Pathologic chemotherapy response score in epithelial ovarian cancer: Surgical, genetic, and survival considerations.

OBJECTIVE: A pathologic chemotherapy response score (CRS) is used to grade ovarian cancer response to neoadjuvant chemotherapy (NACT). We evaluated the prognostic significance of the CRS in a single institution cohort. METHODS: A retrospective review of all consecutive epithelial ovarian cancer patients undergoing interval debulking surgery (IDS) after NACT from 2016 to 2017 were included. Clinical, pathologic, surgical, outcomes, and genetic data were abstracted from medical records. CRS was assigned by pathology based on a section of omentum as follows: 1 = minimal response, 2 = moderate response, and 3 = near complete response. RESULTS: Among the 50 subjects, 14 (28%) were classified as CRS1, 29 (58%) as CRS2, and 7 (14%) as CRS3. The majority of patients were diagnosed with high grade serous histology (94%). Most women in this cohort underwent either an optimal or complete cytoreduction to no gross residual disease (96%). Women in the CRS2 group were most likely to have a pathogenic variant (51.7%) while those in the CRS1 were least likely (7.1%). Most women recurred regardless of CRS. CRS was not associated with progression-free survival (log-rank p = 0.82) or overall survival (log-rank p = 0.30). CONCLUSIONS: Though previous data support the use of CRS as a prognostic indicator, we failed to show a correlation between CRS and survival in our continuous single institution cohort. The high rate of optimal debulking across all CRS groups in this study may mitigate the prognostic significance of the scoring system. Nevertheless, tumors that respond poorly to traditional chemotherapy should remain of avid interest for potential novel therapies.

The Microcystic, Elongated, and Fragmented (MELF) Pattern of Invasion: A Single Institution Report of 464 Consecutive FIGO Grade 1 Endometrial Endometrioid Adenocarcinomas.

MELF invasion has been associated with nonvaginal recurrences and lymph node (LN) metastases in multi-institutional case control studies but has not been well examined in large single-institution cohorts. Hysterectomy specimens with FIGO 1 endometrioid endometrial carcinoma and lymphadenectomies from 2007 to 2012 were identified. Electronic medical records and histologic slides were reviewed. Of 464 identified cases, 163 (35.1%) were noninvasive, 60 (12.9%) had MELF, 222 (47.8%) had a component of the infiltrative invasion pattern without MELF, 13 (2.8%) had pure pushing borders of invasion, 5 (1.1%) had pure adenomyosis-like invasion, and 1 (0.2%) had pure adenoma malignum-like invasion. Sixteen cases had LN metastases. Significantly more MELF cases had positive LNs than non-MELF cases overall (18.3% vs. 1.2%, P<0.001). The results were almost identical when invasive infiltrative cases with and without MELF were compared (18.3% vs. 1.8%, P<0.001). The maximum number of MELF glands per slide did not differ between cases with and without LN metastases, P=0.137. A majority of positive LNs, even in MELF cases, demonstrated nonhistiocyte-like metastases. Only 5 cases (all with MELF invasion) demonstrated micrometastatic lesions or isolated tumor cells only. MELF cases demonstrated a nonsignificant decrease in time to extravaginal recurrence (P=0.082, log-rank test), for which analysis was limited by low recurrence rates. In summary, MELF is associated with LN metastases, even when compared with other infiltrative cases and shows multiple patterns of growth in positive LNs. MELF cases additionally trended toward decreased time to extravaginal recurrence.

Pancreatic neuroendocrine microadenomatosis: A case report of cytology and histology correlation.

Pancreatic neuroendocrine neoplasia is categorized by grade, size, and functional status. Neuroendocrine microadenoma (NEMA) is defined as a neuroendocrine tumor (NET) that measures less than 0.5 cm in diameter. Multiple NEMAs are termed neuroendocrine adenomatosis (NEMAtosis). The surgical pathology and clinical aspects of pancreatic NEMAtosis have been reported, but there has been no report regarding EUS-FNA cytology of NEMAtosis. We report a case of NEMAtosis with cytologic correlation and illustrate the diagnostic challenges and potential pitfalls. The pre-operative cytology can be problematic. The main differential diagnosis of the EUS-FNA specimen includes NET, normal pancreas, and islet cell hyperplasia/aggregation associated with chronic pancreatitis. The helpful cytopathologic feature of NEMAtosis is the presence of two intermingled populations of loosely-cohesive neuroendocrine cell clusters and tight acinar cell groups arranged in microacinar and/or grape-like structures. Although neuroendocrine cells and acinar cells possess different cytomorphology, the distinction is not always straightforward because both types of cells are small and cytologically bland. Cytologic assessment of both architecture and individual cell morphology is imperative to avoid interpretation error and further guide appropriate clinical management. Diagn. Cytopathol. 2017;45:143-147. © 2016 Wiley Periodicals, Inc.

Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.

Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, and afatinib). The basis of this primary resistance is poorly understood. We studied a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients, and found that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770_N771insNPG) reveals an unaltered adenosine triphosphate-binding pocket, and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770_N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763_Y764insFQEA is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763_Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs.

Patterns of care for non-small-cell lung cancer at an academic institution affiliated with a national cancer institute-designated cancer center.

PURPOSE: Evidence-based treatment guidelines for non-small-cell lung cancer (NSCLC) exist to improve the quality of care for patients with this disease. However, how often evidence-based decisions are used for care of NSCLC is poorly understood. PATIENTS AND METHODS: We examined patterns of care and rate of adherence to evidence-based guidelines for 185 new NSCLC patients seen between 2007 and 2009. Evidence-based care status was determined for 150 patients. RESULTS: Eighty-one percent of the patients were white, the mean age was 66 years, 49% were women, 11% were never smokers, 83% had Eastern Cooperative Oncology Group performance status 0 to 1, 49.7% of tumors were adenocarcinomas, 57.1% of never smokers had tumors genotyped (EGFR, ALK, KRAS), and 13.3% participated in clinical trials. The rate of evidence-based treatment adherence was 94.1% (16 of 17), 100% (21 of 21) and 100% (36 of 36) in patients with stages I, II, and III NSCLC, respectively. Stage IV disease, with adherence of 76.3% (58 of 76), was correlated with a higher rate of nonadherence when compared with stages I-III (odds ratio 16.33; 95% CI, 1.94 to 137.73). In patients with stage IV disease, the rate of evidence-based adherence was 95% (72 of 76) for first-line therapy, 95.2% (40 of 42) for second-line therapy, and only 33.3% (6 of 18) for third-line therapy (P < .001). There was no significant correlation between evidence-based adherence status and the patient's age, sex, performance status, smoking history, ethnicity, or the treating physician. CONCLUSION: These data point toward the need for improved evidence-based use of resources in the third-line setting of stage IV NSCLC.

Integrated optical coherence tomography and optical coherence microscopy imaging of ex vivo human renal tissues.

PURPOSE: We evaluated the feasibility of using optical coherence tomography and optical coherence microscopy technology to assess human kidney morphology. MATERIALS AND METHODS: A total of 35 renal specimens from 19 patients, consisting of 12 normal tissues and 23 tumors (16 clear cell renal cell carcinomas, 5 papillary renal cell carcinomas and 2 oncocytomas) were imaged ex vivo after surgical resection. Optical coherence tomography and optical coherence microscopy images were compared to corresponding hematoxylin and eosin histology to identify characteristic features of normal and pathological renal tissues. Three pathologists blinded to histology evaluated the sensitivity and specificity of optical coherence microscopy images to differentiate normal from neoplastic renal tissues. RESULTS: Optical coherence tomography and optical coherence microscopy images of normal kidney revealed architectural features, including glomeruli, convoluted tubules, collecting tubules and loops of Henle. Each method of imaging renal tumors clearly demonstrated morphological changes and decreased imaging depth. Optical coherence tomography and microscopy features matched well with the corresponding histology. Three observers achieved 88%, 100% and 100% sensitivity, and 100%, 88% and 100% specificity, respectively, when evaluating normal vs neoplastic specimens using optical coherence microscopy images with substantial interobserver agreement (κ = 0.82, p <0.01). CONCLUSIONS: Integrated optical coherence tomography and optical coherence microscopy imaging provides coregistered, multiscale images of renal pathology in real time without exogenous contrast medium or histological processing. High sensitivity and specificity were achieved using optical coherence microscopy to differentiate normal from neoplastic renal tissues, suggesting possible applications for guiding renal mass biopsy or evaluating surgical margins.

Integrated optical coherence tomography and microscopy for ex vivo multiscale evaluation of human breast tissues.

Three-dimensional (3D) tissue imaging methods are expected to improve surgical management of cancer. In this study, we examined the feasibility of two 3D imaging technologies, optical coherence tomography (OCT) and optical coherence microscopy (OCM), to view human breast specimens based on intrinsic optical contrast. Specifically, we imaged 44 ex vivo breast specimens including 34 benign and 10 malignant lesions with an integrated OCT and OCM system developed in our laboratory. The system enabled 4-µm axial resolution (OCT and OCM) with 14-µm (OCT) and 2-µm (OCM) transverse resolutions, respectively. OCT and OCM images were compared with corresponding histologic sections to identify characteristic features from benign and malignant breast lesions at multiple resolution scales. OCT and OCM provide complimentary information about tissue microstructure, thus showing distinctive patterns for adipose tissue, fibrous stroma, breast lobules and ducts, cysts and microcysts, as well as in situ and invasive carcinomas. The 3D imaging capability of OCT and OCM provided complementary information to individual 2D images, thereby allowing tracking features from different levels to identify low-contrast structures that were difficult to appreciate from single images alone. Our results lay the foundation for future in vivo optical evaluation of breast tissues, using OCT and OCM, which has the potential to guide core needle biopsies, assess surgical margins, and evaluate nodal involvement in breast cancer.

Ex vivo imaging of human thyroid pathology using integrated optical coherence tomography and optical coherence microscopy.

We evaluate the feasibility of optical coherence tomography (OCT) and optical coherence microscopy (OCM) for imaging of benign and malignant thyroid lesions ex vivo using intrinsic optical contrast. 34 thyroid gland specimens are imaged from 17 patients, covering a spectrum of pathology ranging from normal thyroid to benign disease/neoplasms (multinodular colloid goiter, Hashimoto's thyroiditis, and follicular adenoma) and malignant thyroid tumors (papillary carcinoma and medullary carcinoma). Imaging is performed using an integrated OCT and OCM system, with <4 microm axial resolution (OCT and OCM), and 14 microm (OCT) and <2 microm (OCM) transverse resolution. The system allows seamless switching between low and high magnifications in a way similar to traditional microscopy. Good correspondence is observed between optical images and histological sections. Characteristic features that suggest malignant lesions, such as complex papillary architecture, microfollicules, psammomatous calcifications, or replacement of normal follicular architecture with sheets/nests of tumor cells, can be identified from OCT and OCM images and are clearly differentiable from normal or benign thyroid tissues. With further development of needle-based imaging probes, OCT and OCM could be promising techniques to use for the screening of thyroid nodules and to improve the diagnostic specificity of fine needle aspiration evaluation.

Photothermal optical coherence tomography in ex vivo human breast tissues using gold nanoshells.

We demonstrate photothermal optical coherence tomography (OCT) imaging in highly scattering human breast tissue ex vivo. A 120 kHz axial scan rate, swept-source phase-sensitive OCT system at 1300 nm was used to detect phase changes induced by 830 nm photothermal excitation of gold nanoshells. Localized phase modulation was observed 300-600 microm deep in scattering tissue using an excitation power of only 22 mW at modulation frequencies up to 20 kHz. This technique enables integrated structural and molecular-targeted imaging for cancer markers using nanoshells.

A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry.

PURPOSE: Approximately 5% of lung adenocarcinomas harbor an EML4-ALK gene fusion and define a unique tumor group that may be responsive to targeted therapy. However ALK-rearranged lung adenocarcinomas are difficult to detect by either standard fluorescence in situ hybridization or immunohistochemistry (IHC) assays. In the present study, we used novel antibodies to compare ALK protein expression in genetically defined lung cancers and anaplastic large cell lymphomas. EXPERIMENTAL DESIGN: We analyzed 174 tumors with one standard and two novel monoclonal antibodies recognizing the ALK protein. Immunostained tissue sections were assessed for the level of tumor-specific ALK expression by objective quantitative image analysis and independently by three pathologists. RESULTS: ALK protein is invariably and exclusively expressed in ALK-rearranged lung adenocarcinomas but at much lower levels than in the prototypic ALK-rearranged tumor, anaplastic large cell lymphoma, and as a result, is often not detected by conventional IHC. We further validate a novel IHC that shows excellent sensitivity and specificity (100% and 99%, respectively) for the detection of ALK-rearranged lung adenocarcinomas in biopsy specimens, with excellent interobserver agreement between pathologists (kappa statistic, 0.94). CONCLUSIONS: Low levels of ALK protein expression is a characteristic feature of ALK-rearranged lung adenocarcinomas. However, a novel, highly sensitive IHC assay reliably detects lung adenocarcinomas with ALK rearrangements and obviates the need for fluorescence in situ hybridization analysis for the majority of cases, and therefore could be routinely applicable in clinical practice to detect lung cancers that may be responsive to ALK inhibitors.