Small-Cell Malignancies of Thyroid: Challenge Solved?

“Small-cell malignancies of thyroid” is an unsolved dilemma. This term represents an umbrella terminology in thyroid, encompassing for a small group of tumors in which some of them are well-recognized tumors like medullary thyroid carcinoma, poorly differentiated thyroid carcinoma, and primary thyroid lymphomas and teratoma, whereas the remaining are less known as primary neuroendocrine carcinoma of thyroid, primary extraskeletal Ewing family tumors, and adamantinoma-like Ewing sarcoma. When the issue comes to evaluate a cytological sample predominantly composed of small-cell morphology, metastatic small-cell carcinomas to thyroid also should be excluded. In this review, our group focused on the main cytomorphological and clinical clues of each entity that help to set up a correct differential diagnosis. The literature discussions were also included for the entities that are not yet recognized by the mother publication WHO. A key point of the issue’s simple algorithm based on FNAC with small-cell morphology of thyroid was suggested by the authors.

Challenges in the Intraoperative Consultation of Low-Grade Epilepsy-Associated Neuroepithelial Tumors by Cytomorphology in Squash Preparations

<b><i>Introduction:</i></b> Low-grade epilepsy-associated neuroepithelial tumors (LEATs) create a diagnostic challenge in daily practice and intraoperative pathological consultation (IC) in particular. Squash smears are extremely useful in IC for accurate diagnosis; however, the knowledge on cytopathologic features of LEATs is based on individual case reports. Here, we discuss the 3 most common and well-established entities of LEATs: ganglioglioma (GG), dysembryoplastic neuroepithelial tumor (DNT), and papillary glioneuronal tumor (PGNT). <b><i>Methods:</i></b> Thirty patients who underwent surgery for GG, DNT, and PGNT between 2001 and 2021 were collected. Squash smears prepared during intraoperative consultation were reviewed by 1 cytopathologist and an experienced neuropathologist. <b><i>Results:</i></b> Among the 30 tumors, 16 (53.3%) were GG, 11 (36.6%) DNT, and 3 (10%) PGNT. Cytomorphologically, all of the 3 tumor types share 2 common features such as dual cell population and vasculocentric pattern. GG smears were characteristically composed of dysplastic ganglion cells and piloid-like astrocytes on a complex architectural background of thin- to thick-walled vessels. DNT, on the other hand, showed oligodendroglial-like cells in a myxoid thin fibrillary background associated with a delicate capillary network. Common cytological features of PGNT were hyperchromatic cells with narrow cytoplasm surrounding hyalinized vessels forming a pseudopapillary pattern and bland cells with neuroendocrine nuclei dispersed in a neuropil background. <b><i>Conclusion:</i></b> A higher diagnostic accuracy can be obtained when squash smears are applied with frozen sections. However, it is important to integrate clinical and radiologic features of the patient as well as to know the cytopathologic features of the LEAT spectrum in the context of differential diagnosis to prevent misinterpretation in the IC.

Application of the Paris Reporting System for Urine Cytology: The Three-Year Experience of a Single Tertiary Care Institute in Thailand

<b><i>Introduction:</i></b> Urothelial carcinoma is one of the most common human cancers, both in Thailand and worldwide. Urine cytology is a screening tool used to detect urothelial carcinoma. The Paris System for Reporting Urinary Cytology (TPSRUC) was first published in 2016 to standardize the procedures, reporting, and management of urothelial carcinoma. Diagnostic categories include negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells (AUCs), suspicious for HGUC (SHGUC), HGUC, low-grade urothelial neoplasm, and other malignancies. <b><i>Material and Methods:</i></b> In a retrospective review, urine cytology specimens from 2016 to 2019 were reevaluated using the TPSRUC. The risk of high-grade malignant neoplasm (ROHM) for each diagnostic category was calculated. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of prediction of high-grade malignant neoplasms were evaluated for cases with histological follow-up specimens. <b><i>Results:</i></b> In total, 2,178 urine cytology specimens were evaluated, of which 456 cases had follow-up histological specimens. The ROHM in each diagnostic category was as follows: NHGUC, 17.4%; AUC, 49.9%; SHGUC, 81.2%; HGUC, 91.3%; and other malignant neoplasms, 87.5%. The sensitivity, specificity, PPV, NPV, and accuracy for high-grade malignant neoplasm prediction were 63%, 92.8%, 89%, 73.1%, and 78.5% when AUC was included as malignant in the comparison and 82.6%, 74.7%, 75.1%, 82.3%, and 78.5% when AUC was not considered malignant. <b><i>Conclusions:</i></b> TPSRUC provides reliable results that are reproducible by different interpreters and is a helpful tool for the detection of HGUC.

Comparison of Morphological Similarities and Differences between Liquid-Based Cytology and Conventional Techniques of Serous Effusion Cytology Specimens

<b><i>Introduction:</i></b> The aim of this study is to discover a fast and efficient method for the diagnosis of serous effusion cytology specimens by comparing the cytomorphological features of SurePath (SP) smears and smears prepared by cytospin. After the macroscopic features of the incoming material were recorded, it was divided into 2 for conventional technique (CT) and liquid-based technique. Cytospin was used for CT and SurePath for liquid-based technique in this study. <b><i>Materials and Methods:</i></b> 243 serous effusions (33 thoracentesis and 92 paracentesis fluids, 118 peritoneal lavage fluids) were investigated. After shaking the effusion gently, it was centrifuged for 5 min at 1,250 rpm for cytospin smear. SP smear was prepared according to the “BD PrepStain slide processor”. Two smears were prepared with these 2 methods and then stained with Papanicolaou. The smears were examined under a light microscope in terms of fixation, background, cellularity, nucleus, and structural features. All statistical analysis of the data was performed using the SPSS 17.0 software. For each microscopic feature, the χ² test was used to assess the significance of the relationship between cytospin and SP, and level of agreement in between the methods was assessed using the kappa statistic. <b><i>Results:</i></b> A statistically significant difference was observed between the 2 methods in background (<i>p</i> &#x3c; 0.001), cellularity (<i>p</i> &#x3c; 0.001), nucleus features (<i>p</i> &#x3c; 0.001), and structural features (<i>p</i> &#x3c; 0.05). There was no significant difference in fixation. Low level of agreement was observed with the kappa statistic in fixation, background, and cellularity. Moderate level of agreement was observed in the nucleus and structural feature groups with the kappa statistic. <b><i>Discussion/Conclusion:</i></b> Although there are advantages of liquid-based technique such as standardized fixation and cleaner background, since the cellular and background components required for morphological analysis and diagnosis are better preserved in cytospin, it is considered to be better to use liquid-based technique not alone but together with CT.

Primary Small Cell Malignancies of the Breast: Are They Rare Malignancies?

In contrast with the other organs such as the lung, small cell tumors have been less studied in the breast due to their relatively less frequency. Although rare, neuroendocrine neoplasms, some lymphomas, and some small cell sarcomas such as undifferentiated small round cell sarcoma and rhabdomyosarcoma can be seen in small cell morphology in the breast. Many cytological specimens such as fine-needle aspiration biopsies and touch imprint cytology are used for diagnosis and further prognostic/predictive marker determination in primary breast masses, sentinel and axillary lymph nodes, and metastatic masses. Lobular carcinoma deserves to be considered in the small cell tumor group because of its small, monomorphic, discohesive, scant cytoplasmic cytological features. Since so many different types of tumors in the breast can have small cell characteristics, they should be divided into small cell neuroendocrine tumors and small cell nonneuroendocrine tumors. When evaluating small cell breast tumors cytologically, wide tumor diversity should be kept in mind, and clinical, hematological, and radiological features should be taken into consideration.

Clinical Usefulness of Endometrial Cytology in Determining the Therapeutic Effect of Fertility Preserving Therapy

<b><i>Introduction:</i></b> The significance of endometrial cytology in determining the therapeutic efficacy of medroxyprogesterone acetate (MPA) therapy is unclear. This study aimed to evaluate the clinical usefulness of endometrial cytology during MPA therapy. <b><i>Methods:</i></b> Overall, 77 patients who underwent dilatation and curettage (D&amp;C) to evaluate the therapeutic efficacy of MPA therapy at our hospital between January 2018 and December 2019 were retrospectively analyzed. The results of D&amp;C, cytological evaluation, and other clinicopathological factors were analyzed based on the patients’ medical records. <b><i>Results:</i></b> The sensitivity and specificity of cytology were 61% and 92%, respectively, with D&amp;C being the gold standard for diagnosis in 142 D&amp;C/cytological examinations. Among patients with no residual disease on D&amp;C, 5 (4%) had suspicious or positive cytology. Although MPA therapy was terminated in 3 of these patients, only 1 patient had early recurrence, and the frequency of recurrence was similar to that of patients who showed negative results in both D&amp;C and cytology. <b><i>Discussion/Conclusion:</i></b> The sensitivity of endometrial cytology in determining the therapeutic effect of MPA therapy is low, and we confirmed that the omission of D&amp;C is unacceptable. Our findings also suggested that the addition of cytological evaluation to D&amp;C during MPA therapy had a low clinical significance.

Cytology Reporting System for Lung Cancer from the Japan Lung Cancer Society and the Japanese Society of Clinical Cytology: An Extensive Study Containing More Benign Lesions

<b><i>Introduction:</i></b> The Japan Lung Cancer Society (JLCS) and the Japanese Society of Clinical Cytology (JSCC) have proposed a new four-tiered cytology reporting system for lung carcinoma (JLCS-JSCC system). Prior to the proposal, the Papanicolaou Society of Cytopathology (PSC) had proposed a revised reporting system (PSC system), which comprises the “neoplastic, benign neoplasm, and low-grade carcinoma” category (N-B-LG category), in addition to the 4 categories of the JLCS-JSCC system. This study aimed to evaluate the interobserver agreement of the JLCS-JSCC system with an additional dataset with more benign lesions in comparison with the PSC system. <b><i>Methods:</i></b> We analyzed 167 cytological samples, which included 17 benign lesions, obtained from the respiratory system. Seven observers classified these cases into each category by reviewing one Papanicolaou-stained slide per case according to the JLCS-JSCC system and PSC system. <b><i>Results:</i></b> The interobserver agreement was moderate in the JLCS-JSCC (<i>k</i> = 0.499) and PSC (<i>k</i> = 0.485) systems. Of the 167 samples, 17 samples were benign lesions: 7 pulmonary hamartomas, 5 sclerosing pneumocytomas, 2 squamous papillomas, one solitary fibrous tumor, one meningioma, and one lymphocytic proliferation. There were diverse sample types as follows: 11 touch smears, 3 brushing smears, 2 aspirations, and one sputum sample. Fourteen samples (82.3%) were categorized into “negative” or “atypical” by more than half of the observers in the JLCS-JSCC system. Conversely, 3 samples were categorized as “suspicious” or “malignant” by more than half of the observers in the JLCS-JSCC system. On the other hand, 11 samples (64.7%) were categorized into the N-B-LG category by more than half of the observers in the PSC system. <b><i>Conclusions:</i></b> The concordance rate in the JLCS-JSCC system was slightly higher than that in the PSC system; however, the interobserver agreement was moderate in both the JLCS-JSCC and PSC systems. These results indicate that both the JLCS-JSCC and PSC systems are clinically useful. Therefore, both systems are expected to have clinical applications. It may be important to integrate the 2 systems and construct a universal system that can be used more widely in clinical practice.

Application of Hans Algorithm for Subcategorization of Diffuse Large B-Cell Lymphoma in Fine-Needle Aspiration Biopsy Cytology

<b><i>Introduction:</i></b> Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with remarkably variable clinical presentation and outcome. Hans algorithm subclassified DLBCL into prognostically distinct molecular subtypes by using immunohistochemistry (IHC). Fine-needle aspiration biopsy cytology (FNABC) is a first-line diagnostic modality in lymphadenopathy. The study aims to perform IHC on FNABC cell blocks (CBs) for subclassifying according to the Hans algorithm and correlate with case-matched histopathology. <b><i>Methods:</i></b> This was a retrospective study carried out between January 2017 and December 2019. All DLBCL FNABC cases with CBs and smears and which had follow-up histopathology were included in the study. Detailed cytomorphological evaluation and CD10, B-cell lymphoma 6 (BCL6), and multiple myeloma oncogene 1 IHCs were performed on CBs. The cases are divided into 3 distinct molecular subtypes based on the Hans algorithm as germinal centre B-cell (GCB), activated B-cell (ABC), and unclassified subtypes. The results were compared with the final histopathology. <b><i>Results:</i></b> A total of 44 cases were diagnosed as DLBCL, and 33 cases with sufficient material for further IHC were included in the study. Twelve cases were of the GCB type, 19 were of the ABC type, and 2 remained unclassified. Follow-up histopathology was available in 20 cases. Overall, histopathological concordance was found in 95% of cases (19/20). The single discordant case was classified as GCB on FNABC and was ABC on histopathology. <b><i>Conclusion:</i></b> FNABC with CBs is an acceptable alternative to biopsy for providing a complete diagnosis of DLBCL as per the current WHO classification.

Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Is Not a Cytological Diagnosis, but It Influences Cytological Diagnosis Outcomes: A Systematic Review and Meta-Analysis

Background: A low-risk thyroid tumour, non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced in 2016. NIFTP criteria require a thorough histological examination to rule out capsular and lymphovascular invasion, which denies the possibility of preoperative cytological diagnosis. Nevertheless, since the adoption of the new entity, the cytology of NIFTP has been a subject of interest. Objectives: The present systematic review and meta-analysis investigate the cytological diagnosis of NIFTP. Method: An online PubMed literature search was conducted between March 1, 2020, and June 30, 2020, for all original articles considering the cytology of histologically proven NIFTP. The studies including data on fine needle aspiration specimens classified by The Bethesda System for Reporting Thyroid Cytology (TBSRTC) categories, risk of malignancy (ROMs) in the TBSRTC categories, and cytomorphological features of NIFTP were included in the meta-analysis. Non-English studies and case reports were excluded. The data were tabulated and statistical analysis was performed with Open Meta-Analyst program. Results: Fifty-eight studies with a total of 2,553 NIFTP cases were included in the study. The pooled prevalence of NIFTP cases was calculated among 25,892 surgically resected cases from 20 studies and the results show that NIFTP consisted 4.4% (95% confidence interval [CI]: 3.5–5.4%) of all cases. Most of the NIFTP cases (79.0%) belonged to the intermediate categories of TBSRTC. The pooled distribution of NIFTP cases in each TBSRTC category was 1.3% (95% CI: 0.8–1.7%) in non-diagnostic (ND), 8.9% (95% CI: 6.9–10.8%) in benign, 29.2% (95% CI: 25.0–33.4%) in atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS), 24.2% (95% CI: 19.6–28.9%) in follicular neoplasm (FN), 19.5% (95% CI: 16.1–22.9%) in suspicious for malignancy (SM), and 6.9% (95% CI: 5.2–8.7%) in malignant. Compared to pre-NIFTP era, the pooled risk differences of ROM were reduced by 2.4% in ND, 2.7% in benign, 8.2% in AUS/FLUS, 8.2% in FN, 7.3% in SM, and 1.1% in the malignant category. The cytomorphological features of NIFTP were similar to follicular variant of papillary thyroid carcinoma (FVPTC) but lesser to papillary thyroid carcinoma (PTC). Conclusions: Based on our results, NIFTP remains a histological diagnosis. Although cytomorphological features cannot be used in differentiating NIFTP from FVPTC, they may guide in separating NIFTP from PTC. Features such as papillae, microfollicles, giant cells, psammoma bodies, and the amount of papillary-like nuclear features should be taken into account when suspicious of NIFTP. NIFTP should not have papillae or psammoma bodies, and giant cells were rarely observed.