis of some tumors, this working group has determined that tumors previously classified as the encapsulated follicular variant of papillary carcinoma—without any evidence of capsular or vascular invasion, provided that the entire periphery of the tumor (capsule if encapsulated or periphery if well circumscribed) has been sampled—can be reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features. There are several major inclusion and exclusion criteria.

Papillary thyroid cancer

The so-called lateral aberrant thyroid is usually a lymph node metastasis from a papillary thyroid carcinoma. Papillary microcarcinoma is a subset of papillary thyroid cancer defined as measuring less than or equal to 1 cm. The highest incidence of papillary thyroid microcarcinoma in an autopsy series was reported by Harach et al. in 1985, who found 36 of 101 consecutive autopsies to have an incidental microcarcinoma. Michael Pakdaman et al. report the highest incidence in a retrospective surgical series at 49.9 percent of 860 cases. Management strategies for incidental papillary microcarcinoma on ultrasound (and confirmed on FNAB) range from total thyroidectomy with radioactive iodine ablation to observation alone. Harach et al. suggest using the term "occult papillary tumor" to avoid giving patients distress over having cancer. It was Woolner et al. who first arbitrarily coined the term "occult papillary carcinoma" in 1960, to describe papillary carcinomas ≤ 1.5 cm in diameter.

Carcinoma of the thyroid with description of a new scanning technic.

A statistical analysis of 193 patients with thyroid carcinoma encountered at Vanderbilt University Hospital from 1925 to 1974 is reported, from which the following conclusions are drawn: (1) Papillary thyroid carcinoma is an extremely favorable lesion that when grossly limited to one thyroid lobe can usually be managed successfully by ipsolateral total lobectomy. (2) Cervical lymph node enlargement in patients with papillary carcinoma requires lymph node dissection. When feasible, the spinal accessory nerve should be preserved. (3) Failure to cure papillary and follicular thyroid carcinoma is influenced by advanced age, inadequate local extirpation, and unresectability of the carcinoma. (4) Prophylactic lymph node dissection is rarely indicated in the treatment of follicular carcinoma. A new isotope scanning procedure, developed at Vanderbilt University Hospital, promises to be helpful in preoperatively differentiating benign  from malignant solitary thyroid nodules.

Follicular thyroid cancer

Follicular carcinoma tends to metastasize to lung and bone via the bloodstream. Papillary thyroid carcinoma commonly metastasizes to cervical lymph nodes. HMGA2 has been proposed as a marker to identify malignant tumors. Treatment Treatment is usually surgical, followed by radioiodine.

Surgery_Schwartz

out to be malignant. This category also includes lesions suspicious for medullary carcinoma and lymphoma, and ancillary testing such as immunohistochemical analysis and flow cytometry may be helpful. The risk of malignancy in lesions classified as “malignant” by FNA is 97% to 99%, and near-total/total thyroidectomy is recommended.Laboratory Studies Most patients with thyroid nodules are euthyroid. Determining the blood TSH level is helpful. If a patient with a nodule is found to be hyperthyroid, the risk of malignancy is approximately 1%. Serum Tg levels cannot dif-ferentiate benign from malignant thyroid nodules unless the lev-els are extremely high, in which case metastatic thyroid cancer should be suspected. Tg levels are, however, useful in following patients who have undergone total thyroidectomy for thyroid cancer and also for serial evaluation of patients undergoing nonoperative management of thyroid nodules. Serum calcitonin levels should be obtained in patients with MTC or a

Abbreviations: NIFTP: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features EFVPTC: Encapsulated follicular variant of papillary thyroid carcinoma. PTC: Papillary thyroid carcinoma. The new classification will be included in the World Health Organization's new Classification of Endocrine Organ Tumours, due out in 2017. Imaging findings Clinical evaluation is usually done with ultrasound studies, which will usually show a solid, well demarcated mass, often showing limited shadowing (hypoechoic). Depending on the specific character on ultrasound and other clinical findings, a fine needle aspiration is often performed.

Surgery_Schwartz

patients will have benign adenomas. Total thyroidectomy is recommended by some surgeons in older patients with follicular lesions >4 cm because of the higher risk of cancer in this setting (50%) and certainly should be performed in patients with atypia on FNA, a family history of thyroid cancer, or a history of radiation exposure. Intraoperative frozen-section examination usually is not helpful, but it should be performed when there is evidence of capsular or vascular invasion or when adjacent lymphadenopa-thy is present. Total thyroidectomy should be performed when thyroid cancer is diagnosed. There is debate among experts about whether patients with minimally invasive follicular can-cers should undergo completion thyroidectomy because the prognosis is so good in these patients. A diagnosis of frankly invasive carcinoma or follicular carcinoma with angioinvasion, with or without capsular invasion, necessitates completion of total thyroidectomy primarily so that 131I can be used to

[Surgical treatment of differentiated thyroid carcinoma].

This paper reports the results and experiences of 95 cases with differentiated thyroid carcinoma managed by surgical treatment. Eighty-two patients were followed up with an average time of 6.2 years, the longest was fifteen years and six months, 96% of patients were survival over 5 years. The factors influencing prognosis are as follows: 1. Age: Elder predicts worse prognosis. 2. Papillary is better then follicular. 3. The stage of thyroid carcinoma: Bigger mass, tumor cells spreading out of thyroid capsule with invasion of adjacent tissues and regional lymph nodes, and intravascular tumor cell embolus almost always shows higher recurrence and mortality. 4. Simple tumor removal before admission gives no reasonable cure, but increasing risk of spreading as showed in our cases. Therefore, we emphasize that thyroid carcinoma should be treated primarily with radical operation. By our experience thyroid carcinoma should be treated with lobectomy for affected site, excision of isthmus, and contralateral subtotal thyroidectomy. Because of the low grade malignancy in differentiated thyroid carcinoma, modified neck dissection is the surgical procedure of choice. Patients undergoing such surgical procedure as stated above can be prevented from sequelae.

Thyroglobulin

A subsequent elevation of the thyroglobulin level is an indication of recurrence of papillary or follicular thyroid carcinoma. In other words, a rise in thyroglobulin levels in the blood may be a sign that thyroid cancer cells are growing and/or the cancer is spreading. Hence, thyroglobulin levels in the blood are mainly used as a tumor marker for certain kinds of thyroid cancer (particularly papillary or follicular thyroid cancer). Thyroglobulin is not produced by medullary or anaplastic thyroid carcinoma. Thyroglobulin levels are tested via a simple blood test. Tests are often ordered after thyroid cancer treatment.

Thyroid Adenoma -- Evaluation

Fine needle aspiration (FNA) has ultimately been used in evaluating a thyroid nodule with suspicious radiology features, especially in patients with a high risk of malignancy. It should be mentioned that fine-needle aspiration may not provide a definite diagnosis in all cases. In patients with thyroid adenoma, the cytological sample has organized follicular epithelial cells. On the other hand, aspiration can show follicular cells with abnormal architecture and atypia. These patients are characterized as having atypia of undetermined significance. [26] A benign thyroid adenoma is confirmed only after ruling out capsular and vessel invasion in the final histological examination done by pathologists after a partial or total thyroidectomy operation. Genetic testing has also helped a lot in predicting the risk of thyroid cancer, and it has frequently been used in the final decision-making of proceeding to surgical intervention of removing a thyroid nodule versus not. [27]

Influence of presence/absence of thyroid gland on the cutoff value for thyroglobulin in lymph-node aspiration to detect metastatic papillary thyroid carcinoma.

Thyroglobulin measurement with fine-needle aspiration (Tg-FNA) is a sensitive method for detecting metastatic papillary thyroid carcinoma (PTC). However, the diagnostic threshold is not well established and the influence of the thyroid gland on the cutoff value is also controversial. In this study, patients were classified into two groups according to the presence or absence of thyroid tissue, to determine an appropriate cutoff value for clinical practice. Patients with a history of thyroid nodules or surgery for PTC and with enlarged cervical lymph nodes on an FNA examination were enrolled for Tg-FNA detection. One hundred ninety-six lymph nodes (189 patients) were included: 100 from preoperative patients, 49 from patients treated with partial thyroid ablation, and 47 from patients with total thyroid ablation. In 149 lymph nodes from patient with thyroids, the cutoff value for Tg-FNA was 55.99 ng/mL (sensitivity, 95.1%; specificity, 100%), whereas in 47 lymph nodes from patients without a thyroid, it was 9.71 ng/mL (sensitivity, 96.7%; specificity, 100%). Thus, the cutoff value for Tg-FNA was higher in patients with thyroids than in patients without thyroids. The cutoff value for Tg-FNA is influenced by residual thyroid tissue, and a higher cutoff value is recommended for patients with thyroids than for patients without thyroids.

Papillary thyroid cancer

Several variants are recognized, although classic papillary thyroid carcinoma is the most frequent: microscopic-follicular variant, diffuse-sclerosing variant, tall-cell variant, columnar-cell variant, hobnail variant, and others. The encapsulated-follicular variant, specifically when noninvasive, has been newly reclassified as the noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Although papillary carcinoma has a propensity to invade lymphatics, it is less likely to invade blood vessels. These kinds of tumors are most commonly unencapsulated, and they have a high tendency to metastasize locally to lymph nodes, which may produce cystic structures near the thyroid that are difficult to diagnose because of the paucity of malignant tissue. Furthermore, papillary tumors may metastasize to the lungs and produce a few nodules or the lung fields may exhibit a snowflake appearance throughout.

Additional Tissue Sampling Trials Did Not Change Our Thyroid Practice.

This study aimed to determine whether additional tissue sampling of encapsulated thyroid nodules would increase the frequency of follicular thyroid carcinoma (FTC) diagnoses. We examined thyroid tissue specimens from 86 patients suspected of FTC (84.9% female; mean age, 49.0 ± 17.8 years). The number of tissue blocks created for pathological assessments ranged from 3 to 20 (mean, 9.1 ± 4.1); the numbers in the previous method recommended by the Japanese General Rules for the Description of Thyroid Cancer and additional blocks ranged from 1 to 12 (mean, 6.0 ± 2.8) and from 1 to 8 (mean, 3.1 ± 2.0), respectively. The additional blocks were subsequently examined to determine whether any diagnoses changed from those based on the previous method. Five patients were diagnosed with FTC using the previous method; however, additional tissue blocks led to the diagnosis of FTC in 6 patients, as 1 diagnosis was revised from follicular adenoma to FTC. It has been reported that increasing the number of tissue blocks used for pathological assessments can increase the frequency of FTC diagnoses; however, this was not clinically significant in thyroid carcinoma, which requires completion thyroidectomy and radioactive iodine treatment. It resulted in no benefits to the patient because all minimally invasive FTCs, follicular tumors of uncertain malignant potential (FT-UMP), and follicular adenomas are treated with lobectomy alone in Japan. Additional tissue sampling only had a slight impact on our thyroid practice; therefore, we decided to cease it.

Papillary thyroid cancer

Papillary thyroid carcinomas are also discovered when a hard nodule is found in multinodular goiter, when enlarged cervical lymph nodes are detected, or when there are unidentified metastatic lesions elsewhere in the body. Expanding lesions found in the thyroid gland, especially if they are painful, should be examined as they may indicate the presence of papillary thyroid carcinoma. Other clinical signs that could indicate papillary thyroid are fixation to the trachea, a firm neck mass, damage to recurrent laryngeal or cervical sympathetic nerves. Five percent of the population can have thyroid nodules, and the majority will be benign. Appropriate workup includes an ultrasound of the neck, followed by lab studies. Patients will usually meet with both an endocrinologist and a surgeon (head and neck surgeon or endocrine surgeon).

[Prospective therapy study in differentiated thyroid carcinoma].

Controversy still exists regarding the appropriate treatment for differentiated thyroid carcinoma, i.e. the extent of surgery and the usefulness of prophylactic 131I thyroid ablation. However, the debate is nowadays confined to those patients who may be categorized as having a favorable prognosis with respect to tumor-related death or serious recurrence, and the point of discussion is essentially the optimal treatment to prevent curable recurrences. From the literature it may be deduced that patients with a node negative papillary tumor of stage I and II in the age-related TNM classification system, and patients with a minimally invasive follicular carcinoma, have an excellent prognosis with respect to survival and recurrence. In a prospective study during a 20-year period from one surgical and one pathological institution 136 consecutive patients were treated. Patients with an incidental pT1 N0 tumor, or with a stage I or II node negative papillary carcinoma, or with a minimally invasive follicular carcinoma respectively, had a reduced extent of treatment. This consisted in resection for the concomitant benign goiter (7%), hemithyroidectomy (32%), or total thyroidectomy without 131I ablation (18%). All other patients, including those with a node positive tumor in stage I or II, had total thyroidectomy and 131I ablation (43%). Patients with a multifocal tumor had total thyroidectomy with or without 131I ablation. Hemi- or total thyroidectomy was technically carried out by capsular dissection with identification of the parathyroids, as introduced by Kocher and Halsted. Peritracheal and -laryngeal nodes were regularly searched for, and functional neck dissection was done in node positive tumors. Total thyroidectomy was carried out by completion thyroidectomy in 29 (35%) of the 83 patients. 5 patients (7%) with papillary carcinoma, all in stage III or IV, and 5 patients (8%) with follicular carcinoma, all with a high degree of capsular angio-invasion, died from the tumor 6 months to 16 years after diagnosis. A further patient with a high degree follicular carcinoma is alive with residual disease. All these patients with an unfavorable course underwent total thyroidectomy and 131I ablation as initial therapy. Two patients with papillary carcinoma had a presumptively curable recurrence, namely, a node recurrence in a pT1 N1 tumor (following total thyroidectomy and radio-iodine ablation), and a contralateral recurrence after hemithyroidectomy in a pT2 N0 tumor in a young patient. In sum, in no case with an unfavorable course was a radical therapy omitted initially, and less than total thyroidectomy with 131I ablation (n = 77 [57%]) led to a (curable) recurrence in only one instance (1.3%).(ABSTRACT TRUNCATED AT 400 WORDS)

[Thyroid cancers].

During the last two decades, the incidence of thyroid cancer has doubled, mainly do to the early detection of small papillary tumors. However, mortality stayed stable (0.05/100.000). Well differentiated cancers (papillary and follicular) demonstrated a excellent survival prognosis (95 % at 30 years for the majority of the patients), factors of prognosis: age, size of the initial tumor, presence (or not) of distant metastases, lymph node involvement (only in patients 45 year or older). Surgery is the main treatment and should be with curative intent, hence the importance of a thorough preoperative work-up: sonography, needle aspiration cytology and MRI of cervicomediastinum for large tumors and/or suspected lymph nodes. Total thyroidectomy is mandatory, excepted for well selected patients with small (pT1) unilateral tumors under the age of 45. Central compartment lymph node clearance is advocated (but not evidence based) with presentation of the recurrent laryngeal nerves and of the parathyroids. Ablation of residual thyroid tissue (Iode 131) should be advocated for patients at high (or intermediary) risk of recurrence, only after multidisciplinary concertation. Unlimited follow-up checking the thyroglobulin serum local after the total thyroidectomy and radioactive ablation, the availability of recombinant rhTSH avoids the withdrawal of thyroid hormones (hypothyroid period). Anaplastic carcinomas are very aggressive, no therapeutic solution, excepted in some selected case for when radical surgery is possible (flap reconstruction) followed by chemoradiation. Calcitoninenia to detect and to follow medullary thyroid cancer after total thyroidectomy and lymph node clearance.

Computed tomography of the thyroid

On CT scans, a malignant lesion is suspected when the margins are ill-defined and there is extra-thyroid extension, lymph node involvement, or invasion of the surrounding structures. The absence of these features does not exclude malignant tumours, especially papillary, follicular, and medullary thyroid carcinomas (Fig. 3). Therefore, ultrasound is the modality of choice for thyroid lesion evaluation, due to its superior spatial resolution compared to CT examinations. Sonographic features of malignancy are micro-calcifications, acoustic shadowing, anti-parallel orientation, marked hypoechogenicity, irregular or microlobulated margins, and increased vascularity. CT scans lack the ability to detect these reliable sonographic signs of malignancy. Therefore, further management of ITNs, if required, usually begins with thyroid ultrasound and FNA should be considered according to the ultrasound findings.


Answer 1 can be ruled out visu visu,

The correct answer would be 2, HORMONE AND HER2 RECEPTOR STUDY, since positive HER2 receptors imply greater aggressiveness of the tumor but treatment with trastuzumab and positive hormone receptors would imply the use of hormone therapy. Answer 1 can be ruled out visu visu, while answers 3 and 4 should be ruled out since, being the first woman in the family with breast carcinoma, the study of the patient's relatives would not be obligatory. Likewise, e-cadherin is important for the differential diagnosis of a lobular breast carcinoma, not a ductal one.

[HIDDEN] since positive HER2 receptors imply greater aggressiveness of the tumor but treatment with trastuzumab and positive hormone receptors would imply the use of hormone therapy. [HIDDEN], while [HIDDEN], being the first woman in the family with breast carcinoma, the study of the patient's relatives would not be obligatory. Likewise, e-cadherin is important for the differential diagnosis of a lobular breast carcinoma, not a ductal one.

A 67-year-old woman diagnosed with an infiltrating ductal carcinoma of the breast and no family history of neoplasia. What additional studies should be performed on the tumor for its clinical-therapeutic implications?

Complete phenotypic study by flow cytometry.

Study of hormone receptors, e-cadherin and study of first degree relatives.

Study of BRCA 1-2 and study of first-degree relatives.

The significance of family history for patients with carcinoma of the breast.

Since the risk of carcinoma of the breast is increased in women with a family history of the disease, new primary carcinomas of the breast may be increased after treatment. Women with several relatives with carcinoma of the breast are thought to be at higher risk of having a second primary carcinoma of the breast develop and mastectomy is more frequently recommended. The computerized registry of the Mount Sinai Medical Center Breast Service was used to identify 1,337 patients with complete information concerning family history. Three hundred fifty-nine patients with a family history of carcinoma of the breast were compared with women with no family history. Compared with patients with no family history of carcinoma of the breast, patients with a family history of carcinoma of the breast were significantly younger (54.0 versus 55.8 years of age, p < 0.01), were significantly more likely to have used oral contraceptives (26 versus 13 percent, p < 0.001), had significantly more ductal carcinoma in situ (10 versus 4 percent, p < 0.01), and were significantly more often treated with breast conservation (42 versus 31 percent, p < 0.001). Simultaneous contralateral carcinoma of the breast was diagnosed more frequently in patients with a family history (3 versus 1 percent, p < 0.025), but metachronous contralateral carcinomas were not increased. In comparing the two groups, there were no significant differences in proportion premenopausal, parity, use of postmenopausal hormones, tumor size, tumor differentiation, nodal involvement, TNM stage, estrogen receptor status, or use of adjuvant radiation, chemotherapy, or tamoxifen. Complete five-year follow-up evaluation for 748 patients, 179 with a family history, found no differences in local, distant, or disease-free survival rates for mastectomy or breast conservation in relation to family history. Outcome for patients with first-degree affected relatives and those with more than one affected relative was the same as those with no family history. These results indicate that women with a family history of carcinoma of the breast should be treated no differently than women with no family history.

BRCA mutation

Relative indications for testing for a mutation in BRCA1 or BRCA2 for newly diagnosed or family members include a family history among 1st (FDR), 2nd (SDR), or 3rd(TDR) degree relatives usually on the same side of the family but not limited: A known mutation (BRCA1 or BRCA2) in a cancer susceptibility gene within the family Women affected with any breast cancer diagnosed under the age of 30 Women affected with triple negative breast cancer (TNBC) (estrogen receptor negative, progesterone receptor negative, and HER2/neu negative) under the age of 50 Two relatives (FDR/SDR) diagnosed under the age of 45 Three relatives (FDR/SDR) diagnosed with average age of 50 or less Four relatives at any ages Ovarian cancer with either an additional diagnosed relative or a relative with male breast cancer A single family member with both breast and ovarian cancer Male breast cancer Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the family

Clinical features and first degree relative breast cancer, their correlation with histological tumor grade: a 5-year retrospective case study of breast cancer in Mizoram, India.

The aim was to assess the association of histological tumor grade with other clinical features and epidemiological factors of women with invasive breast carcinoma. A retrospective study of 103 Mizo breast cancer patients visiting hospitals was made in Aizawl, Mizoram, Northeast India. With a prior consent, information on epidemiological factors and family history in relation to cancer was obtained. Clinical reports were obtained from their medical records. The frequency of distribution was calculated for age at diagnosis and tumor characteristics. Statistical analysis for different variables was done using a chi-square test. p < 0.05 was considered significant. The histological tumor grades in our studies were found to be associated with lymph node invasion (p < 0.021), different subtype of hormone receptor such as ER status (p < 0.004), ER/PR status (p < 0.007), HER2/neu status (p < 0.014), and ER/PR/HER2 status (p < 0.025). A patient with a family history of breast cancer in their 1st degree relative is also seen to have association in determining the tumor grade (p < 0.003). Reproductive history, lifestyle and dietary habits, tobacco, and alcohol consumption were found to have no influence on breast cancer tumor grade. Our results showing significant correlation between status of lymph node, ER, PR, and HER2/neu oncoprotein and family history with 1st degree relative breast cancer are the first time report to target and focus on the possible role of biomarkers for diagnosis among the Mizo tribal breast cancer patients.

Influence of young age at diagnosis and family history of breast or ovarian cancer on breast cancer outcomes in a population-based cohort study.

The objective of this study was to examine the association of: (i) diagnosis at age </=35, (ii) first-degree family history of breast or ovarian cancer (BOC) and (iii) a research based definition of genetic risk, with tumor characteristics, treatment and survival in breast cancer (BC). Consenting female participants in the population-based Ontario Familial Breast Cancer Registry diagnosed with primary invasive BC between 1996 and 1998 were followed prospectively until 2005. Among 967 women, 105 were </=35 years old at diagnosis and 686 were classified as genetic risk cases, including 349 with a first-degree family history. Individuals diagnosed at age </=35 were more likely to self-detect tumors, to present with inflammatory BC, to have invasive ductal carcinoma of no special type, high T stage, and tumors with lymphovascular invasion (LVI), high grade and negative estrogen receptors. Younger women were more likely to receive chemotherapy and less likely to receive hormonal therapy. Diagnosis </=35 years old was associated with significantly reduced distant recurrence free survival, an effect that did not persist after adjustment for tumor and treatment related variables. Poor outcomes were restricted to younger women with hormone responsive BC. Family history was associated with increased rates of mammographic detection of BC, lower tumor stage and less frequent inflammatory BC, but had no association with BC outcomes. Women diagnosed with BC at age </=35 have more aggressive tumors; these adverse tumor characteristics, rather than age, lead to poor outcomes. Family history was not associated with survival.

Cancer biomarker

Similarly, additional laboratory research has shown that tumor cells undergoing apoptosis can release cellular components such as cytochrome c, nucleosomes, cleaved cytokeratin-18, and E-cadherin. Studies have found that these macromolecules and others can be found in circulation during cancer therapy, providing a potential source of clinical metrics for monitoring treatment. Recurrence Cancer biomarkers can also offer value in predicting or monitoring cancer recurrence. The Oncotype DX® breast cancer assay is one such test used to predict the likelihood of breast cancer recurrence. This test is intended for women with early-stage (Stage I or II), node-negative, estrogen receptor-positive (ER+) invasive breast cancer who will be treated with hormone therapy. Oncotype DX looks at a panel of 21 genes in cells taken during tumor biopsy. The results of the test are given in the form of a recurrence score that indicates likelihood of recurrence at 10 years.

Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics.

Double heterozygosity (DH) for BRCA1 and BRCA2 mutations is a very rare finding, particularly in non-Ashkenazi individuals, and only a few cases have been reported to date. In addition, little is known on the pathological features of the tumors that occur in DH cases and on their family history of cancer. Four carriers of pathogenic mutations in both BRCA1 and BRCA2 were identified among women who underwent genetic counseling for hereditary susceptibility to breast and ovarian carcinoma at three different Italian institutions. Clinical, pathological, and family history data were collected from medical records and during genetic counseling sessions. All identified DH cases developed breast carcinoma and three of them were also diagnosed with ovarian carcinoma. Mean ages of breast and ovarian cancer diagnosis were 42.7 and 48.6 years, respectively. The majority of breast cancers showed a BRCA1-related phenotype, being negative for hormone receptors and HER2. Two cases reported different gastrointestinal tumors among relatives. Although the individuals described in this study show more severe clinical features in comparison to previously reported BRCA1 and BRCA2 DH cases, our observations support the hypothesis of a non specific phenotype of DH cases in terms of age of disease onset. In addition, our observations indicate that in DH patients breast carcinogenesis appears to be driven mainly by the mutations in BRCA1. The possible association of DH for BRCA gene mutations with gastrointestinal tumors is in keeping with previous reports, but needs to be confirmed by further analyses.

Family history of breast cancer in first-degree relatives and triple-negative breast cancer risk.

Triple-negative breast cancer accounts for less than 20% of breast cancers overall, but is the predominant subtype among carriers of mutations in BRCA1. However, few studies have assessed the association between breast cancer family history and risk of triple-negative breast cancer. We examined the relationship between having a family history of breast cancer in first-degree relatives and risk of triple-negative breast cancer, and risk of two other breast cancer subtypes defined by tumor marker expression. We evaluated data collected by the Breast Cancer Surveillance Consortium from 2,599,946 mammograms on 1,054,466 women, among whom 15% reported a first-degree family history of breast cancer. Using Cox regression in this cohort, we evaluated subtype-specific associations between family history and risk of triple-negative (N = 705), estrogen receptor-positive (ER+, N = 10,026), and hormone receptor-negative/HER2-expressing (ER-/PR-/HER2+, N = 308) breast cancer among women aged 40-84 years. First-degree family history was similarly and significantly associated with an increased risk of all the subtypes [hazard ratio (HR) = 1.73, 95% confidence interval (CI): 1.43-2.09, HR = 1.62, 95% CI: 1.54-1.70, and HR = 1.56, 95% CI: 1.15-2.13, for triple-negative, ER+, and ER-/PR-/HER2+, respectively]. Risk of all the subtypes was most pronounced among women with at least two affected first-degree relatives (versus women with no affected first-degree relatives, HR(triple-negative) = 2.66, 95% CI: 1.66-4.27, HR(ER+) = 2.05, 95% CI: 1.79-2.36, HR(ER)-(/PR)-(/HER2+) = 2.25, 95% CI: 0.99-5.08). Having a first-degree family history of breast cancer was associated with an increased risk of triple-negative breast cancer with a magnitude of association similar to that for the predominant ER+ subtype and ER-/PR-/HER2+ breast cancer.

Seven-year survey of classical and pleomorphic invasive lobular breast carcinomas in women from southeastern Serbia: Differences in clinicopathological and immunohistochemical features.

The occurrence of different variants of invasive lobular carcinoma (ILC) of the breast is variable. For example, the pleomorphic variant of ILC has an incidence of around 5%; however, the number of analyzed cases of ILC is shadowed by the number of ductal type carcinoma (IDC). Thus, we aimed to analyze the classical and pleomorphic ILCs in women from southeastern Serbia. Analyzed were 296 cases (11.91%) diagnosed with ILC, out of 2486 cases of all breast cancers (BCs), during a 7-year period (2005-2011) from southeastern Serbia. The differences in clinicopathological and immunohistochemical features (estrogen receptor/ER, progesterone receptor/ PR, HER-2, Ki-67, BRCA-1, p53 and E-cadherin) of these cases of ILCs were assessed and compared. Pleomorphic ILC occurred relatively rarely compared to other variants, however almost one fifth of the ILC cases were pleomorphic. No statistically significant correlation was found between patient age, tumor stage and the presence/absence of multifocality (MFC), multicentricity (MCC) and bilaterality (BL) on one side, and ILC variant on the other. Only the expression of two prognostic and predictive immunohistochemical markers, important for endocrine therapy, ER and PR, showed significant correlation with the ILC variant. Although higher tumor stage, incidence of multicentricity, overexpression of HER2 and higher p53 positivity were deemed to be characteristic of pleomorphic ILC, in our study that included a much larger number of cases than previous studies did, such correlations were not observed. Thus, it appears that the only two features of pleomorphic ILCs is absence of ER and PR positivity.

Negative/low HER2 expression alone or combined with E-cadherin positivity is predictive of better prognosis in patients with breast carcinoma.

The loss of E-cadherin expression leads to absence of tissue integrity, an essential step in tumor progression. Methylation of CpG islands in the promoter region of the CDH1 gene coding E-cadherin might be an alternative for gene silencing. In the present study, we investigate the expression of E-cadherin and hormone receptors in invasive ductal breast carcinoma (IDCs). Protein expression was analysed immunohistochemically in 87 cases, including 26 familial tumors. The most interesting results revealed a significantly reduced E-cadherin expression in cases with familial history compared to sporadic tumors (p=0.009), as well as with tumors ≤5 cm (p=0.022). Moreover, HER2 over-expression was associated with distant metastasis (p=0.011) and overall survival (p log rank=0.028). Tumors displaying negative/low HER2 expression combined with E-cadherin positivity confer better patient survival (p=0.052). Triple Negative tumors (TN) were more frequently found in patients with advanced grade (GIII) (p=0.001) and TNM (III+IV) (p=0.018) which supports the aggressive behavior of TN tumors. On the other hand, hypermethylation of CDH1 gene promoter was observed in 46% of hereditary cases and strongly associated with loss of E-cadherin expression (p=0.002). Furthermore, patients with unmethylated CDH1 pattern have a better 5-year disease free survival (p=0.021). In conclusion, in patients with hereditary breast cancer, the CpG methylation event contributes to the loss of E-cadherin expression. On the other hand, HER2 over-expression is predictive of worse prognosis, either alone or combined with loss of E-cadherin expression in Tunisian patients with breast cancer.

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications.

Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics. Most BRCA1 carcinomas have the basal cell phenotype, a subtype of high-grade, highly proliferating, estrogen receptor- and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor- and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas. Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma.

Breast cancer and family history: a multivariate analysis of levels of tumor HER2 protein and family history of cancer in women who have breast cancer.

The HER2 gene, located on the long arm of chromosome 17, codes for a protein with the characteristics of a growth factor receptor. In a preliminary study, we reported that high levels of tumor HER2 (erbB-2/neu) protein are associated with a family history of breast cancer (that is, one or more female blood relatives with breast cancer). We have now collected a larger number of subjects (94) and performed a multivariate analysis of the independent variables family history of breast cancer, tumor estrogen receptor, age, and tumor DNA index. Family history of breast cancer was assessed by questioning the patient, in many cases by telephone. HER2 levels were significantly higher in women with a family history of breast cancer (p = 0.015, two-tailed t-test). The 27 women with family history were predominantly postmenopausal, mean age 61 +/- 2.3 (mean +/- SEM), versus a mean age of 56 +/- 1.7 for the 67 women with no family history. Of the 27 women with a family history of breast cancer, 13 had a first-degree relative (mother or sister) with the disease. The remaining 14 women had other relatives (grandmothers, aunts, cousins, or a niece) with breast cancer. The results of multiple linear regression analysis, with HER2 as the dependent variable, showed that family history of breast cancer was significantly associated with elevated HER2 levels in the tumors (p = 0.0038), after controlling for the effects of age, tumor estrogen receptor, and DNA index. The association of family history of breast cancer and elevated tumor HER2 protein suggests that postmenopausal familial breast cancer may be associated with altered HER2 expression.

BRCA1/BRCA2 mutations in Japanese women with ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) is considered a component of the clinical spectrum of breast cancer even in those with BRCA1/2 mutation. The aim of this study was to report the feature of DCIS raised in Japanese women with BRCA1/2 mutations. A total of 325 Japanese women with breast cancer (BC) (with or without invasive cancer) were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes in Showa University Hospital between December 2011 and August 2016. And 49 of them who were pathologically diagnosed as DCIS were included in this study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status. A Cox proportional hazards model is used to predictive value of parameters for Ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR). (a) Of 325 patients (with or without invasive cancer), 19.1% (62/325) tested positive for BRCA1/BRCA2 mutations. And 18.4% (9/49) was positive for BRCA1/BRCA2 mutations in DCIS, compared with 19.2% (53/276) in IDC (p = 1.000). Among BRCA mutations, 14.5% (9/62) had DCIS compared with nonmutations (15.2%, 40/263). Incidence of DCIS was 3.0% (1/33) of BRCA1 mutations and 27.5% (8/29) of BRCA2 mutation (p = 0.009). (b) Median age of diagnosis in BRCA mutation carriers was 39 years, compared with 46 years in noncarriers. Age, Family history (FH) of BC, FH of first or second BC and total number of relatives with BC diagnosis (DX) has significant difference between BRCA mutation carriers and noncarriers in univariate analysis. In a multivariate logistic model, total relatives with BC DX ≥ 2 (odds ratio [OR], 5.128; 95% confidence interval [CI], 1.266-20.763; p = 0.022), age at diagnosis ≤35 years (OR 0.149, 95% CI 0.023-0.954, p = 0.045) and ER+/HER2+ status (OR 5.034, 95% CI 1.092-23.210, p = 0.038) remained as independent significant predictors for BRCA mutation. Ki67 index (cut off by 14% or 30%) did not differ between BRCA mutation carriers and noncarriers (p = 0.459 and p = 0.651). (c) There was a significant difference in ER-positive tumors among BRCA2 carriers and noncarriers (p = 0.042). Subgroup analysis showed BRCA2 carriers tend to be of higher grade (Grade 2 and 3), more frequently ER+/PR+ (p = 0.041) and lower proliferation (Ki67 index) than noncarriers, whereas differences in nuclear grade and ki67 index were not found significantly in our study. (d) BRCA mutation was not associated with an increased risk of IBTR and CBTR. DCIS is equally as prevalent in patients who were BRCA mutation carriers as in high familial-risk women who were noncarriers, but occurs at earlier age. BRCA2 carriers have higher incidence in DCIS than that of BRCA1 carriers, and tend to be higher grade and more frequently ER positive and lower proliferation. Total relatives with BC DX ≥2, age at diagnosis ≤35 years and ER+/HER2+ might be independent predictors for BRCA mutation in Japanese women with DCIS and patients of these risk factors should be recommended to receive genetic counseling and BRCA testing.

Basal-like carcinoma

The most common histopathological type is invasive ductal carcinoma. It can also be metaplastic carcinoma, medullary carcinoma and adenoid cystic carcinoma, with high grade, high mitosis count. Central necrosis, apoptotic cells, and stroma lymphocyte reaction and a small amount of interstitial components can be seen through microscopic examination. In BLBC, p53 mutations are usually found and the expression epidermal growth factor receptor (EGFR or HER-1) and c-kit are usually positive. Through the genetic hybridization techniques, BLBC is verified to have the most complex gene phenotypes. The relationship between BLBC and familial BRCA1-associated breast cancer has been discussed in recent years. Several studies have demonstrated that BRCA1-associated breast cancer is more likely to be a BLBC. However, there are few BRCA1 mutations in BLBC, indicating that it is likely to be epigenetic changes. Studies have reported that the negative regulatory factor of BRCA1 gene, ID4, is often

Metaplastic carcinoma

Metaplastic carcinoma, otherwise known as metaplastic carcinoma of the breast (MCB), is a heterogeneous group of cancers that exhibit varied patterns of metaplasia and differentiation along multiple cell lines. This rare and aggressive form of breast cancer is characterized as being composed of a mixed group of neoplasms containing both glandular and non-glandular patterns with epithelial and/or mesenchymal components. It accounts for fewer than 1% of all breast cancer diagnoses. It is most closely associated with invasive ductal carcinoma of no special type. (IDC), and shares similar treatment approaches. Relative to IDC, MCB generally has higher histological grade and larger tumor size at time of diagnosis, with a lower incidence of axillary lymph node involvement. MCB tumors are typically estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER-2) negative, meaning hormone therapy is generally not an effective treatment option, which correlates to

Breast cancer expression of E-cadherin does not differ between patients with positive and negative oncological history.

The question of whether or not non-sporadic breast malignancies have different immunohistochemical features than sporadic malignancies has not been investigated previously. Consequently, the purpose of this study was to compare the expression of E-cadherin (EC) in breast cancer patients with positive and negative oncologic histories. The study included 98 breast cancer patients divided into two groups: 1) without the personal or familial history of previous malignancies, and 2) with the personal history of previous malignancies and/or with the data on cancer episodes in first- and/or second-degree relatives. There were no significant differences in the expression of EC between breast malignancies of the two groups. Moreover, statistical relationships were not observed between the positive or negative oncologic history, the age, and the menopausal status of patients, or histological tumor grade. Although the results of our series revealed no significant differences in the expression of EC between assumed sporadic and assumed non-sporadic malignancies, there is a need for further comparative studies on the immunohistochemistry of both the breast carcinoma types in order to find the other biological markers that could suggest or exclude cancer susceptibility in a given patient. Nevertheless, the results of our study suggest that EC immunohistochemistry cannot be used as a surrogate marker for screening for hereditary breast cancer.

Male Breast Cancer -- Etiology

Similarly to women, males have a higher risk of breast cancer if they have a first- or second-degree relative with breast cancer. Studies have shown that an affected sibling or parent of either gender may increase the risk of breast cancer in either the males or females in the family. Bevier et al. (2012) noted in their study that the relative risk (RR) of breast cancer was similar in either offspring when the father or mother was affected (RR = 1.73 and 1.74, respectively), but the risk was slightly higher in the females when the brother is affected as opposed to when the sister is affected (RR = 2.48 and 1.39, respectively). [3] Also, in addition to a family history of breast cancer, males with a BRCA mutation appear to have increased risk for breast cancer as well. Although rare for a male to have a BRCA mutation, those with BRCA2 carrier mutation have a 6% increased risk and BRCA1 with a 4% risk of developing the disease. [4] Other genetic disorders have been implicated in increasing the risk of MBC, including Klinefelter syndrome (47, XXY), Cowden syndrome ( PTEN tumor suppressor gene), Li-Fraumeni syndrome ( TP53 ), Lynch syndrome ( PALB2 and mismatch repair genes). [2] [4]

Somatostatin receptor 2

other components of the endocrine system and nervous system, so it can be drawn that the receptor family has great influence among these systems. The family was first discovered in a segment of a rat's pituitary gland known as the tumor cell line. A cell line is grown as a culture under controlled conditions, so the first discovery was found by culturing these cells in controlled conditions and in an environment outside of its norm. There, researchers found that the tumor cell line expresses a cell dividing inhibitor known as the transforming growth factor beta (TGF-beta) and also acts as an inhibitor to the milk producing hormone in female mammals, prolactin, and growth hormones. Researchers studied the activity of the receptors by conducting an assay with Ligand binding studies, which basically means they were conducting studies to see how prevalent the binding of the receptors occurred. Differences in how prevalently they receptors bonded revealed the existence of multiple

Does family history influence survival in breast cancer cases?

A few studies have suggested a relatively better prognosis for breast cancer (BC) cases reporting a positive family history (FH). We aimed at comparing the survival of patients according to FH in a large hospital-based series of 1,278 BC cases. Information on FH for BC was obtained at diagnosis by interview. All cases reporting a first- or second-degree FH for breast carcinoma were compared with cases without FH. Overall survival was estimated using a product-limit method. Hazard ratios (HRs) and the corresponding 95% confidence intervals (95% CIs), adjusted for confounding factors, were computed using proportional hazard models. Overall, 240 (18.8%) cases reporting, at diagnosis, a positive FH (156 with at least 1 first-degree relative and 84 with at least 1 second-degree relative) were compared with 1,038 patients without FH for BC. No significant differences were found in terms of distribution of age at diagnosis, tumor stage, nodal involvement, receptor status and histology. Cumulative survival rates at 5 years for cases without FH and with first-degree and second-degree FH for BC were 79.8 (95% CI 77.0-83.0), 78.6 (95% CI 70.0-88.0) and 80.2 (95% CI 68.0-92.0), respectively (log-rank test, chi(2) (2) = 0.02, p = 1.0). After adjustment for age, pathologic size and nodal involvement, the HR among cases of invasive cancer with a first-degree FH of BC was 0.91 (95% CI 0.55-1.48); however, the HR for cases with second-degree FH was 1.18 (95% CI 0.62-2.25) compared to cases without FH. Our study, based on a large series of consecutive invasive BC cases, did not find any significant survival differences associated with a positive FH for breast carcinoma, suggesting the existence of a large heterogeneity among BC cases with FH.

Combined small-cell lung carcinoma

Pemetrexed has been shown to improve survival in non-squamous cell NSCLC, and is the first drug to reveal differential survival benefit in large cell lung carcinoma. C-SCLC appear to express female hormone (i.e. estrogen and/or progesterone) receptors in a high (50–67%) proportion of cases, similar to breast carcinomas. However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC. Prognosis Current consensus is that the long-term prognosis of c-SCLC patients is determined by the SCLC component of their tumor, given that "pure" SCLC seems to have the worst long-term prognosis of all forms of lung cancer. Although data on c-SCLC is very sparse, some studies suggest that survival rates in c-SCLC may be even worse than that of pure SCLC, likely due to the lower rate of complete response to chemoradiation in c-SCLC, although not all studies have shown a significant difference in survival.

Clinical characteristics of breast cancer patients with family history.

This study was conducted to acquire information as to the clinicopathological characteristics of breast cancer patients with family history. Of 583 patients with breast cancer, 60 (10.3%) had family history in at least one relative within the second-degree. The affected family member was most frequently a sister (43%), followed by the mother (23%) and an aunt (20%). Comparison of the data for the patients between with and without family history revealed no significant differences for any of mean age, menopausal status, histological type, histological staging, and estrogen receptor status. Although the sample size was small, neither the survival rate nor the bilaterality of disease was influenced by the family history of breast cancer.

Selective estrogen receptor modulator

Tamoxifen is a first-line hormonal treatment of ER-positive metastatic breast cancer. It is used for breast cancer risk reduction in women at high risk, and as adjuvant treatment of axillary node-negative and node-positive, ductal carcinoma in situ. Tamoxifen treatment is also useful in the treatment of bone density and blood lipids in postmenopausal women. Adverse effects include hot flushes and more serious is two to three times higher relative risk of developing endometrial cancer compared to women of an age-matched population. Toremifene, a chlorinated tamoxifen derivative, causes fewer DNA adducts in liver than seen with tamoxifen in preclinical studies and was developed to avoid hepatic carcinomas. It is used as endocrine therapy in women with ER/PR-positive stage 4 or recurrent metastatic breast cancer and has demonstrated similar efficacy compared to tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer.

Parathyroid hormone 1 receptor

Interactions Parathyroid hormone 1 receptor has been shown to interact with Sodium-hydrogen exchange regulatory cofactor 2 and Sodium-hydrogen antiporter 3 regulator 1. Model organisms Model organisms have been used in the study of PTH1R function. A conditional knockout mouse line called Pth1rtm1a(EUCOMM)Hmgu was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping See also Parathyroid hormone receptor References Further reading External links G protein-coupled receptors

Prognosis of breast cancer patients with familial history classified according to their menopausal status.

Breast cancer patients were classified in the family history positive (FHP) group when they had at least one second-degree relative who was a breast cancer patient. The results of a comparative study with patients classified in the family history negative (FHN) group showed the prognosis of the FHP group was significantly better than that of the FHN group. However, when those patients were classified according to their menopausal status at onset, there were no significant differences in survival rates between the FHP and FHN groups with onset before menopause, whereas the survival rate of the FHP group was significantly higher than that of the FHN group with onset after menopause. The same results were found when the FHP group was subgrouped into the FHP group with first-degree relatives and the FHP group with second-degree relatives. Further investigations on background factors revealed that the patients with onset before menopause showed no significant differences between the FHP and FHN groups in age at surgery, diameter of the tumor, histologic grade, the number of metastatic lymph nodes, body weight, estrogen receptor (ER) status, and the values of CEA and CA15-3 before surgery. On the other hand, the FHP patients with onset after menopause showed significantly lower numbers of metastatic lymph nodes and trends showing higher ER values and lower CA15-3-values. Therefore the favorable prognosis in the FHP group seems to be attributable to the higher survival rate of the FHP patients with onset after menopause.

Karen E. Knudsen

Research Knudsen is an oncology researcher whose studies are focused on precision medicine in advanced prostate cancer, with an emphasis on understanding therapeutic relapse and designing new means of clinical intervention. Her translational studies have resulted in new clinical trials targeting DNA repair, cell cycle, and hormonal regulation pathways in patients with advanced disease. Knudsen and her colleagues discovered the mechanisms by which androgen signaling impacts cancer cell proliferation and DNA repair processes, and identified novel strategies for therapeutic intervention. Notable discoveries include identification of RB tumor suppressor loss as a major mechanism of therapeutic bypass, discovery of the androgen-DNA repair axis, and elucidation of androgen receptor function in the mitotic cell cycle. Her discoveries were amongst the first to propose utilization of PARP 1/2 inhibitors for advanced disease, now an FDA-approved agent for selected prostate cancers.

A clinicopathological analysis of breast cancer in patients with a family history.

A study was conducted to investigate the clinical and pathological characteristics of breast cancer in patients with a family history (FH). Among 4,481 primary breast cancer patients, 394 (8.8%) had families which included two or more breast cancer patients within three generations (FH(+)group). This group was compared with the remaining 3,969 patients (FH(-) group) with the following results: (1) The tumor diameter in the FH(+) group was slightly less than that in the FH(-) group [not significant (NS)], with fewer lymph node metastases (P < 0.05); (2) the positive rates for the estrogen receptor were 52% (138/266) and 49% (1,216/2,481), respectively (NS); (3) expression of the c-erbB-2 protein was observed in 14 out of 40 (35%) and 32 out of 100 cases (32%), respectively (NS); (4) the relative risk of bilateral occurrence in the FH(+) group was 1.4, with a 95% confidence interval of 0.9-2.4; (5) the 15-year survival rate was 72% and 60%, respectively, suggesting a better prognosis for the FH(+) group (P < 0.01); and (6) multivariate analysis showed that the contribution of FH to postoperative survival was marginal (P = 0.07). Factors related to the hormonal environment such as age at menarche (P = 0.08) and age at menopause (P = 0.08) made a greater but non-significant contribution to the prognosis of the FH(+) group than to that of the FH(-) group. However, further genetic and molecular biological analyses of familial breast cancer are needed in order to clarify the mechanisms of cancer accumulation within families.

Abemaciclib

As of early 2016, abemaciclib was involved in 3 Phase III clinical trials: The JUNIPER Study is comparing abemaciclib against erlotinib in patients with stage IV non-small-cell lung carcinoma Due to collect data until September 2017. The MONARCH 2 study is investigating the effectiveness of abemaciclib in combination with fulvestrant for women with breast cancer. It is due to end in Feb 2017. In March 2017, Eli Lilly announced that it had met its primary endpoint of superior progression-free survival (PFS) over placebo plus fulvestrant in patients with estrogen receptor positive and HER2 negative advanced or metastatic breast cancer. This result led to the September 2017 FDA approval. The MONARCH 3 study is investigating the effectiveness of abemaciclib, plus either anastrozole or letrozole, as a first-line treatment for women with breast cancer. The trial is expected to end in June 2017.

Dynamic angiothermography

DATG is able to detect changes in blood flow that are indicative of breast cancer, may be used for younger patients, is completely non-invasive (no need for radiation or contrast agent, no need for compression of the breast) and is lower cost than alternatives requiring minimal facilities. This technology, performed quickly (5–6 minutes for visit) and very precise, is useful for screening and is also able to detect precancerous lesions. Studies have been conducted that have shown how it is possible, by means of this methodology, to diagnose invasive ductal carcinoma and infiltrating lobular carcinoma with the same accuracy. DATG can be strategic for young patients, or patients with dense breasts where the contrastive performance of mammography is challenged. Another application of DATG is the monitoring of at-risk patients with increased changes of breast cancer who take hormone replacement therapy (sometimes taken to reduce menopause symptoms) and participate in in-vitro

Linking Histopathology and Family History in Breast Cancer.

In order to assess the prognostic value of family history (FH) of malignancies in patients afflicted with breast cancer (BC), we examined FH and histopathologic characteristics of 542 Iranian primary BC patients. Cases with distant metastasis at the time of diagnosis were excluded. Mean age of the studied population was 49 and the most common presenting stage was stage IIA followed by stage IIB. Data on a total of 6089 relatives (1st to 4th generations with the assumption of probands as the 3rd generation) were gathered. FH of BC and other malignancies (OM) was positive in 29 and 54% of cases, respectively. The most common OM's were gastric (67), lung (52) and uterus (47) cancers. We found that a FH of BC does not have any significant correlation with proven prognostic factors but a history of BC among relatives at or before the age of 36 is associated with more aggressive tumours. On the other hand, although FH of OM was associated with an older age of the probands (which is generally associated with a favourable prognosis), tumours of the cases with FH of OM had higher grades, lymphatic invasion being detected more frequently. Also we noted that the younger the age of the relatives diagnosed with cancer, the higher the stage of the probands themselves. All together our study indicates the possibility of a relation between FH of BC and OM, and histopathologic characteristics of the probands' tumours which would put forward FH as a prognostic factor rather than a simple risk factor in BC.

Retrospective analysis of clinicopathological characteristics and family history data of early-onset breast cancer: a single-institutional study of Hungarian patients.

Patients at young age (≤ 35 years) diagnosed with breast cancer (BC) are considered to have poor prognosis. The aim of the present study was to retrospectively analyse clinicopathological characteristics and prognosis in a group of young BC patients. We included women diagnosed with invasive breast carcinoma younger than/or at the age of 35 years. Between 1999 and 2009, 107 women with early-onset BC were selected from the database of the 2nd Department of Pathology at Semmelweis University. For clinicopathological comparison, 55 women (36-45 years), 214 women (46-65 years), 110 women (66-75 years) and 58 women (76 ≤ years) were also included in the analysis. Family history, clinicopathological and follow-up data were analysed. The tissue specimens were reviewed for histological type, nuclear grade, and estrogen receptor (ER), progesterone receptor (PgR), Ki67 and HER2 status (IHC4). The mean age in the study group was 31.6 years at the time of diagnosis. Histology showed a high incidence of grade III tumours in this group of patients (67.9 %), while only four cases (3.8 %) were considered grade I. According to the immunohistochemical results, 35.3 % of the study cases were considered as Luminal B (LumB: either being higly proliferative or co-expressing HER2) and 33.3 % as triple negative breast carcinomas (TNBC). The detailed questionnaire related to family history was completed and received in 49/107 cases (45.8 %). Analysis of these data revealed an affected family history of breast or ovarian carcinoma in first and second degree relatives in 51.0 %. A high proportion (52.0 %) of TNBC was observed among young women with a family history of the disease. Survival analysis of the 107 patients showed that 25 (23.3 %) women died until 31 December 2012. No significant difference in survival was detectable considering the regimen of systemic treatment (p = 0.188). Regarding clinicopathological parameters, the immunophenotypes, grade, pT and pN values differred substantially between the age groups (p = 0.001, for all), and the shortest relapse-free survival was seen among the youngest BC patients. This analysis illustrates that breast cancer arising in young women is characterized by the presence of less favorable subtypes such as LumB and TNBC. The increased proportion of TNBC was especially remarquable in the group of patients presenting with family history of the disease. The fact that a high rate of death occurred and no significant difference in OS were notable regarding the scheme of systemic therapies (neoadjuvant vs. adjuvant) highlight the necessity of the development of new treatment strategies.

Family History and Risk of Second Primary Breast Cancer after <i>In Situ</i> Breast Carcinoma.

<bBackground:</b Incidence rates of <iin situ</i breast carcinomas have increased due to widespread adoption of mammography. Very little is known about why some women with <iin situ</i breast cancer later develop second primary breast cancers.<bMethods:</b In this population-based nested case-control study among <iin situ</i breast cancer survivors, including 539 cases with a second primary breast cancer and 994 matched controls, we evaluated the association between first-degree family history of breast cancer and risk of developing a second primary breast cancer.<bResults:</b First-degree family history of breast cancer was associated with an increased risk of developing a second primary breast cancer among women with a previous <iin situ</i breast cancer [odds ratio (OR) = 1.33, 95% confidence interval (CI), 1.05-1.69] and those with two or more affected first-degree relatives had an even higher risk (OR = 1.94; 95% CI, 1.15-3.28). Those whose relative was diagnosed at less than 50 years old were more likely to develop a second primary breast cancer (OR = 1.78; 95% CI, 1.24-2.57). No difference in risks associated with number or age of affected relatives was observed by menopausal status.<bConclusions:</b Results from this study suggest that first-degree family history of breast cancer may be an important risk factor for development of a second primary breast cancer among women with a previous <iin situ</i breast cancer.<bImpact:</b Given the growing population of <iin situ</i breast cancer survivors, a better understanding of risk factors associated with development of a second primary breast cancer is needed to further understand risk. <iCancer Epidemiol Biomarkers Prev; 27(3); 315-20. ©2018 AACR</i.

CDH1 (gene)

Clinical significance Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis. E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues. E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive ductal carcinoma, E-cadherin expression is markedly reduced or absent in the great majority of invasive lobular carcinomas when studied by immunohistochemistry. E-cadherin and N-cadherin temporal-spatial expression are tightly regulated during cranial suture fusion in craniofacial development. Interactions CDH1 (gene) has been shown to interact with CBLL1, CDC27, CDON, CDH3, C-Met, CTNND1, CTNNB1, CTNNA1 FOXM1, HDAC1, HDAC2, IQGAP1, FYN, NEDD9, Plakoglobin, Vinculin, PTPmu(PTPRM) PTPrho(PTPRT)

Epidemiologic and genetic follow-up study of 544 Minnesota breast cancer families: design and methods.

In 1944, a case-control family study was initiated at the Dight Institute for Human Genetics at the University of Minnesota to study the influences of childbearing breastfeeding, and hereditary susceptibility on the occurrence and age-of-onset of breast cancer. Index cases (probands) were women ascertained at the Tumor Clinic of the University of Minnesota Hospital. Medical history and life style information were obtained on probands and relatives, and all cancers were histologically verified. A total of 544 families were studied, with probands diagnosed between 1931 and 1952. All of the records and pathology slides have been maintained from the original study; for most probands this includes the original tissue blocks. We are conducting a historical cohort study of selected of selected first- and second-degree female relatives (sisters, daughters, nieces, granddaughters) of the probands and a group of control women identified as the spouses of all male first- and second-degree relatives (brothers, sons, grandsons, and nephews). The subsequent development of breast cancer is being determined to quantify the absolute risk associated with a positive family history. Current disease status is ascertained with mammography, and stromal density is measured using digital imaging. Segregation analysis will be applied to examine how non-genetic factors such as diet, exogenous hormone use, and body fat distribution influence risk in women at high risk because of family history. A subset of families are being selected for molecular analysis of the BRCA1 gene or for linkage analyses to identify putative susceptibility loci other than BRCA1. Documented cancer histories were known for at least three generations, and the current study extends the pedigrees up to four or five generations for every family, allowing a detailed description of familial risk. This cohort study of breast cancer families is likely to be important in both quantity and quality of data and will serve as a major genetic epidemiologic resource, being free of selection bias and having relevant non-genetic exposure determined in at least four generations.