Radiation therapy plays a major role in the treatment of lung cancer patients. However, cancer cells develop resistance to radiation. Tumor radioresistance is a complex multifactorial mechanism which ...may be dependent on DNA damage and repair, hypoxic conditions inside tumor microenvironment, and the clonal selection of radioresistant cells from the heterogeneous tumor site, and it is a major cause of treatment failure in non-small cell lung cancer (NSCLC). In the present investigation caveolin-1 (CAV-1) has been observed to be highly expressed in radiation resistant A549 lung cancer cells. CRISPR-Cas9 knockout of CAV-1 reverted the cells to a radio sensitive phenotype. In addition, CAV-1 overexpression in parental A549 cells, led to radiation resistance. Further, gene expression analysis of A549 parental, radiation resistant, and caveolin-1 overexpressed cells, exhibited overexpression of DNA repair genes RAD51B, RAD18, SOX2 cancer stem cell marker, MMPs, mucins and cytoskeleton proteins in resistant and caveolin-1 over expressed A549 cells, as compared to parental A549 cells. Bioinformatic analysis shows upregulation of BRCA1, Nuclear Excision DNA repair, TGFB and JAK/STAT signaling pathways in radioresistant and caveolin-1 overexpressed cells, which may functionally mediate radiation resistance. Immunohistochemistry data demonstrated heterogeneous expression of CAV-1 gene in human lung cancer tissues, which was analogous to its enhanced expression in human lung cancer cell line model and mouse orthotopic xenograft lung cancer model. Also, TCGA PanCancer clinical studies have demonstrated amplification, deletions and missense mutation in CAV-1 gene in lung cancer patients, and that CAV-1 alteration has been linked to poor prognosis, and poor survival in lung cancer patients. Interestingly, we have also optimized ELISA assay to measure caveolin-1 protein in the blood of A549 radiation resistant human xenograft preclinical mouse model and discovered higher level of caveolin-1 (950 pg/ml) in tumor bearing animals treated with radiation, as compared to xenograft with radiosensitive lung cancer cells (450 pg/ml). Thus, we conclude that caveolin-1 is involved in radio-resistance and contributes to tumor aggression, and it has potential to be used as prognostic biomarker for radiation treatment response, and tumor progression for precision medicine in lung cancer patients.
This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors' review of the literature followed by discussions at the Endometrial Cancer ...Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and nonuniform diagnostic criteria used in many studies. High-grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits >50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these 2 histotypes are p53, p16, DNA mismatch repair proteins, PTEN, and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed "dedifferentiated carcinoma") is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.
Mesonephric‐like adenocarcinoma is a relatively rare neoplasm with morphology similar to mesonephric adenocarcinoma but unassociated with mesonephric remnants. Its relatively recent description and ...rarity make it difficult to diagnose, but it has a high rate of distant metastasis, making distinction from endometrioid carcinoma important. Descriptions of its cytologic features are particularly limited. We describe a case of mesonephric‐like adenocarcinoma diagnosed on transbronchial needle aspiration of the lung, that had been misdiagnosed as endometrioid endometrial adenocarcinoma on a prior hysterectomy. We discuss the characteristic cyto and histomorphology, immunoprofile, molecular alterations, and clinical significance of this uncommon tumor.
Although uterine leiomyosarcoma (ULMS) is a rare disease, it accounts for a significant proportion uterine cancer‐related deaths due to frequent metastasis and chemoresistance. The WHO currently ...recognizes the conventional (spindle), myxoid, and epithelioid variants of ULMS, the latter of which is the rarest, least understood, and cited as clinically more aggressive than the other variants. Descriptions of the histologic features of epithelioid ULMS are extremely limited, and are absent from the cytology literature which has only published descriptions of conventional ULMS or epithelioid variants of other LMS primaries. Therefore, we present a unique case of metastatic epithelioid ULMS to an unusual location, the pancreas, along with its cytologic features on endoscopic ultrasound‐guided fine needle aspiration not previously described including pseudoglandular arrangements, scant cytoplasm, and frequent molding.
The concept of critical diagnoses in anatomic pathology is relatively recent and rigorous study of the issue is quite limited. The College of American Pathologists and Association of Directors of ...Anatomic and Surgical Pathology issued a consensus statement in 2012. There has been no multi-institutional study of communication policies since then.
To survey the policies of anatomic pathology laboratories regarding communication of critical values.
A survey of the Association of Directors of Anatomic and Surgical Pathology membership was performed using a 14-question electronic survey tool.
Responses were received from 38 institutions. Thirty-five of 38 (92%) had a policy on anatomic pathology critical values. Twenty-five of 38 (66%) respondents had read the College of American Pathologists/Association of Directors of Anatomic and Surgical Pathology consensus statement. Twelve of 38 (32%) institutions divided critical values into two categories, of which 9 used the College of American Pathologists/Association of Directors of Anatomic and Surgical Pathology terminology; 24 used only a single term, of which 11 used critical value. There was substantial variation in the diagnoses that were considered critical. A direct phone call to the responsible provider was uniformly considered an acceptable means of communication; all other methods had mixed or low support. The most common time frame was same day; many laboratories did not specify a timeframe. Most laboratories document date, time, and person to whom the result was communicated in the final report or an addendum report. Eighteen of 38 (47%) laboratories report an auditing mechanism for communication.
Policies for communication of critical/urgent/significant, unexpected results in anatomic pathology are the norm. However, there remains significant variation between institutions in the details of these policies.
Context.—
The concept of critical diagnoses in anatomic pathology is relatively recent and rigorous study of the issue is quite limited. The College of American Pathologists and Association of ...Directors of Anatomic and Surgical Pathology issued a consensus statement in 2012. There has been no multi-institutional study of communication policies since then.
Objective.—
To survey the policies of anatomic pathology laboratories regarding communication of critical values.
Design.—
A survey of the Association of Directors of Anatomic and Surgical Pathology membership was performed using a 14-question electronic survey tool.
Results.—
Responses were received from 38 institutions. Thirty-five of 38 (92%) had a policy on anatomic pathology critical values. Twenty-five of 38 (66%) respondents had read the College of American Pathologists/Association of Directors of Anatomic and Surgical Pathology consensus statement. Twelve of 38 (32%) institutions divided critical values into 2 categories, of which 9 used the College of American Pathologists/Association of Directors of Anatomic and Surgical Pathology terminology; 24 used only a single term, of which 11 used critical value. There was substantial variation in the diagnoses that were considered critical. A direct phone call to the responsible provider was uniformly considered an acceptable means of communication; all other methods had mixed or low support. The most common time frame was same day; many laboratories did not specify a timeframe. Most laboratories document date, time, and person to whom the result was communicated in the final report or an addendum report. Eighteen of 38 (47%) laboratories report an auditing mechanism for communication.
Conclusions.—
Policies for communication of critical/urgent/significant, unexpected results in anatomic pathology are the norm. However, there remains significant variation between institutions in the details of these policies.
Background
Thyroid fine‐needle aspiration (FNA) plays a key role in triaging thyroid nodules. Yet many cases are assigned to indeterminate categories. The new category “noninvasive follicular thyroid ...neoplasm with papillary‐like features” (NIFTP) complicates thyroid cytology. Digital image‐derived nuclear measurements might objectively distinguish papillary thyroid carcinoma (PTC) from benign nodules and NIFTP.
Methods
All thyroid FNAs from 2012 to 2016 of atypia of undetermined significance (A; n = 8) and suspicious for malignancy (S; n = 2) with sufficient cellularity and surgical follow‐up, all FNAs preceding NIFTP (n = 6), and a random sample of PTC (n = 9) and benign (n = 10) cytology were studied. A modified Giemsa‐stained slide from each case was scanned using the Aperio imaging system, and long (dl) and short (ds)‐axis diameters were measured for 125 nuclei per case. Nuclear area and elongation were calculated.
Results
Nuclear area was larger in PTC (mean, 77.2 μm2 range, 70.6‐86.0 μm2) than benign (mean, 43.3 μm2 range 38.2‐52.2 μm2) (P < .001). Nuclear areas from indeterminate FNAs segregated according to final histology (A/S PTC mean 72.7 μm2, A/S benign mean 53.7 μm2; P = 0.004), and were not significantly different from definitive FNAs of the same diagnosis. NIFTP nuclear area was smaller than PTC (mean, 54.8 μm2 range, 46.7‐66.1 μm2; P < .001). Nuclear elongation showed similar results, but with greater group overlap.
Conclusion
Nuclear area and elongation can be calculated using a commercial digital imager; both correlate with the final surgical pathology diagnosis of PTC versus benign, including NIFTP. Area provides greater resolution than elongation. This technique could be used to resolve indeterminate cytology in which PTC is considered.
Nuclear area and elongation of thyroid follicular cells in fine‐needle aspiration (FNA) cytology can be readily calculated using a commercially available whole slide imager and digital image analysis software. These measurements successfully stratify thyroid FNAs according to their final surgical diagnosis, including most cases that are initially interpreted as atypia of undetermined significance or follicular lesion of undetermined significance, and also distinguish most cases of noninvasive follicular thyroid neoplasm with papillary‐like features from papillary thyroid carcinoma.
The microtubule-stabilizing agent docetaxel in combination with gemcitabine represents one of the most effective regimens against the aggressive gynecologic tumor leiomyosarcoma (LMS). Upregulation ...of class III β-tubulin has previously been shown to confer taxane resistance in a variety of human cancers. Prostaglandin E2 receptor EP4 is linked to progression of a variety of human cancers and may represent a novel target for tumor inhibition in LMS. We evaluated the hypotheses that EP4 and class III β-tubulin have increased expression in LMS in comparison to normal myometrium or benign tumors and that expression of class III β-tubulin correlates with resistance to taxanes and poor clinical outcome. Gene expression was examined using TCGA data and correlated with clinicopathologic outcome which demonstrated that class III β-tubulin is more highly expressed in more aggressive sarcomas with EP4 being widely expressed in all subtypes of sarcoma. Immunohistochemistry for EP4 and class III β-tubulin was performed on patients with LMS, leiomyomatosis/STUMP, leiomyoma, and normal myometrium. Expression of EP4 and class III β-tubulin were characterized for cell lines SK-UT-1, SK-UT-1B, and PHM-41 and these cell lines were treated with docetaxel alone and in combination with EP4 inhibitors. In taxane-resistant cell lines that overexpress class III β-tubulin and EP4, treatment with EP4 inhibitor resulted in at least 2-fold sensitization to docetaxel. Expression of class III β-tubulin and EP4 in LMS may identify patients at risk of resistance to standard chemotherapies and candidates for augmentation of therapy through EP4 inhibition.
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