Immunocytochemistry Profile of Benign Thyroid Nodules Not Responding to Thermal Ablation: A Retrospective Study.

Purpose: Thermal ablations (TA) are gaining ground as alternative options to conventional therapies for symptomatic benign thyroid nodules. Little is known about the impact of nodule biology on the outcomes of TA. The aim of our study was to evaluate the baseline immunocytochemistry profile of thyroid nodules that were poorly responsive to TA in order to identify potential predictors of the treatment response. Methods: From a cohort of 406 patients with benign thyroid nodules treated with TA and followed for 5 years, we retrospectively selected two groups of patients: NONRESPONDERS (patients who did not respond to TA and were later surgically treated) and RESPONDERS (patients who responded to TA). The fine-needle aspiration cytology (FNAC) slides obtained before TA were stained for Galectin-3, HBME-1, CK-19, and Ki-67. Results: Benign nodules of NONRESPONDERS (n = 19) did not express CK-19 (p = 0.03), as compared to RESPONDERS (n = 26). We combined the absence of CK-19 and the presence of Ki-67 to obtain a composite biomarker of resistance to TA, which discriminated between likelihood of retreatment and no retreatment with an AUC of 0.68 (95%CI: 0.55-0.81) and a sensitivity, specificity, PPV, and NPV of 29%, 91%, 71%, and 64%, respectively. Conclusion: In benign thyroid nodules, the absence of CK-19 was associated with resistance to TA, while the presence of CK-19 was predictive of response to TA. If confirmed, this finding could provide rapid and inexpensive information about the potential outcome of TA on benign thyroid nodules. In addition, as CK-19 can be expressed in adenomatous hyperplasia, it could be speculated that these nodules, rather than follicular adenomas, might be better candidates for TA.

An innovative synthetic support for immunocytochemical assessment of cytologically indeterminate (Bethesda III) thyroid nodules.

Background: Fine needle aspiration (FNA) is the procedure of choice in the evaluation of thyroid nodules. Nodules with indeterminate cytological categories, Bethesda III and IV, pose challenges in clinical practice and are frequently submitted to diagnostic surgery. CytoFoam Core (CFCS) uses an absorbent foam device inserted into the needle hub to collect the cytological sample aspirated during FNA. Specimen is formalin-fixed and paraffin-embedded. Aim of the study: Assessing diagnostic efficacy of CFCS, compared to traditional cytology, in re-evaluating thyroid nodules classified as Bethesda III, using post-surgical histology as reference standard. Method: Retrospective study on 89 patients with a first indeterminate cytological report who were referred to the Department of Endocrinology of Regina Apostolorum Hospital (Albano L. Rome, Italy) for a second FNA. FNA was performed after at least one month under ultrasound guidance with a 23G needle according to the established procedure. During the second procedure, both traditional cytological (TC) smears and a single-pass CFCS specimen were obtained for each patient. On CFCS samples immunocytochemical staining for Galectin-3, HBME-1, and CK-19 was also performed. 51 patients eventually underwent surgery, and their histological diagnoses were compared to the TC and CFCS reports. Four parameters were evaluated: inadequacy rate, rate of persistent indeterminate (Bethesda III and IV) reports, rate of malignancy in persistently indeterminate nodules, and rate of cancer in lesions cytologically classified as malignant. Results: Non-diagnostic samples were 6 (11.8%) in TC vs 3 (5.9%) in CFCS (p=0.4). Persistent indeterminate samples were 31 (60.8%) in TC vs 19 (37.2%) in CFCS (p=0.01). Rate of malignancy in persistently indeterminate nodules was 8/19 (42.1%) in CFCS vs 9/31 (29%) in TC group (p=0.3). Nine/51 (17.6%) samples were classified as benign by TC vs 21/51 (41.2%) samples by CFCS (p<0.01). All nodules resulted benign at post-surgical evaluation. Five/51 (9.8%) samples were classified as suspicious for malignancy/malignant in TC group against 8/51 (15.7%) samples in CFCS (p=0.5). Post-surgical evaluation confirmed malignancy in all these cases. Conclusion: CFCS demonstrated greater diagnostic accuracy than TC in repeat FNA assessment of cytologically indeterminate nodules. CFCS increased the conclusive diagnosis rate and decreased the number of cytologically indeterminate cases.

DOG-1 positive primary acinic cell carcinoma of the lung and investigation of molecular status.

Primary acinic cell carcinoma (ACC) of the lung is an extremely rare neoplasm that more often arises near to a right bronchus. It is characterized by two populations of clear and dark eosinophilic cells, arranged in a glandular acinar pattern. Mitosis are rare and tumor cells show small and eccentric nuclei. Positive stain for PAS, PAS-D, cytokeratin, A1AT and A1ACT is reported, while TTF1, p40, synaptophysin, SMA, and S100 are substantially negative. DOG-1 positive stain was observed in ACC of the salivary glands and its negativity was proposed to distinguish between primary and metastatic ACC of the lung. Here, we report the 30th case of primary ACC of the lung, describing the immunohistochemical positivity for DOG-1 and the molecular status of the neoplasm for the first time.

Evaluating programmed death-ligand 1 (PD-L1) in head and neck squamous cell carcinoma: concordance between the 22C3 PharmDx assay and the SP263 assay on whole sections from a multicentre study.

AIMS: The introduction of immunotherapy for patients with head and neck squamous cell carcinoma (HNSCC) raises the need for harmonisation between different types of antibody and immunohistochemistry platform for evaluating the expression of PD-L1 by use of the combined positive score (CPS) in this tumour. The aim of this study was to compare the expression of PD-L1 as determined with the CPS and two widely used assays (the 22C3 PharmDx assay and the SP263 assay) in a cohort of HNSCCs. METHODS AND RESULTS: We analysed 43 whole sections of HNSCC with two different anti-PD-L1 antibodies, 22C3 and SP263. The results, expressed as the CPS, were evaluated by 10 trained pathologists and statistical analyses were performed. We found a very similar results for PD-L1 expression between the 22C3 PharmDx assay and the SP263 assay in our cohort, and a strong and significant correlation between the two assays for all specimens (P < 0.0001). The interobserver reliability among pathologists for the continuous scores of CPS with the intraclass correlation coefficient and the correlation between the two assays were both good. Moreover, the rate of agreement between assays was high at all cut-offs and was best for the most relevant cut-off of CPS ≥ 1, and the kappa values were always in the range of almost perfect. CONCLUSIONS: Two different assays (the 22C3 PharmDx assay and SP263 assay) for PD-L1 in HNSCC showed high agreement. These data suggest that these two assays are interchangeable in the selection of patients with HNSCC for immunotherapy.

Carcinomas of the Thyroid with Ewing Family Tumor Elements (CEFTEs): A Diagnostic Challenge Before Surgery.

Carcinomas of the thyroid with Ewing family tumor elements (CEFTEs) are small cell thyroid tumors characterized by epithelial differentiation and EWSR1-FLI1 rearrangements. In contrast to primary thyroid Ewing sarcomas, these rare tumors have a favorable prognosis. CEFTEs may co-exist with papillary thyroid carcinoma (PTC) foci and are thought to arise from either PTCs or main cells of solid cell nests (SCN). Due to their rare occurrence, characteristic clinical presentations, preoperatory sonographic (US) findings, and fine-needle aspiration (FNA) cytologic features were ill-defined until now. We report a case of a 40-year-old male who was referred to the thyroid clinic for a progressively enlarging, hard, painless, cervical mass. US examination revealed a hypoechoic nodule with lobulated margins and scant intranodular vascular signals of the right thyroid lobe. Evidence of extracapsular spread was not identified. FNA provided a Bethesda V cytology classification on conventional smears. Repeat FNA sampling with the use of a CytoFoam Core allowed a preoperative diagnosis consistent with undifferentiated thyroid carcinoma. Total thyroidectomy without lymph node dissection was performed. Histologic examination with subsequent molecular studies provided the diagnosis of papillary carcinoma of the thyroid with Ewing family tumour elements (CEFTEs). No additional treatment was rendered and the patient showed no evidence of local or distant disease by clinical examination, US, and 18FDG-TAC/PET after 6 months of follow-up. This is the first reported case of CEFTE with complete clinical, US, cytologic, and immunohistochemical preoperatory assessment.

Colorectal cancer metastatic to the breast: A case report.

BACKGROUND: Breast metastases from colorectal cancer (CRC) are very uncommon. There is no unanimous consensus regarding the best treatment for this rare condition, and management is, especially in elderly patients, limited to diagnosis and palliative care. Capecitabine, an oral fluoropyrimidine derivative, might be helpful in controlling the disease and may be a treatment option for patients unable to receive more aggressive chemotherapy. CASE SUMMARY: We report a case of synchronous massive breast metastasis from CRC in an 85 year old patient who came to the hospital presenting a huge mass originating from the axillary extension of the right breast. A whole body computed tomography also showed a mass in the right colon. The patient underwent a simple right mastectomy along with right hemicolectomy. The resected breast showed massive metastasis from CRC with intense and homogeneous nuclear CDX2 staining, while the colon specimen revealed poorly differentiated adenocarcinoma stage pT4a pN0 pM1 (breast) (Tumor Node Metastasis 2017). Three months later she developed a subcutaneous mass at the site of the previous mastectomy. An ultrasound guided biopsy was carried out again and revealed a metastasis from CRC. The patient then started treatment with capecitabine plus bevacizumab, obtaining stable disease (RECIST criteria) and a clinical benefit after 3 mo of therapy. CONCLUSION: In our experience, capecitabine and bevacizumab may be a useful treatment option for breast metastases from primary CRC in elderly patients.

Morphological and Molecular Assessment in Thyroid Cytology Using Cell-Capturing Scaffolds.

The increased frequency of thyroid nodules is paralleled by the rise of thyroid cancer diagnosis. To define the nature of most thyroid nodules, fine needle aspiration (FNA) followed by cytological evaluation is considered the method of choice. About 20% of FNA biopsies on thyroid nodules, however, show indeterminate cytological features and may require diagnostic surgery. Several immunocytochemical and molecular markers have been proposed to improve classification of thyroid nodules, but these tests require adequate cell amount and cytological paraffin inclusion. Polymeric matrices were recently proposed for the collection of cells for diagnostic purposes. In this study, we evaluated the diagnostic use of a new matrix (CytoMatrix). Morphological, molecular and immunohistochemical investigations were carried out on 23 FNA samples included in CytoMatrix and compared with data obtained from the definitive histology of surgical samples. Our results showed that CytoMatrix is suitable to capture and preserve the cellularity of the samples harvested by FNA and that its paraffin sections mimic the morphology of those obtained from real histological tissue. Immunohistochemistry on CytoMatrix samples was consistent with the immunophenotypical profile of the corresponding histological surgical specimens. Mutational analysis of the BRAF (V600E) gene performed on CytoMatrix inclusions and paired surgical tissue matched in all but one cases while matrix immunohistochemistry identified 91.6% of BRAF mutated samples. In conclusion, we suggest that CytoMatrix could be a reliable tool to overcome the current limits of traditional collection methods for the study of thyroid cytology, thereby improving their reliability for a conclusive diagnostic interpretation.

Predictive Value of Malignancy of Thyroid Nodule Ultrasound Classification Systems: A Prospective Study.

Context: British Thyroid Association (BTA), American Thyroid Association (ATA), and American Association of Clinical Endocrinologists (AACE/ACE/AME) recommend for thyroid nodules an ultrasound (US)-based stratification of risk of malignancy. Aim of our study was to assess the diagnostic accuracy of US classification systems and their reliability for indication to fine-needle aspiration (FNA). Design: Prospective study on 987 thyroid nodules consecutively referred for FNA. US images were independently reviewed by four experts for assignment of malignancy risk. Cytologically benign nodules had confirmation with a second FNA, whereas Bethesda class IV, V, and VI nodules were operated upon. Class III nodules had surgery or follow-up on the basis of clinical, immunocytochemical, and US features. Results: BTA: Malignancy rate was 2.8% in benign, 10.0% in indeterminate, 51.3% in suspicion, and 80.9% in malignant US class. Sensitivity was 0.74, specificity was 0.92, and accuracy was 0.89. ATA: Malignancy rate was 0.0% in benign, 2.2% in very low suspicion, 3.0% in low suspicion, 5.8% in intermediate, and 55.0% in high suspicion US class. Sensitivity was 0.81, specificity was 0.87, and accuracy was 0.86. AACE/ACE/AME: Malignancy rate was 1.1% in low-risk, 4.4% in intermediate-risk, and 54.9% in high-risk US class. Sensitivity was 0.82, specificity was 0.87, and accuracy was 0.86. K correlation coefficient was 78.9%, 76.9%, and 82.0% for BTA, ATA, and AACE/ACE/AME classifications. Conclusions: Classification systems had elevated predictive value of malignancy in high-risk classes. ATA and AACE/ACE/AME systems were effective for ruling out indication to FNA in low-US-risk nodules. A similar diagnostic accuracy and a substantial interobserver agreement was provided by the three- and the five-category classifications.

The use of core needle biopsy as first-line in diagnosis of thyroid nodules reduces false negative and inconclusive data reported by fine-needle aspiration.

BACKGROUND: The reported reliability of core needle biopsy (CNB) is high in assessing thyroid nodules after inconclusive fine-needle aspiration (FNA) attempts. However, first-line use of CNB for nodules considered at risk by ultrasonography (US) has yet to be studied. The aim of this study were: 1) to evaluate the potential merit of using CNB first-line instead of conventional FNA in thyroid nodules with suspicious ultrasonographic features; 2) to compare CNB and FNA as a first-line diagnostic procedure in thyroid lesions at higher risk of cancer. METHODS: Seventy-seven patients with a suspicious-appearing, recently discovered solid thyroid nodule were initially enrolled as study participants. No patients had undergone prior thyroid fine-needle aspiration/biopsy. Based on study design, all patients were proposed to undergo CNB as first-line diagnostic aspiration, while those patients refusing to do so underwent conventional FNA. RESULTS: Five patients refused the study, and a total of 31 and 41 thyroid nodules were subjected to CNB and FNA, respectively. At follow-up, the overall rate of malignancy was of 80% (CNB, 77%; FNA, 83%). However, the diagnostic accuracy of CNB (97%) was significantly (P < 0.05) higher than that of FNA (78%). In one benign lesion, CNB was inconclusive. Four (12%) of the 34 cancers of the FNA group were not initially diagnosed because of false negative (N = 1), indeterminate (N = 2) or not adequate (N = 1) samples. CONCLUSIONS: CNB can reduce the false negative and inconclusive results of conventional FNA and should be considered a first-line method in assessing solid thyroid nodules at high risk of malignancy.

Thin core biopsy should help to discriminate thyroid nodules cytologically classified as indeterminate. A new sampling technique.

Indeterminate neoplasms (IN) represent the gray zone of thyroid cytology in which malignant and benign tumors cannot be discriminated. Recently, the approach by thin core needle biopsy has been proposed. Here we report a new thin core needle biopsy approach in 40 consecutive patients with thyroid IN at cytology. In this study, a 21-G needle was inserted into the nodule, advanced within the lesion, and moved ahead reaching extranodular tissue. The resulting sample allowed to evaluate the cytomorphology of nodular tissue, its relationship with extranodular parenchyma, and the nodule's capsule when present. All biopsies were adequate for diagnosis but one. Of the 39 adequate samples, 5 cases were papillary cancer as confirmed at histology, while 14 nodules avoided surgery because of Hürthle cell hyperplasia in thyroiditis (n = 6) and microfollicular adenomatous hyperplasia (n = 8). The remaining 20 cases were assessed as follicular neoplasms because of encapsulation and were evaluated by immunohistochemistry. Of these, 6 had positive markers in different degree and 1/6 has follicular cancer at histology, while the other 14 were benign after surgery. Overall, this approach by thin core needle biopsy identified benignancy in 14/40 (35 %) IN avoiding surgery. As a conclusion, thin core biopsy should help to discern the nature of thyroid lesions cytologically classified as indeterminate, and it should be used as a complementary test in thyroid nodule assessment.

Analysis of differential therapeutic strategies for primary breast lymphoma: two case reports.

Primary breast lymphoma (PBL) is a rare form of extranodal non-Hodgkin's lymphoma (NHL), whose own specific biological characteristics still need to be fully defined. No significant prognostic factor has been found and the optimal therapeutic strategy is uncertain. However, an intensified systemic therapy has been advocated to prevent relapse, even in patients who show a complete response to local treatment. We report two cases of primary diffuse large B-cell breast lymphoma, review the literature about this topic, and discuss treatment options. We conclude that differential therapeutic strategies based on the risk of relapse associated with the International Prognostic Index (IPI) are a reasonable way to approach PBL, and can avoid undue toxicity deriving from treatment.

Kaposi sarcoma of the stomach: a case report.

A 60-year-old man presented with persistent dysphagia and weight loss of 2-months duration. An upper GI endoscopy revealed mycotic oesophagitis and chronic gastritis with two ulcers of the gastric body and antrum. Repeat endoscopy was performed after medical treatment failed, and histological examination on new biopsy samples led to a diagnosis of Kaposi sarcoma of the stomach. HIV infection was not known at this time; however, the patient was tested after the diagnosis of Kaposi sarcoma was made and found to be HIV positive. An adequate biopsy sampling was required for histological diagnosis and the use of immunohistochemical markers, especially human herpesvirus 8 (HHV8) antibodies, supplied valid diagnostic support. This case underlines the importance of an accurate evaluation of vascular proliferation in gastrointestinal biopsies even in patients without clinical evidence of HIV-related pathology.

Percutaneous laser ablation in the treatment of hepatocellular carcinoma with small tumors: analysis of factors affecting the achievement of tumor necrosis.

PURPOSE: To identify the factors that affect the achievement of tumor necrosis with percutaneous laser ablation (PLA) in patients with hepatocellular carcinoma (HCC) and tumor size no larger than 4.0 cm. MATERIALS AND METHODS: Ultrasound-guided biopsy results were retrospectively studied in 99 lesions (range, 0.5-4.0 cm; mean, 2.7 cm) from 82 patients (44 men, 38 women; age range, 50-80 years; median, 68 y) who had undergone PLA. RESULTS: Complete tumor ablation was obtained in 90 lesions (90.9%). Of the nine cases in which complete tumor necrosis was not achieved, six had tumors located in sites that did not allow the optimal placement of fibers, and five of these had a tumor diameter greater than 3 cm. Early discontinuation of PLA as a result of decompensation of liver cirrhosis was the reason for not achieving a complete tumor ablation in three other cases. There was a clear relationship between the energy delivered and the volume of necrosis achieved (r = 0.56; P < .001) regardless of the initial size of HCC tumors. The number of illuminations required, and consequently the amount of energy delivered, was also affected by tumor location. In fact, lesions adjacent to large vessels (> or = 3 mm) required a greater number of illuminations than the other lesions to achieve complete ablation (2.9 +/- 1.4 vs 2.3 +/- 0.9; P = .043). The eight cases with undifferentiated histology required more illuminations than the cases with other histologic types (3.4 +/- 0.9 vs 2.2 +/- 0.9; P < .001). However, these cases were located in sites that did not allow the optimal placement of fibers, therefore requiring multiple treatments. CONCLUSION: PLA is a highly effective treatment in HCC with a tumor size of 4.0 cm or smaller. In this setting, two variables, tumor size and tumor location, affect the achievement of complete tumor ablation and the number of treatments required to obtain tumor necrosis.

Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features.

The aim of the study was to correlate the sonographic [ultrasound (US)] and color-Doppler (CFD) findings with the results of US-guided fine needle aspiration biopsy (FNA) and of pathologic staging of resected carcinomas to establish: 1) the relative importance of US features as risk factors of malignancy; and 2) a cost-effective management of nonpalpable thyroid nodules. Four hundred ninety-four consecutive patients with nonpalpable thyroid nodules (8-15 mm) were evaluated by US, CFD, and US-FNA. Ninety-two patients with inadequate cytology were excluded from the study. All patients with suspicious or malignant cytology underwent surgery, whereas subjects with benign cytology had clinical and US control 6 months later. Thyroid malignancies were observed in 18 of 195 (9.2%) solitary thyroid nodules and in 13 of 207 (6.3%) multinodular goiters. Cancer prevalence was similar in nodules greater or smaller than 10 mm (9.1 vs. 7.0%). Extracapsular growth (pT(4)) was present in 35.5%, and nodal involvement in 19.4% of neoplastic lesions, with no significant differences between tumors greater or smaller than 10 mm. At US cancers presented a solid hypoechoic appearance in 87% of cases, irregular or blurred margins in 77.4%, an intranodular vascular pattern in 74.2%, and microcalcifications in 29.0%. Irregular margins (RR 16.83), intranodular vascular spots (RR 14.29), and microcalcifications (RR 4.97) were independent risk factors of malignancy. FNA performed on hypoechoic nodules with at least one risk factor was able to identify 87% of the cancers at the expence of cytological evaluation of 38.4% of nonpalpable lesions. The majority of nonpalpable thyroid tumors can be identified by cytological evaluation of lesions presenting hypoechoic appearance in conjunction with one independent risk factor. Due to the nonnegligible prevalence of extracapsular growth and nodal metastasis, US-FNA should be performed on all 8-15 mm hypoechoic nodules with irregular margins, intranodular vascular spots or microcalcifications. Nonpalpable lesions of the thyroid without risk factors should be followed by means of clinical and US evaluation.