Clinical relevance of gene mutations and rearrangements in advanced differentiated thyroid cancer.

BACKGROUND: Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making. MATERIALS AND METHODS: We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development. RESULTS: A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006). CONCLUSIONS: Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC.

Adenocarcinoma classification: patterns and prognosis.

Lung cancer is the most frequent human malignancy and the principal cause of cancer-related death worldwide. Adenocarcinoma is now the main histologic type, accounting for almost half of all the cases. The 2015 World Health Organization has adopted the classification recently developed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification has incorporated up-to-date advances in radiological, molecular and oncological knowledge, providing univocal diagnostic criteria and terminology. For resection specimens, new entities have been defined such as adenocarcinoma in situ and minimally invasive adenocarcinoma to designate adenocarcinomas, mostly nonmucinous and ≤ 3 cm in size, with either pure lepidic growth or predominant lepidic growth with ≤ 5 mm invasion, respectively. For invasive adenocarcinoma, the new classification has introduced histological subtyping according to the predominant pattern of growth of the neoplastic cells: lepidic (formerly non mucinous brochioloalveolar adenocarcinoma), acinar, papillary, micropapillary, and solid. Of note, micropapillary pattern is a brand new histologic subtype. In addition, four variants of invasive adenocarcinoma are recognized, namely invasive mucinous (formerly mucinous brochioloalveolar adenocarcinoma), colloid, fetal, and enteric. Importantly, three variants that were considered in the previous classification have been eliminated, specifically mucinous cystadenocarcinoma, signet ring cell, and clear cell adenocarcinoma. This review presents the changes introduced by the current histological classification of lung adenocarcinoma and its prognostic implications.

[Thyroid maltoma: report of a case without coexistent Hashimoto's thyroiditis]. / Maltoma della tiroide: presentazione di un caso non associato a tiroidite di Hashimoto.

Maltomas of the thyroid are rare neoplasms that originate from parafollicular B lymphocytes and are often associated with autoimmune thyroiditis (Hashimoto's disease). The authors describe a case of a primary thyroid lymphoma in which no evidence for a previous thyroiditis could be found during clinical evaluation (clinical progression of the tumor, diagnostic studies, preoperative cytology, histology of the surgical specimen). Noteworthy was the development of a severe form of pure red cell aplasia (PRCA) about 6 months after the operation without detectable autoantibodies or signs of previous viral infection. The aplasia resolved completely with corticosteroid therapy.

Oncocytic carcinoma (malignant oncocytoma) of the breast.

Three cases of oncocytic carcinoma of the breast observed in two women and one man are reported. One tumor was in situ and two were invasive. All three tumors were composed mostly of cells with "low-grade" nuclei and abundant granular eosinophilic cytoplasm. More than 70% of the neoplastic population in each case was immunoreactive with an antimitochondrion antibody. The presence of numerous mitochondria also was demonstrated at the ultrastructural level. Apocrine cells and oncocytes share similar morphologic features at the hematoxylin-eosin level; however, there are some differences that allow a confident distinction between these two cell types. Mitochondria in apocrine cells usually are in a perinuclear location and are not so numerous and diffusely dispersed as in oncocytes. In addition, apocrine cells display features of active secretory elements: prominent microvilli, well-developed Golgi complex, and electron dense secretory granules polarized toward the luminal pole; all these features were lacking in the three cases described. The cells constituting the present cases were not positive at the immunohistochemical and molecular levels for GCDFP-15/PIP mRNA, which are typical markers of apocrine differentiation. We suspect that mammary oncocytoma is a more common tumor than the meager number of reported cases suggests.

Breast tumor resembling the tall cell variant of papillary thyroid carcinoma: report of 5 cases.

Five cases of a hitherto undescribed breast tumor having histologic features similar to those of the tall cell variant papillary thyroid carcinoma are described. They were composed of columnar mitochondrion-rich to oxyphilic cells arranged in nests, papillae, and follicle-like structures. In addition, the neoplastic cells showed numerous nuclear grooves and, in two cases, nuclear pseudo-inclusions. None of the patients had previous concomitant or subsequent evidence of a thyroid tumor. Immunohistochemistry further excluded a metastasis from the thyroid in the four cases tested, as they were consistently thyroglobulin and thyroid transcription factor 1 negative.

Small cell neuroendocrine carcinoma with skeletal muscle differentiation: report of three cases.

Three cases of neuroendocrine carcinoma showing skeletal muscle differentiation are presented. The tumors were located in the skin and subcutaneous tissue, the urinary bladder, and the nasal cavity respectively, and were composed by two cell types admixed intimately with each other. One cell type had features identical to those seen in conventional small cell neuroendocrine carcinoma, including scanty cytoplasm, round nuclei with fine granular chromatin, immunohistochemical reactivity for neuron-specific enolase, chromogranin and cytokeratins, and electron-dense granules on ultrastructural examination. The second cell type was either plasmacytoid or elongated and straplike, with abundant eosinophilic cytoplasm and irregular nuclei with prominent nucleoli. These cells showed immunohistochemical positivity for desmin, sarcomeric actin, myoglobin, and myogenin. They also exhibited ultrastructural evidence of rhabdomyoblastic differentiation in the form of contractile filaments with abortive Z-band formation. An origin from a cell capable of dual differentiation toward neuroendocrine and rhabdomyoblastic elements is postulated for these tumors.

Evaluation of a new ambulatory blood pressure device.

We assessed the OSCILL-IT ambulatory blood pressure (BP) recorder (FIGI sr1, Rome, Italy) according to the performance criteria set out by the British Hypertension Society (BHS) protocol. The OSCILL-IT is a portable, noninvasive recorder that uses a process that correlates systolic, mean, and diastolic areas, identified on the oscillations, to the cuff absolute pressure. According to the recommendations of BHS, a large heterogeneous population (100 subjects: 52 men aged from 19 to 79--median 44 and 48 women from 19 to 74--median 54) was recruited in order to assess accuracy and to analyze, in addition, the effects of observer agreement and BP level on the observer-device differences. With reference to BP level, we suggest also a new graphic approach. Four sets of sequential, same arm, comparative BP measurements were obtained, performed by the OSCILL-IT recorder and two skilled clinicians using a mercury column, for each subject. We used a linear combination for the statistical evaluations. We confirmed the observer agreement through the frequency distribution of BP as a function of the observer and through the differences between observers. We compared OSCILL-IT with sphygmomanometric readings: the differences were not significant. A visual inspection, with the addition of regression lines, showed that there were no variations in differences at the changing of BP level. The difference between observers and OSCILL-IT was 0.2 +/- 5.3 mm Hg and 0.2 +/- 5.8 mm Hg both for systolic BP (SBP) and diastolic BP (DBP). The level of agreement, according to BHS criteria, showed that 64% of all systolic and 70% of all diastolic readings obtained by the OSCILL-IT were within 5 mm Hg of the sphygmomanometric determinations. Therefore, the grade is C for SBP, even if 93% of SBP and 95% of DBP obtained by the OSCILL-IT were within 10 mm Hg of the sphygmomanometric determinations. These analyses demonstrate that the OSCILL-IT satisfies the accuracy parameters and the additional linear regression yields graphics more immediate.

Cytologic grading of aggressive and nonaggressive variants of papillary thyroid carcinoma.

To distinguish preoperatively between the usual nonaggressive (classic, follicular, and mixed-papillary and follicular variants) and the aggressive (tall-cell, columnar-cell, and sclerosing diffuse) variants of papillary thyroid carcinoma (PTC), the fine-needle aspiration cytologic smears of 30 cases of PTC were retrospectively reviewed. A three-class grading system, based on the evaluation of four cytologic parameters (cell size, number of nuclear pseudoinclusions, nuclear pleomorphism, and type of chromatin), was applied to each case. A statistically significant association between the cytologic classes and the histologic features of the cases was found. All cytologic grade 1 cases corresponded to the nonaggressive histologic variants, whereas all cytologic grade 3 cases showed features of the aggressive variants of PTC at histologic level.

Gynecomastia in type-1 neurofibromatosis with features of pseudoangiomatous stromal hyperplasia with giant cells. Report of two cases.

We describe the histological finding in two cases of gynecomastia in patients with von Recklinghausen's disease. The histological and immunohistochemical features of the two cases were reviewed and compared with those of five cases of gynecomastia in men without clinical evidence of neurofibromatosis. In both patients bearing von Recklinghausen's disease, the breast stroma showed features consistent with pseudoangiomatous stromal hyperplasia (PASH). It was characterised by anastomosing empty spaces lined by spindle and multinucleated giant cells which were positive with CD34 and anti-vimentin antisera and negative with anti-FVIII and CD31 antisera. In two of five of the control cases without neurofibromatosis, the mammary stroma showed focal areas with features of PASH, but no multinucleated giant cells were present in any case. PASH with giant cells should be recognised as a feature of gynecomastia in von Recklinghausen's disease. The presence of multinucleated giant cells is very unusual and, although more cases have to be studied, these cells seem to be a feature of PASH occurring in patients with von Recklinghausen's disease.

GANT-like gastrointestinal pacemaker cell tumours with oncocytic features.

We describe two cases of gastrointestinal stromal tumours with prominent oncocytic features. Both had features consistent with differentiation towards the interstitial cells of Cajal (CC). They were composed of nests and bundles of cells with abundant, deeply granular, eosinophilic cytoplasm. Immunohistochemical investigations revealed positivity with c-kit, vimentin and CD34 antibodies in both neoplasms. Ultrastructurally the neoplastic cells showed characteristic features of CC; they had synapse-like structures and dense core cytoplasmic granules. Oncocytic features were confirmed by immunohistochemistry using anti-mitochondrion antibody in both cases and by electron microscopy in one case (case 1). Although the CC are frequently described as mitochondrion-rich cells, oncocytic changes have not previously been reported as a feature of gastrointestinal autonomic nerve tumour (GANT)-like stromal tumours.

Solitary fibrous tumour (myofibroblastoma) of the breast.

Three new cases of the spindle cell tumour of the breast, usually termed myofibroblastoma, are reported. The histology and the immunological profile (expression of vimentin, CD34 antigen and of muscular markers) appear similar to those of solitary fibrous tumours recently described in various sites. It is proposed to include these mammary lesions into the group of solitary fibrous tumours and to regard breast as an additional site of origin.

Acinic cell carcinoma of the breast: an immunohistochemical and ultrastructural study.

The clinicopathological features of six cases of breast carcinomas showing features of acinic cell differentiation, which are similar to those seen in homologous tumors of salivary glands, are presented. The patients, all women, were 35-80 years of age. One case recurred after 4 years, and in two cases axillary lymph node metastases were found at the time of surgery. Histologically the tumors showed a microglandular pattern merging with solid areas. Cytologically, immunohistochemically, and ultrastructurally the tumors were very similar to cases of acinic cell carcinoma of the parotid gland. The differential diagnostic criteria with microglandular adenosis and carcinomas showing granular cytoplasm are discussed. It seems that acinic cell carcinomas of the breast have to be added to the long list of tumors that affect the salivary glands and can also arise in the breast.

Mammary foam cells. Characterization by immunohistochemistry and in situ hybridization.

Cells showing abundant, finely vacuolized cytoplasm (foam cells) are found frequently in most benign lesions of the breast and in certain malignant breast tumours. The origin of mammary foam cells (FCs) has not been clarified, and we therefore studied the morphological features of mammary FCs in a series of 50 benign lesions. The FCs were subdivided, on the basis of their distribution into FCs lining the glandular lumina, intraluminal FCs, intraepithelial-pagetoid FCs, and stromal FCs. The lesions were tested with a panel of antibodies against macrophage (MAC 387, CD68) and epithelial (epithelial membrane antigen [EMA], gross cystic disease fluid protein 15 [GCDFP15] and cytokeratin) markers. The lesions were examined for the presence of PIP/GCDFP15-specific mRNA by an in situ hybridization technique. Three different types of FCs were identified. Type A FCs are epithelial cells (positivity with EMA and cytokeratin) and show apocrine differentiation (positivity with GCDFP15 antiserum and expression of PIP/GCDFP15 mRNA). Type B FCs are of macrophage origin, as they are positive with the macrophage markers and lack cytokeratin and PIP/GCDFP15 mRNA. Finally, type C FCs show an intermediate profile between an epithelial cell and a macrophage: they are both CD68 and GCDFP15 positive and show a thin peripheral rim of positivity with anti-cytokeratin antibody. They lack PIP/GCDFP15 mRNA. Our results indicate the possibility of a spectrum of phenotypes in mammary FCs, from epithelial-apocrine cells to macrophage-derived phagocytic cells.

Myoepithelial cells and basal lamina in poorly differentiated in situ duct carcinoma of the breast. An immunocytochemical study.

A retrospective study was made of 38 selected brest tumours with a poorly differentiated in situ duct component. These were classified on haematoxylin and eosin (H&E) as ductal carcinoma in situ (DCIS; 10 cases), DCIS with invasion (17 cases) and DCIS with features suggestive of for stromal invasion (11 cases). The last were these lesions composed of neoplastic ducts with irregular outlines and a myoepithelial layer that was not clearly evident or large neoplastic ducts growing close together or surrounded by inflammatory desmoplastic stroma. Cases of DCIS involving areas of sclerosing adenosis were included in this category. Consecutive sections obtained from each case were studied with a panel of antibodies against myoepithelial cells (alpha smooth muscle actin and calponin) and basal lamina (BL) components (laminin and type IV collagen). It was found that in situ lesions showed well-formed basal lamina and/or an evident myoepithelial layer. These features were lacking in the invasive areas. Nine of the 11 cases with suggestive features of stromal invasion were reclassified as invasive duct carcinoma (5 cases)and DCIS (4 cases), according to the absence or presence of a continuous myoepithelial layer and/or basal lamina. In 2 such cases immunohistochemistry yielded equivocal results and the label "suggestive of invasion" was therefore pertinent. Immunohistochemistry facilitates the diagnosis of breast DCIS; myoepithelial and basal lamina markers are useful in differentiating microinvasive from in situ ductal carcinomas of the breast.

Analysis of blood pressure rhythms for drug efficacy evaluation.

This study analyzes some methods of evaluating the effects of antihypertensive drugs on blood pressure circadian rhythm. We reviewed four different approaches: hourly averages, trough-to-peak ratio, cosinor method, and Fourier series applied to the same data to prove the time course of the effects of isradipine administered once daily. A total of 141 patients of both sexes (mean age 53 years, range 30-76) with mild to moderate essential hypertension were enrolled in this multicenter trial after a 2-week placebo run-in. Treatment with isradipine SRO 5 mg/day administered between 8 and 9 AM was started. Each patient underwent ambulatory BP monitoring at the time of entry and after 6 weeks of treatment. Calculation of hourly averages showed decreases after 4 AM, and from about 8-9 AM, when the drug was administered, and the decreases practically did not vary until about 10 PM. Subsequently, the decreases became smaller and indicated reduced drug activity. However, this hypothesis no longer held after 4 AM. The trough-to-peak ratio was calculated including hourly averages after the dose divided by the lowest hourly average. Both systolic and diastolic blood pressure showed constant reduction from 3 PM (time of peak) to 11 PM. However, after 11 PM, higher trough-to-peak ratios paradoxically occurred due to a major reduction obtained with placebo, and the negative percentages just before the next dose cannot be attributed to treatment. Applying the cosinor method, maximal values were greatly underestimated, nocturnal values were overestimated, and the absolute maximum occurred in proximity to the minimum relating to postprandial dip. The generalized cosinor model, known as Fourier partial series, was always curtailed to the third harmonic. Fourier analysis was able to describe the daily trend of BP both before and after isradipine administration. We used statistical tests to determine if the differences described by the models were significant. The tests indicated significant mean level reductions after therapy and no appreciable amplitude and phase-related variations. The nocturnal and periawakening intervals, in which BP changed linearly, oscillated between 3 and 4 hours. Within these intervals BP rose by 13-16 mm Hg or fell by 14-19 mm Hg. The intervals, ranges, and speed differences were tested and were never significant. The medication tested was effective only at the mean level, the variables used to characterize the time course of its effect remaining unchanged. There was no significant phase shift of the curves, and BP rhythm was preserved.

Predictors of death and neurologic impairment in pediatric submersion injuries. The Pediatric Risk of Mortality Score.

OBJECTIVE: To evaluate the Pediatric Risk of Morality Score (PRISM score) as a tool to distinguish which patients presenting to the emergency department (ED) or pediatric intensive care unit (PICU) would survive neurologically intact from those who would die or survive with severe neurologic impairment following a submersion incident. DESIGN: Retrospective chart review. SETTING: A regional tertiary care ED and PICU. MATERIALS: Medical records of drowning and near-drowning patterns between the ages of 1 day and 18 years who were admitted to the ED or PICU from January 1986 through December 1995. MAIN OUTCOME MEASURES: For each patient, a PRISM score was calculated based on data collected at the time of arrival to the ED or PICU. A "probability of outcome" was calculated using the PRISM score. Outcomes were defined as survival with intact neurologic function, survival with severe neurologic impairment, or death, and were assessed using the Pediatric Cerebral Performance Category Scale. Scores and probabilities of outcome were compared with the actual outcome for both the ED and PICU patients using the Fisher exact test (2 tailed). RESULTS: All Ed patients with PRISM scores less than 25 or a probability of outcome less than 50% (n = 40) survived with intact neurologic function (P < .001). All ED patients with PRISM scores of 25 or greater or a probability of outcome of 50% or greater (n = 10) either died or survived with severe neurologic impairment (P < .001). All PICU patients with a PRISM score of 5 or less (n = 25) or a probability of outcome less than 4% (n = 30) survived with intact neurologic function (P < .05). All PICU patients with a PRISM score greater than 20 or a probability of outcome greater than 50% either died or survived with severe neurologic impairment (P < .05). Outcomes could not accurately be predicted in PICU patients when the PRISM scores were 6 or greater and < or = 20 or less (n = 10), or when the probability of outcomes was 4% or greater and 50% or less. CONCLUSIONS: The PRISM scoring system accurately distinguished ED patients who would survive neurologically intact from those who would die or suffer neurologic impairment. There was not a specific PRISM score or probability of outcome that could distinguish PICU patients who would survive neurologically intact from those who would die or suffer severe neurologic impairment. The PRISM scoring system appeared to be more accurate in distinguishing intact survival from death or neurologic impairment in ED patients than in PICU patients.

Ambulatory blood pressure recording in diabetic patients with abnormal responses to cardiovascular autonomic function tests.

The aim of our study was to analyse the 24-h periodic pattern of blood pressure (BP) in diabetic patients with abnormal responses to cardiovascular reflexes, in order to evaluate the extent of the initial autonomic damage. We studied 44 patients with diabetes mellitus (14 insulin-dependent, 30 non-insulin-dependent; mean duration of disease 6.5 +/- 1.8 years) in good metabolic control (fasting glycaemia less than 140 mg/dl, postprandial glycaemia less than 180 mg/dl, fructosamine less than 285 mg/dl), divided into two subgroups, containing 21 normotensives (13 males and 8 females aged 28-72 years) and 23 hypertensives (13 males and 10 females aged 32-70 years) respectively. All patients showed abnormal responses to at least two out of four tests: deep breathing, lying to standing, Valsalva manoeuvre and postural hypotension. Two sex- and age-matched control groups were recruited, comprising 20 normotensive and 20 hypertensive diabetic patients without dysautonomia, respectively. The reference group consisted of 248 normotensives (135 males and 113 females, aged 18-76 years) and 212 mild-moderate hypertensives (130 males and 82 females, aged 27-66 years). Each patient underwent ambulatory BP monitoring for at least 24 h, using an auscultatory automatic device. Data concerning biological rhythms were analysed by means of periodic functions. We limited the Fourier partial sums to the first three harmonics.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary rhabdomyosarcoma of the ileum in an adult.

We report a case of primary rhabdomyosarcoma of the ileum occurring in a 45-year-old man. The rhabdomyoblastic nature was immunohistochemically confirmed by positivity with anti-myoglobin and anti-striated actin antisera. We discuss the differential diagnosis with similar tumors. To our knowledge, ileal rhabdomyosarcomas have not been previously reported in adults.

Eosinophilic and granular cell tumors of the breast.

Eosinophilic and granular cell tumors of the breast are a heterogeneous group encompassing both epithelial and mesenchymal lesions. A granular appearance of the cytoplasm may be caused by the accumulation of secretory granules, mitochondria, or lysosomes. In the breast, mucoid carcinomas, carcinomas showing apocrine differentiation, and neuroendocrine carcinomas are well known entities, while tumors with oncocytic and acinic cell differentiation have been only recently recognized. An abundance of lysosomes is characteristic of Schwannian granular cell neoplasms, but smooth muscle cell tumors also may have this cytoplasmic feature. Awareness of all these possibilities when granular cells are found in breast lesions improves diagnostic accuracy and helps to avoid misdiagnosis of both benign lesions and malignant tumors.