Marino E. Leon

Evaluation of ThyroSeq v2 performance in thyroid nodules with indeterminate cytology

ThyroSeq v2 claims high positive (PPV) and negative (NPV) predictive values in a wide range of pretest risks of malignancy in indeterminate thyroid nodules (ITNs) (categories B-III and B-IV of the Bethesda system). We evaluated ThyroSeq v2 performance in a cohort of patients with ITNs seen at our Academic Cancer Center from September 2014 to April 2016, in light of the new diagnostic criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Our study included 182 patients (76% female) with 190 ITNs consecutively tested with ThyroSeq v2. Patient treatment followed our institutional thyroid nodule clinical pathway. Histologies of nodules with follicular variant papillary thyroid carcinoma or NIFTP diagnoses were reviewed, with reviewers blinded to molecular results. ThyroSeq v2 performance was calculated in nodules with histological confirmation. We identified a mutation in 24% (n = 45) of the nodules. Mutations in RAS were the most prevalent (n = 21), but the positive predictive value of this mutation was much lower (31%) than that in prior reports. In 102 resected ITNs, ThyroSeq v2 performance was as follows: sensitivity 70% (46-88), specificity 77% (66-85), PPV 42% (25-61) and NPV 91% (82-97). The performance in B-IV nodules was significantly better than that in B-III nodules (area under the curve 0.84 vs 0.57, respectively; P = 0.03), where it was uninformative. Further studies evaluating ThyroSeq v2 performance are needed, particularly in B-III.

A randomized phase II efficacy and correlative studies of cetuximab with or without sorafenib in recurrent and/or metastatic head and neck squamous cell carcinoma

INTRODUCTION A combination of cetuximab and sorafenib in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) were assessed for potential benefit. MATERIAL AND METHODS In a randomized phase II study, R/M HNSCC patients were treated with cetuximab 400mg/m(2) IV on day 1 followed by 250mg/m(2) IV weekly (Arm A), or cetuximab at the same dose/schedule plus sorafenib 400mg PO twice-a-day (Arm B). Each cycle was 21days. Tumor p16 and HPV status, and plasma immunomodulatory cytokine levels were assessed. RESULTS Of 55 patients enrolled (Arm A-27, Arm B-28), 52 patients received assigned treatments and 43 were evaluable for response. Overall response rate was 8% for both arms. Median overall survival (OS) and progression-free survival (PFS) were 9.0 and 3.0months in Arm A, and 5.7 and 3.2months in Arm B, respectively. Forty-four patients had tumors available for p16 staining (35-negative, 9-positive). Three of nine p16-positive tumors were also HPV positive. The p16-negative patients had significantly better PFS compared to the p16-positive patients (3.7 vs. 1.6months; p-value: 0.03), regardless of study arms. Twenty-four plasma samples were tested for 12 cytokine levels and patients with higher TGFβ1 levels had inferior PFS compared to lower levels (1.9 vs. 4.7months; adjusted p-value: 0.015), regardless of study arms. CONCLUSIONS A subset of R/M patients with p16-negative tumors or lower plasma TGFβ1 levels had longer PFS given the cetuximab-based therapy. However, both arms showed only modest response and sorafenib given with cetuximab did not demonstrate clinical benefit.

Institutional prevalence of malignancy of indeterminate thyroid cytology is necessary but insufficient to accurately interpret molecular marker tests

OBJECTIVE Several molecular marker tests are available to refine the diagnosis of thyroid nodules. Knowing the true prevalence of malignancy (PoM) within each cytological category is considered necessary to select the most appropriate test and to interpret results accurately. We describe our institutional PoM among cytological categories and report our experience with molecular markers. DESIGN Single-center retrospective study. METHODS We calculated the institutional PoM for each category of the Bethesda system (Bethesda) on all thyroid nodules with cytological evaluation from October 2008 to May 2014. We estimated the predictive values for Afirma, miRInform, and ThyroSeq v2, based on published sensitivity and specificity. Finally, we assessed our own experience with miRInform. RESULTS The PoMs for Bethesda III and IV categories were 21 and 28%, respectively. ThyroSeq v2 achieves the highest theoretical negative and positive predictive values (NPV and PPV) in Bethesda III (98 and 75%) and Bethesda IV categories (96 and 83%). At our institution, miRInform detected a mutation in 16% of 109 indeterminate nodules tested, all in Bethesda IV specimens. Histology was available in 56 (51%) nodules. The observed sensitivity and specificity in Bethesda IV specimens were 63 and 86%, yielding an NPV and a PPV of 75 and 77%, respectively. CONCLUSIONS For our current Bethesda III and IV PoM, the actual performance of miRInform was worse than expected. Theoretically ThyroSeq v2 should have the best performance, but it could be affected in the same way as miRInform, given the similarities between the tests. Assessing the institutional performance of each test is necessary along with PoM individualization.

Diagnostic digital cytopathology: Are we ready yet?

Background: The cytology literature relating to diagnostic accuracy using whole slide imaging is scarce. We studied the diagnostic concordance between glass and digital slides among diagnosticians with different profiles to assess the readiness of adopting digital cytology in routine practice. Materials and Methods: This cohort consisted of 22 de-identified previously screened and diagnosed cases, including non-gynecological and gynecological slides using standard preparations. Glass slides were digitalized using Aperio ScanScope XT (×20 and ×40). Cytopathologists with (3) and without (3) digital experience, cytotechnologists (4) and senior pathology residents (2) diagnosed the digital slides independently first and recorded the results. Glass slides were read and recorded separately 1-3 days later. Accuracy of diagnosis, time to diagnosis and diagnostician′s profile were analyzed. Results: Among 22 case pairs and four study groups, correct diagnosis (93% vs. 86%) was established using glass versus digital slides. Both methods more (>95%) accurately diagnosed positive cases than negatives. Cytopathologists with no digital experience were the most accurate in digital diagnosis, even the senior members. Cytotechnologists had the fastest diagnosis time (3 min/digital vs. 1.7 min/glass), but not the best accuracy. Digital time was 1.5 min longer than glass-slide time/per case for cytopathologists and cytotechnologists. Senior pathology residents were slower and less accurate with both methods. Cytopathologists with digital experience ranked 2 nd fastest in time, yet last in accuracy for digital slides. Conclusions: There was good overall diagnostic agreement between the digital whole-slide images and glass slides. Although glass slide diagnosis was more accurate and faster, the results of technologists and pathologists with no digital cytology experience suggest that solid diagnostic ability is a strong indicator for readiness of digital adoption.

Sinonasal small round blue cell tumors: An approach to diagnosis.

The differential diagnosis for small round cell tumors in the sinonasal tract is diverse and as the body of literature documenting not only uncommon presentations but also availability of ancillary studies grows, so does the need for a reminder to take a conservative and thorough approach before rendering a diagnosis. Small tissue samples are particularly problematic, with limitations that include volume of tumor cells available for studies, lack of architectural context and a non-specific gross description. Incorporation of patient history and presentation, radiologic findings, clinical impression and concurrent studies often guide the course of studies performed by the pathologist. If these are non-specific, the pathologist may need to perform ancillary studies, including a broad panel of immunohistochemical stains and molecular studies. If tissue is limited, a precise classification may not be achievable. Although the expectation to render a definitive diagnosis is high, the pathologist should never feel compelled to go further with a diagnosis than the tissue itself supports.

Salivary Duct Carcinoma of the Parotid Outcomes with a Contemporary Multidisciplinary Treatment Approach

Objective Salivary duct carcinoma (SDC) is a rare and aggressive malignancy for which an optimal treatment algorithm is lacking. We endeavored to assess the current treatment outcomes for SDC with a multimodality treatment approach combining surgery with adjuvant radiotherapy ± concurrent chemotherapy. Study Design Case series with chart review. Setting A National Cancer Institute–designated comprehensive cancer center. Subjects and Methods The clinical record of 17 patients with salivary duct carcinoma were analyzed to assess locoregional control, recurrence-free survival, and overall survival. Results All SDC cases (n = 17) were managed with surgical resection, followed by adjuvant radiotherapy (47.1%) or concurrent chemotherapy and radiotherapy (52.9%). Median patient follow up was 37 months. An aggressive disease course was generally observed, with 3-year recurrence-free survival and overall survival of 34.4% and 35.5%, respectively. The majority of recurrences were distant. Intensification with adjuvant concurrent chemotherapy was not associated with improved outcomes on univariate survival analysis. Conclusion For salivary duct carcinoma, a multimodality treatment approach is associated with acceptable locoregional control rates but poor distant control and overall survival. Novel systemic therapies may be needed to optimize clinical outcomes.

Assessment of cholecystokinin 2 receptor (CCK2R) in neoplastic tissue

The expression of cholecystokinin 2 receptor (CCK2R, CCKBR or gastrin receptor) has been reported on a diverse range of cancers such as colorectal, liver, lung, pancreatic, ovarian, stomach, thyroid and numerous neuroendocrine/carcinoid tumors. Some cancers of the colorectum, lung, pancreas and thyroid have been shown to overexpress CCK2R in relation to normal matched tissues of the same organ. This reported overexpression has led to the development of a number of CCK2R-ligand targeted imaging and therapeutic agents. However, no comprehensive study comparing the expression of CCK2R in multiple cancers to multiple normal tissues has been performed. Herein, we report the immunohistochemical analysis of cancer samples from gastrointestinal stromal tumor (GIST), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), pancreatic adenocarcinoma, and thyroid cancer against multiple normal tissue samples from esophagus, liver, lung, pancreas, stomach, spleen and thyroid. These results show that CCK2R expression is present in nearly all cancer and normal samples tested and that none of the cancer samples had expression that was statistically greater than that of all of the normal samples.

Molecular Assays in Cytopathology for Thyroid Cancer

BACKGROUND Despite lack of adequate, validated, independently performed clinical studies, several molecular tests are commercially available on the market and are being used on indeterminate thyroid nodules to guide patient-care decisions. METHODS We summarize the current evidence on the role and limitations of molecular tests used in combination with thyroid cytopathology to refine the presurgical diagnosis of thyroid nodules. RESULTS The clinical performance of molecular tests depends on the pretest risk of malignancy within the specific cytological group being assessed. This risk is variable and should be assessed at each institution to optimize the selection of the molecular test and the interpretation of its results. Next-generation sequencing has increased the sensitivity of oncogene panels while maintaining high specificity. Tests assessing the gene expression pattern have shown promising results, with high sensitivity but low specificity. The impacts of molecular markers on clinical practice remains in flux and their effect on health care costs remains poorly understood. CONCLUSIONS Further large, independent, confirmatory, clinical validation studies and real-world, cost-effectiveness studies are necessary before the widespread adoption of these tests can be endorsed as standard of care.

Hypermetabolism on (18)F-Fluorodeoxyglucose Positron Emission Tomography Scan Does Not Influence the Interpretation of Thyroid Cytopathology, and Nodules with a SUVmax <2.5 Are Not at Increased Risk for Malignancy.

BACKGROUND Hypermetabolism of thyroid nodules on (18)F-fluorodeoxyglucose positron emission tomography (PET) is associated with a higher prevalence of malignancy. However, the definition of hypermetabolism and its impact on cytological interpretation are unclear. METHODS Medical records of all patients with thyroid nodules who had undergone cytological evaluation at the Moffitt Cancer Center between October 2008 and May 2014 were retrospectively reviewed. Those with a PET scan performed within one year of the cytology composed the study group, and the rest were used as controls. The distribution of the cytological categories, percentage of resection, and prevalence of malignancy among each Bethesda category was compared between both groups. RESULTS Fifteen percent (436) of all thyroid nodules with cytological evaluation were in the study group. Maximum standardized uptake values (SUVmax) were directly associated with the probability of having a malignant or a follicular neoplasm cytological diagnosis; and inversely associated with the probability of having a benign cytological diagnosis. However, the prevalence of cancer within each Bethesda category was not associated with SUVmax values. It was found that the prevalence of malignant cytology increased to >5% with SUVmax values ≥2.5. SUVmax values were significantly higher in malignant than in benign nodules on histology (mean values 10.8 vs. 5) but with significant overlap between both groups for either the whole cohort or nodules with indeterminate cytology only limiting its use for differential diagnosis. CONCLUSIONS The prevalence of malignancy in thyroid nodules with a SUVmax <2.5 is similar to the general population, and management should not be modified in those patients. The increased prevalence of malignancy among hypermetabolic thyroid nodules (SUVmax ≥2.5) is well characterized by cytology and does not impact the interpretation of cytological categories. Therefore, SUVmax value does not add relevant information once cytology is available.

Regarding Bocklage et al. “Regarding Dettloff et al. Mammary Analog Secretory Carcinoma (MASC) Involving the Thyroid Gland: A Report of First 3 Cases”

Dear Dr. Thompson, This letter is in response to the letter by Dr. Therese J. Bocklage et al. [1]. Our original intention was to indicate the fact that our publication was the first series of thyroid cases (albeit small) under the following title: Mammary Analog Secretory Carcinoma (MASC) involving the thyroid gland: a report of the first 3 cases [2]. We agree that the chronological events presented by Bocklage et al. are correct and the words ‘‘the first’’ should be removed for clarity [1]. Our paper was submitted and was received by Head and Neck Pathology on May 11, 2016. Our revision was submitted for final review on June 13, 2016. Our paper was accepted for publication on June 24, 2016 and was available for as electronic publication on July 11, 2016 [2]. Of note, in our publication, we did include the first published case of thyroid involvement by a carcinoma with mammary analog secretory carcinoma morphology [3]. The case by Reynolds et al. became available on line as electronic publication ahead of print in Head and Neck Pathology on April 13, 2016 [4]; this single case was included in our discussion and in our references [2]. On June 10, 2016, the publication by Dogan et al. [5] became available on line as electronic publication ahead of print. This latter publication was not included in our review of literature. We echo the sentiments of the authors in that these cases are important to identify since they would (as expected) not appear to respond to radioactive iodine. We would also add given the limited case number and followup, there is still concern that at least some of the cases reported to date may be metastases or extension from