Role of immunocytochemistry in cervical cancer screening.

The cervical cancer screening has been based conventionally on cytologic analysis. With advances in understanding the role of human papillomavirus, cotesting has been applied. But most of the patients subjected to colposcopy did not benefit, except in cases with HSIL [high-grade squamous intraepithelial lesion] cytology. Because of this, a step to increase the sensitivity to detect cancers and pre-cancers but with higher specificity with minimal overdiagnosis leading to prevention of unindicated cervical biopsies is highly desired. Such triaging step in cases with abnormal screening results is expected to minimize invasive interventions because of low false positivity. With availability of methodologies leading to quantitatively and qualitatively enhanced cell-blocks from residual liquid based cytology specimens, immunostaining can be performed for multiple immunomarkers with potential objectivity to triage initial screening test results. This is enhanced further with inclusion of AV marker in the cell-blocks and application of SCIP (subtractive coordinate immunoreactivity pattern) approach. The cell-blocks are also resource for performing other ancillary studies including molecular pathology and proteomics/metabolomics as potential tests in future. This review explores application of residual liquid based cytology specimen for cell-blocking with application of ancillary studies in algorithmic manner as adjunct to ASCCP management guidelines for improved patient care.

Atypical glandular cells (AGC): Cytology of glandular lesions of the uterine cervix.

The Pap smear is a well-known screening tool for squamous lesions of the uterine cervix. However, its screening role in glandular lesions is less effective. The incidence of squamous cell carcinoma of the cervix has dramatically decreased with the advent of Pap smear and recent understanding related to HPV carcinogenesis of cervical cancers including the advent of HPV vaccines. However, in recent years, the incidence of glandular abnormalities, diagnosed on Pap smears, has increased with greater sensitivity and precision. The incidence of atypical glandular cells (AGC) is approximately 0.18-0.74% of all cervical smears with a reported prevalence of 2.5% among all Pap smears. A high degree of suspicion, good clinical history, and the presence of diagnostic cytomorphological findings are essential for the proper interpretation of glandular cell abnormalities. A methodical approach to evaluate Pap smear greatly helps interpretation and avoids the diagnostic pitfalls. The Bethesda System for reporting cervical cytology has categorized glandular cell abnormalities into various categories as follows: Endocervical adenocarcinoma in situ (AIS)Atypical glandular cells (AGCs) Endocervical cells: a1 NOS or specify in comments; a2 Favor neoplasticEndometrial cells: NOS or specify in comments Adenocarcinoma (AdCa) EndocervicalEndometrialExtrauterineNOS Subtle differences in quantitative and qualitative cytologic features are essential for distinguishing one category from another. In this chapter, we highlight an organized approach for the interpretation of glandular abnormalities in Pap smear for our readers. This is an overview of the Bethesda categories, the reason for classification, and differential diagnosis with key characteristic features. An approach to the methodical evaluation of hyperchromatic crowded groups is discussed with key cytomorphologic differences. An algorithmic approach is suggested to facilitate the interpretation of various AGC categories.

Serous fluid: Reactive conditions.

This chapter highlights the steps that would help to analyze any fluid. It highlights importance of knowing gross analysis of fluid along with biochemical information. These parameters along with clinical information are very important in arriving at a differential diagnosis. Morphologic appearances in the fluid can often become challenging and occasionally reactive conditions can reveal changes that may mimic malignancies. This chapter provides not only a framework of approach to assessment of fluid cytology but also shows how to distinguish some of the challenging reactive conditions from the diagnosis of carcinoma. The chapter also utilizes two cases to demonstrate approach to reactive conditions. This review article will be incorporated finally as one of the chapters in CMAS (CytoJournal Monograph/Atlas Series) #2. It is modified slightly from the chapter by the initial authors in the first edition of Cytopathologic Diagnosis of Serous Fluids.

Immunocytochemistry of effusions: Processing and commonly used immunomarkers.

Definitive cytopathological interpretation of some of the effusion fluids may not be possible based on cytomorphological evaluation alone. As discussed in other reviews, this is due to various reasons specifically applicable to effusion fluids including remarkably wide morphologic spectrum of reactive mesothelial cells overlapping with some well to moderately differentiated metastatic carcinoma. The challenge is subject to various factors including level of interpreter training or experience, institutional demographics (such as type of prevalent diseases, predominant sex and age group), technical advances in ancillary support, and expertise in cytopreparatory processing. In such cases immunohistochemistry performed on cell-block sections is simple objective adjunct with or without other ancillary techniques. Ongoing increase in number of immunomarkers along with rabbit monoclonal antibodies with relatively higher affinity is further refining this field. SCIP (subtractive coordinate immunoreactivity pattern) approach, discussed as separate dedicated review article, facilitates refined interpretation of immunoreactivity pattern in coordinate manner on various serial sections of cell-blocks. However, many variables such as delay after specimen collection, specimen processing related factors including fixation and storage; ambient conditions under which paraffin blocks are archived (for retrospective testing); antigen retrieval method; duration of antigen retrieval step; antibody clone and dilution; and antibody application time are common with application of immunohistochemistry in other areas. This review is dedicated to highlight technical aspects including processing of effusion specimens for optimum immunocytochemical evaluation along with commonly used immunomarkers in effusion cytopathology. This review focuses on the technical and general information about various immunomarkers.

Immunocytochemistry of effusion fluids: Introduction to SCIP approach.

Due to the remarkably wide morphologic spectrum of reactive mesothelial cells, some of the effusion fluids may be difficult to interpret with objective certainty by cytomorphology alone. Cytomorphology of well to moderately differentiated adenocarcinomas (responsible for the bulk of malignant effusions) may overlap with floridly reactive mesothelial cells. Even mesotheliomas including diffuse malignant epithelioid mesothelioma, are usually cytomorphologically bland without unequivocal features of malignancy. The intensity of challenge depends on the interpreter's training or experience level, institutional demographics of patients (such as type of prevalent diseases, predominant sex and age group), technical support, and quality of cytopreparatory processing. In general immunocytochemistry is valuable adjunct to facilitate objective interpretation with or without other ancillary techniques as indicated. An increasing number of immunomarkers is further refining the contribution of immunohistochemistry to this field. However, application of immunohistochemistry to effusion fluids is relatively challenging because of many variables. Multiple factors such as delay after specimen collection, specimen processing related factors including fixation and storage; ambient conditions under which paraffin blocks are archived (for retrospective testing); antigen retrieval method; duration of antigen retrieval step; antibody clone and dilution; and antibody application time are identical to application of immunohistochemistry in other areas. The significant challenge related to the potential compromization of the immunoreactivity pattern due to exposure to non-formalin fixatives / reagents is also applicable to effusion fluid specimens. The immunoreactivity results would be compared and corelated with cumulative metadata based on the reported studies performed and validated on formalin-fixed paraffin-embedded tissue sections. Deviating from such protocols may lead to suboptimal results, which is not uncommon in clinical practice with potential compromization of patient care and related liability. Because of this, it is critical to perform immunocytochemistry on formalin-fixed cell-block sections only. In addition, unless the interpretation criteria for immunohistochemical evaluation of effusion fluids are not modified specifically, it may not be productive in resolving some challenging cases. However, this aspect is not well elaborated in the literature. A basic and critical challenge is finding and locating the cells of interest in cell-block sections of effusion fluids. A unique approach is to choose a fundamental immunopanel which highlight the mesothelial and inflammatory cells in reactive effusion fluids to create the basic map. This allows detection of a 'second-foreign' population which can be immunocharacterized further with the help of subtractive coordinate immunoreactivity pattern (SCIP) approach elaborated here.

Metastatic Carcinoma in Effusions.

Serous cavity may be involved by any neoplasm, including very rare examples of involvement by central nervous system tumors leading to a malignant effusion. The serous cavity lining is rich in lymphatics with lymphatic lacunae opening directly through narrow gaps (stoma) in the lining. Carcinomas mainly metastasize to serosa via the lymphatic vessels, which may be blocked leading to effusion. Primary carcinomas of organs such as lung, intestines, liver, ovary, etc., lined by serosal membranes may spread by direct extension, resulting in malignant effusions. As standard of practice, unless specified, cytopathologic examination of serous effusions implies detection of malignant cells. As compared to a surgical biopsy from a small focal area of an extensive serosal surface, effusion fluid from respective cavity exfoliates the cells from the entire serosal surface with minimal chance of sampling artifact. Because of this, effusion fluid cytology generally provides a higher diagnostic yield as compared to biopsy of the serous lining, as demonstrated by some studies. However, various challenges related to effusion fluid cytology makes the interpretation of effusion fluid cytology a field with potential misinterpretations, especially for those without proper experience or training. Developing and following a methodical approach is important for appropriate cytologic examination of effusion fluids. Proper approach may achieve definitive interpretation even without ancillary tests. However, lack of appropriate approach and processing may introduce a significant variation in interpretation due to combination of well-recognized diagnostic pitfalls, which may lead to lower reproducibility and even serious misinterpretations. Current review discusses in brief appropriate approach to processing and evaluating effusion fluid cytology for metastatic carcinoma. At general level, this is comparable to that of other specimens; however, it is critical to modify with reference to the limitations associated with effusion cytology.

Squamous intraepithelial lesions (SIL: LSIL, HSIL, ASCUS, ASC-H, LSIL-H) of Uterine Cervix and Bethesda System.

For every 100,000 women in the United States, eight new cervical cancer cases and two deaths are reported as per the most recent (2017) Center of Disease Control and Prevention statistics. Of all the gynecologic cancers (ovary, uterus, cervix, vagina, and vulva), only cervical cancer has a screening test. Cervical Pap test (or Pap smear) is the best screening method for cervical precancerous lesions and is best reported using a unified and a well-established reporting system like The Bethesda System. In this system, "Epithelial cell abnormality: Squamous" includes squamous intraepithelial lesion (SIL) category which encompasses a spectrum of squamous cell lesions starting from the precancerous lesions of low-grade SIL (LSIL) to high-grade SIL (HSIL), and ultimately invasive squamous cell carcinoma. However, depending on the qualitative and quantitative limitations with the specimen, some equivocal morphological features suggestive of squamous cell abnormality may fall under equivocal category: "Atypical Squamous Cells" (ASCs), which are subdivided into two categories; "Atypical Squamous Cells of Undetermined Significance" (ASC-US) or "Atypical Squamous Cells, HSIL cannot be excluded" (ASC-H), based on the suspected underlying lesion LSIL versus HSIL, respectively. This review provides the key cytologic features that distinguish Bethesda squamous categories from other important entities, using algorithmic approach and illustrations of common cytomorphologic patterns for clear identification of those entities in practice. The important mimickers which may be considered during the differential interpretation of SIL are discussed and presented here in a brief cytomorphologic review.

Pleural effusion in hematological pathology.

A 51-year-old male with a history of chronic myelomonocytic leukemia-2 (CMML-2) presented with fatigue, night sweats, dyspnea, and right-sided chest pain exacerbated by deep breath. Computed tomography scan demonstrated right-sided pleural effusion with atelectasis. Pleural fluid cytology showed reactive mesothelial cells mixed with atypical cells [Figure 1]. The immunostains are performed using the SCIP approach.[1] The atypical cells were immunoreactive for vimentin, CD68, and CD163, while non-immunoreactive for cytokeratin, calretinin, BerEP4, and MOC31.

Cell-blocks and other ancillary studies (including molecular genetic tests and proteomics).

Many types of elective ancillary tests may be required to support the cytopathologic interpretations. Most of these tests can be performed on cell-blocks of different cytology specimens. The cell-block sections can be used for almost any special stains including various histochemistry stains and for special stains for different microorganisms including fungi, Pneumocystis jirovecii (carinii), and various organisms including acid-fast organisms similar to the surgical biopsy specimens. Similarly, in addition to immunochemistry, different molecular tests can be performed on cell-blocks. Molecular tests broadly can be divided into two main types Molecular genetic tests and Proteomics.

The panorama of different faces of mesothelial cells.

All effusions in serous cavities represent a pathologic processes secondary to inflammatory, neoplastic, hemodynamic, or mechanical/traumatic etiologies. This elicits reactive changes in the extremely sensitive mesothelial cells lining the serosal surfaces. The result is hypertrophy and hyperplasia which lead to broad changes with a wide range of morphological appearances. These reversible alterations may resolve entirely after the recovery of underlying pathology. Under the tertiary care situations, neoplastic effusion specimens are encountered more frequently. Although some non-neoplastic pathologic process may demonstrate a few diagnostic features, cytologic evaluation of malignant effusions usually show diagnostic malignant cells. However, the most versatile mesothelial cells demonstrate a very wide cytomorphological spectrum secondary to reactive challenges. These mesothelial cells are usually referred to as 'reactive mesothelial cells'. In addition other terms such as reactive mesothelial proliferation, reactive mesothelial hyperplasia, irritated mesothelial cells, activated mesothelial cells, hyperplastic mesothelial cells, hypertrophic mesothelial cells, and proliferative mesothelial cells. Rarely atypical mesothelial cells, although not recommended, is used inadvertently. Although there is a lack of general agreement defining these terms, some of these including atypical mesothelial cells, should not be preferred. With reference to this CMAS series, usually favored term 'reactive mesothelial cells' is preferred. The size of reactive mesothelial cells range from 15 to 30 µm (but may be up to 50 µm). These polyhedral cells with variable amount of cytoplasm and enlarged nuclei may show variation in sizes and shapes with conspicuous nucleoli. Bi- and multi-nucleation is frequent. Cohesive groups of mesothelial cells as sheets and three dimensional groups may be present. Some floridly reactive mesothelial cells with hyperchromatic enlarged nuclei with prominent nucleoli and scant cytoplasm may resemble malignant cells. This astonishingly wide morphological spectrum of reactive mesothelial cells is a significant interpretation challenge in effusion fluid cytology. Methodical interpretation approach with appropriate knowledge about this wide spectrum is important aspect in diagnostic cytopathology of effusion fluids.

Introduction to the second edition of 'Diagnostic Cytopathology of Serous Fluids' as CytoJournal Monograph (CMAS) in Open Access.

Serous fluids are excessive accumulation of fluids in a serous cavity as effusion. However, traditionally this area also covers cytopathologic evaluation of washings of these cavities including pelvic/peritoneal washing. This is the introductory review article in series on this topic with the application of simplified algorithmic approaches. The series would be compiled finally as a book after minor modifications of individual review articles to accommodate the book layout on the topic as second edition of 'Diagnostic Cytopathology of Serous Fluids' book. The approach is primarily directed towards detection of neoplastic cells based on morphology alone or with the help of various ancillary tests, including commonly applied immunocytochemistry to be interpreted as second foreign population with application of SCIP (subtractive coordinate immunoreactivity pattern) approach in effusion fluid tapings. As the role of molecular pathology tests is increasing, this component as ancillary testing will also be covered as applicable. Because a picture and sketches are worth a thousand words, illustrations and figures are included generously even at the risk of moderate repetition. The clinically important serous cavities include peritoneal cavity, pericardial cavity, and two pleural cavities. The primary topic of this series is specimens from these cavities as effusion fluids and washings including cytopathologic evaluation of peritoneal/pelvic washing. It is expected that some readers may not read the entire series or the final book from beginning to end, but refer to the individual review articles and chapters sporadically during their clinical practice. Considering this practical limitation, some brief repetition may be observed throughout the book. Some of the important themes will be highlighted as italicized and bolded text for quick reference. Dedicated articles/chapters are assigned for technical and other reference material as appendices. Tables, algorithms, sketches, and combination of pictures are included generously for quick reference. Most of the illustrations are attempted to be labeled appropriately with arrows and other indicators to avoid equivocation, especially for beginners in the field. This introductory review article describes general details under the following three broad headings: Histology and general cytology of serous cavity lining Effusion (general considerations) Ancillary techniques in brief.

Approach to Diagnostic Cytopathology of Serous Effusions.

Collection of most serous fluids from various effusions is a relatively simple procedure. Because of this, serous fluids are commonly submitted for pathologic examination including cytopathologic evaluation by various clinical institutions. As a consequence, even a general pathology laboratory which may not have expertise with highly trained cytopathologist would be confronted with serous fluids for cytologic evaluation. However, cytopathologic evaluation of serous fluids is complex as compared to evaluation of fine needle aspiration cytology. This signifies the fact that all pathologists, irrespective of subspeciality cytopathology training and level of subspeciality expertise, should be conversant with the diagnostic challenges and pitfalls of effusion fluid cytology. Although, majority of effusions are due to reactive and non-neoplastic etiologies, cancer is one of the causes of an effusion as a manifestation of advanced cancer. Detecting neoplastic cells in effusion specimens in most of clinical settings is related to the advanced status of the disease, which usually is equivalent to incurable stage. Thus, interpretation of cytopathology as positive for cancer cell is highly critical in planning the trajectory of the clinical management with an obvious negative impact of false positive interpretation. Apart from cancer, effusions may be secondary to hemodynamic pathologies such as heart failure, hypoalbuminemia, cirrhosis etc. in addition to the different inflammatory conditions including parasitic infestations, bacterial, fungal, or viral infections, and other non-neoplastic etiologies including collagen diseases. Due to the cytomorphologic overlap of reactive mesothelial cells with malignant cells, general cytologic criteria for diagnosis of malignancy in single cells cannot be applied in most of the effusion specimens. This challenge is further amplified because of surface tension related phenomenon which 'round up' the cells after exfoliation in serous fluids. As a result, the native shapes of cancer cells cannot be a guiding feature. Thus the cytomorphologic features of cancer cells in serous fluids may not be same as seen in routine cytopathology of exfoliative, brushing, and fine-needle aspiration specimens. The cancer cells may continue to proliferate after exfoliation in the nutrient rich effusion fluids and may form proliferation spheres. It is crucial to consider these factors when interpreting effusion cytology. Amongst malignant effusions, adenocarcinomas are the most common cause of metastatic cancers, but almost any type of malignancy including melanomas, hematopoietic neoplasms, sarcomas, and mesotheliomas may involve serous cavities. The interpreter must be aware of the wide range of the cytomorphologic appearances of reactive mesothelial cells in effusion fluids. It is essential to understand these and other nuances related to effusion fluid cytology. Understanding potential pitfalls during various stages from processing to application of ancillary studies would increase the diagnostic accuracy and minimize atypical interpretations and false positivity.

Diagnostic pitfalls in effusion fluid cytology.

Effusion fluid cytology has propensity for both false positives (in up to 0.5%) and false negatives (in up to 30%) results. Methodical approach from collection step to final interpretation stage could prevent both false positives and false negatives, if the interpreter is familiar with various factors responsible for diagnostic pitfalls in effusion fluid cytology. For this discussion, these factors are categorized as mentioned below: Surface tension-related alterations in cytomorphologyImproper specimen processingMany faces of reactive mesothelial cells, overlapping with those of cancer cellsProliferation-related featuresDegenerative changes, such as nuclear hyperchromasia and cytoplasmic vacuolationUnexpected patterns and unusual entities.

Pattern of cervical biopsy results in cases with cervical cytology interpreted as higher than low grade in the background with atrophic cellular changes.

OBJECTIVE: The cytomorphological changes associated with atrophic cellular pattern (ACP) in cervical cytology smears may mimic high-grade squamous intraepithelial lesion (HSIL). Due to this, there may be higher chances of cytomorphological overinterpretation in cases with ACP. Estrogen therapy (ET) (topical or systemic) would reverse the changes related to atrophy and repeat Pap smear after ET should correct the false positives. This approach would minimize the unindicated invasive interventions. However, performing immediate biopsies following "higher than low-grade squamous intraepithelial lesion (LSIL) (atypical squamous cells-cannot exclude HSIL, low-grade squamous intraepithelial lesions-cannot exclude HSIL, and HSIL) interpretations" in such cases, is a general trend. Pap smears with "higher than LSIL interpretations" in association with ACP over a period of 10 years were selected. MATERIALS AND METHODS: A total of 657,871 cases over 10 years were reviewed, of which 188 Pap smears interpreted as higher than LSIL interpretations with ACP were selected randomly for this study. RESULT: Of these 188 cases, 67 underwent biopsies which were reviewed and compared with 67 biopsies performed for "higher than LSIL interpretation" cases without ACP. The follow-up biopsy material was reviewed including elective p16 immunohistochemistry with other clinical details including high-risk HPV test results as indicated. CONCLUSION: The findings demonstrated that Pap smears with ACP have higher false positives due to tendency for cytomorphologic overinterpretation as compared to non-ACP group.

Dual-color immunocytochemistry (Ki-67 with LCA) for precise grading of pancreatic neuroendocrine tumors with applicability to small biopsies and cell blocks.

Ki-67 (MIB-1) immunostaining to quantify the proliferative index of neuroendocrine tumors (NETs) has been recommended (especially for small biopsies). However, this has a number of challenges with nonrepresentative Ki-67 index due to interference by Ki-67 immunoreactive proliferating lymphocytes infiltrating the tumor and also some proliferating stromal cells including endothelial cells in the background. Our pilot project showed that dual-color immunostaining with inclusion of leukocyte common antigen (LCA) (Ki-67: nuclear brown; LCA: cytoplasmic red) can facilitate the weeding out of lymphocyte interference. We analyzed the results with 23 surgical cases of pancreatic NETs. This was followed by poststudy examination of 11 cases of endoscopic ultrasound-guided fine-needle aspiration of the pancreatic NETs (PanNETs) to evaluate the findings of the study. Dual-color immunostaining for Ki-67 with LCA increased the precision of quantifying Ki-67 index, due to ability to exclude LCA immunoreactive lymphocytes. Other nontumor Ki-67 immunoreactive cells such as endothelial and stromal cells could be distinguished morphologically. Digital methods were also attempted, but this approach could not distinguish infiltrating lymphocytes and other cells in sections resulting in erroneous results. This study demonstrated that grading of PanNET can be performed with increased precision with dual-color Ki-67 immunostaining protocol standardized in this study. As evaluated on a few cytopathology cases, this protocol is especially useful for the evaluation of small biopsies and cell block sections of fine-needle aspiration biopsy material where 50 high-power fields cannot be evaluated but have >500 tumor cell nuclei.

CellBlockistry: Chemistry and art of cell-block making - A detailed review of various historical options with recent advances.

Cell-blocks are paraffin-embedded versions of cytology specimens comparable to the formalin-fixed paraffin-embedded (FFPE) tissue from surgical pathology specimens. They allow various elective ancillary studies on a variety of specimens with enhanced cytopathologic interpretation, including opportunity to perform molecular tests. However, different dictionaries and internet search engines primarily project "cellblock" and "cell block" definition in relation to prisons. Most of the top searches lead to information related to "prison cells" followed by a few cytopathology-related searches. Due to this in the current review, it is recommended that the word for cytopathology purposes should be hyphenated and spelled as "cell-block." Cell-blocks have been increasingly indicated on most cytology specimens. Its role is growing further with the ongoing addition of new immunohistochemistry (IHC) markers with technical advances including multicolor IHC and the SCIP (subtractive coordinate immunoreactivity pattern) approach. In addition, it is an important source of tissue for many ancillary studies even as archived material retrospectively at later stage of management if the cell-blocks are improved qualitatively and quantitatively. Because of this, the significance of cell-block is critical with the increasing number of molecular markers standardized predominantly on FFPE tissue. As compared to core biopsies, high-quality cell-blocks prepared with enhanced methodologies predominantly contain concentrated diagnostic tumor cells required for the molecular tests without significant stromal contamination. This review introduces the terminology of CellBlockistry as the science of studying chemistry and the art of achieving quantitatively and qualitatively improved cell-blocks from different types of specimens. The review addresses the cell-block making process as "cell-blocking" and discusses different historical limitations with emphasis on recent advances.

An algorithmic approach to overcome diagnostic challenges in FNAC in large-cell poorly differentiated thyroid carcinomas.

INTRODUCTION: Poorly differentiated thyroid carcinoma (PDTC) is a distinct entity and a rare carcinoma of thyroid follicular origin with an intermediate prognosis. It is defined by the Turin criteria set in 2007. Although this entity is well known, with widely available literature on histological features, specific studies describing the cytological features of PDTC (especially the large cell type) are lacking. In this study, we describe the cytological and clinical features of PDTC showing large cells (PDTC-LC) with abundant cytoplasm. MATERIALS: Twelve cases of PDTC showing abundant cytoplasm between 2007 and 2016 were retrieved from the departmental archives and studied. RESULTS: The cases occurred predominantly in women with a mean age of 54.3 years. The mean tumor size was 4.3 cm. Fine-needle aspiration cytology (FNAC) smears showed singly scattered large cells with abundance of cytoplasm admixed with microfollicular and insular pattern. Lymph node metastasis was noted in 7 cases and distant metastasis to bone and visceral organs were also seen in 7 cases. CONCLUSIONS: Microfollicular pattern may lead to these cases being misinterpreted as a differentiated follicular neoplasm on FNAC, and the dissociated large cells may mimic Hürthle cell neoplasm. Immunocytochemistry is not helpful in this scenario, although it does resolve the diagnostic dilemma when the differential diagnoses include medullary thyroid carcinoma and metastatic tumors. It is important to identify these tumors on FNAC as this facilitates proper management.