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Genomic alterations are increasingly important in the current paradigms for the classification, diagnosis, and treatment of renal cell carcinoma. Biallelic alterations involving NF2 have been identified across several currently recognized subtypes of renal cell carcinoma including clear cell renal cell carcinoma and papillary renal cell carcinoma among others and may be associated with a more aggressive disease course as well as advanced stage at presentation. In addition, emerging evidence suggests the existence of a clinicopathologically distinct subset of renal cell carcinoma cases driven by biallelic loss of NF2 expression. This subset of tumors is morphologically characterized by a constellation of morphologic features including hyalinizing fibrosis, eosinophilic cytology, psammomatous calcifications, and a nested growth pattern. These tumors include the recently described entities of biphasic hyalinizing psammomatous renal cell carcinoma as well as renal cell tumor with sex cord/gonadoblastoma-like features. Despite their oftentimes aggressive behavior, there is some evidence that these tumors may respond favorably to treatment regimens incorporating immune checkpoint inhibitors.

Context.— Pembrolizumab is used in patients with metastatic head and neck squamous cell carcinoma contingent upon the programmed death ligand-1 (PD-L1) combined positive score (CPS). Objective.— To compare PD-L1 CPS scores derived from paired resected primary tumors (PTs) and lymph node metastases (LMs) in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC). Design.— We identified 38 resected p16+ OPSCCs for which paired PTs and LMs were available. PD-L1 immunohistochemistry using the SP263 antibody clone was done on both the PT and the LM. CPS scoring was performed by 4 observers, and data were analyzed at the CPS cut points of greater than or equal to 1 and 20 in regard to interobserver and interspecimen agreement. Results.— Overall agreement between consensus CPS scoring of PT and LM was seen in 76% of paired specimens (κ = 0.53). No specimen received a negative consensus score. Interobserver agreement for both PT and LM was fair to substantial (κ = 0.54 and 0.51, respectively) and was inferior to that seen in a prospective series of unselected head and neck squamous carcinoma cases evaluated at our institution (κ = 0.84). Conclusions.— Given the high rates of interobserver and interspecimen variability, evaluation of additional material or by additional observers may be of value in performing CPS scoring in cases of p16+ OPSCC. This is particularly the case when a negative or low-positive result is being evaluated in a patient who is otherwise a good candidate for immunotherapy.

Genetic alterations involving NF2 occur at low frequencies in renal cell carcinoma across all of the major histologic subtypes and have been associated with adverse outcomes. To better characterize tumors harboring these alterations, we identified 14 cases with NF2 mutations that had been previously diagnosed as papillary renal cell carcinoma; renal cell carcinoma, unclassified; or translocation associated renal cell carcinoma. These tumors were characterized by a tubulopapillary architecture, sclerotic stroma, microscopic coagulative necrosis, and psammomatous calcifications. All the cases displayed eosinophilic cytology as well as a high nuclear grade (World Health Organization/International Society of Urological Pathology [WHO/ISUP] grade 3 to 4) in all but 1 case. A subset of cases shared features with the recently described biphasic hyalinizing psammomatous renal cell carcinoma. Next-generation sequencing demonstrated mutations involving NF2 gene in all cases. In 10 cases, this was paired with the loss of chromosome 22. Additional mutations involving PBRM1 were found in 5 cases that were associated with a more solid growth pattern. Eight patients presented with metastatic disease including all 5 with PBRM1 mutations. Despite the aggressive disease course seen in many of the patients in our series, 2 patients exhibited a dramatic response to immunotherapy. Our results support the existence of a distinct group of cases of renal cell carcinoma characterized by distinct although admittedly nonspecific morphology, an aggressive disease course, and NF2 mutations, often paired with the loss of chromosome 22.

Human papillomavirus (HPV) is an important cause of head and neck squamous cell carcinoma (HNSCC) and accounts for a large majority of new cases. The purpose of this study is to determine whether there is an association between nodal calcification and HPV positivity in the setting of metastatic HNSCC.Consecutive patients with HNSCC who underwent CT were retrospectively identified. Patients were then divided into two groups: those with HPV-positive HNSCC and those with HPV-negative HNSCC. Demographic, clinical, and CT data were compared between the two groups to determine factors associated with HPV-positive HNSCC.A total of 179 patients with HNSCC were included in the final analyses, 104 (58%) of whom had HPV-positive tumors. Univariate analyses demonstrated that those with HPV-positive HNSCC were more likely to have calcified lymph nodes (p = 0.044). Analyses also confirmed previously known associations with male gender (p = 0.001), primary oropharyngeal tumors (p 0.001), and cystic lymph nodes (0.001). The HPV-positive HNSCC group was also less likely to have necrotic lymph nodes (p 0.001).In addition to known clinical and imaging factors associated with HPV-positive metastatic HNSCC, such as male gender, oropharyngeal primary location, and cystic lymph nodes, the presence of calcifications within cervical lymph nodes, although infrequent, provides an additional useful feature to predict HPV positivity in HNSCC. Additionally, if calcified lymph nodes are present, then a primary oropharyngeal tumor site should be considered.

Image-guided procurement of tissue or fluid for diagnostic purposes has become one of the most commonly performed procedures in medicine. Although the focus of this Atlas is cytologic analysis of tissue specimens, we would note that cytologic, biochemical, and microbiologic evaluation of fluids obtained in this manner is similarly important, and for the purposes of this text the term “biopsy” will be assumed to cover both settings.

Introduction Although the utility of high-risk human papillomavirus (hrHPV) testing is established in the triage of ASC-US Papanicolaou tests from the general population, its role in women who have been treated for cervical cancer and other HPV-related cancers is less clear. Materials and methods Records of patients with ASC-US Papanicolaou tests and HPV testing results submitted by our gynecologic oncology service with a history of malignancy between 2006 and 2012 were reviewed. Results Thirty-nine women with a history of treatment for HPV-related cancer and ASC-US Papanicolaou tests who had undergone hrHPV testing were identified. hrHPV was detected in the in specimens from 12 of the 39 patients. Among the 12 patients with ASC-US/hrHPV+ Papanicolaou tests, 2 had a subsequent Papanicolaou test with high-grade squamous intraepithelial lesion (HSIL) and 1 had a cervical biopsy that showed invasive squamous cell carcinoma. Among the 27 patients with ASC-US/hrHPV– Papanicolaou tests with pathologic follow-up, none had HSIL or worse. In patients with treated non-HPV-related cancers, hrHPV was detected in cervical/vaginal cytology specimens from 11 of 47 patients. Of 11 patients with ASCUS/hrHPV+ Papanicolaou tests, 1 had an HSIL Papanicolaou test and a negative vaginal biopsy within 18 months. None of the 36 patients with ASC-US/hrHPV– Papanicolaou tests had HSIL or worse on follow-up. Conclusion The rates of hrHPV positivity in ASC-US Papanicolaou tests from women treated for both HPV-related (31%) and non-HPV-related (23%) gynecologic malignancies were similar to those reported in women older than 45 years. hrHPV testing identified all women with ASC-US Papanicolaou tests who subsequently developed HSIL or worse.

In 2012, the College of American Pathologists and American Society for Colposcopy and Cervical Pathology published the "LAST" recommendations for histopathology reporting of human papilloma virus-related squamous lesions of the lower anogenital tract, including the use of a 2-tier nomenclature (low-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion [LSIL/HSIL]) and expanded use of the biomarker p16 to classify equivocal lesions as either precancer (HSIL) or low-grade lesions (LSIL)/non-human papilloma virus changes. We aimed to determine (1) the frequency with which the poorly reproducible diagnosis of intermediate-grade (-IN 2) lesion in the lower anogenital tract would be downgraded on the basis of p16 results, and (2) whether p16 status was predictive of subsequent higher-grade lesions. A total of 200 specimens diagnosed as an intermediate-grade (-IN 2) lesion of the cervix (168), vagina (2), vulva (2), and anus (28) were reviewed and immunostained for p16. Slides were independently reviewed by 2 pathologists, with discrepant p16 interpretations adjudicated by a third pathologist. Of the 200 cases, 32% were negative for p16. Among the 166 patients with subsequent pathology (including 131 excisions), 26.2% of p16-positive cases versus 4.4% of p16-negative cases were associated with a subsequent diagnosis of HSIL (-IN 3) or worse (P=0.002). Reproducibility of the biopsy diagnosis was fair, with no significant difference with the addition of p16 or using 2 versus 3 tiers. In 11.5% of cases, there was discordance in p16 interpretation (κ 0.735, good agreement). The results indicate that using the Lower Anogenital Squamous Terminology recommendations would result in approximately one third of equivocal (-IN 2) diagnoses being downgraded to LSIL over 1 year in a busy academic practice. The significant association of p16 expression with a higher risk for HSIL on a subsequent specimen suggests that use of p16 to adjudicate equivocal (-IN 2) diagnoses in lower anogenital tract specimens as either LSIL or HSIL would likely predict lesion grade more accurately and avoid unnecessary excisional procedures.

Background Given the lack of recent literature regarding the aspiration cytology of immunohistochemically confirmed malignant mesothelioma (MM), we were interested in reviewing the experience of our institution and establishing useful morphologic criteria. Methods Seventeen aspiration and touch preparation specimens with a diagnosis of MM obtained between 2002-2013 were reviewed along with 20 cases of adenocarcinoma and 16 cases of squamous cell carcinoma. The utility of a number of morphologic features was evaluated. Results In most cases of MM, a consistent pattern emerged. Aspirates and touch preps were cellular with irregularly shaped 2 and 3 dimensional clusters. The individual cells were predominantly angulated and had dense cytoplasm with eccentric nuclei. In every case, a minority of tumor cells contained prominent microvacuoles. The chromatin pattern tended to be fine with small nucleoli. While most cases were cytologically monotonous, five cases displayed striking pleomorphism and three cases contained occasional large atypical cells. Two cases contained metachromatic background material. Features which were most useful in discriminating MM from adenocarcinoma were angulated cell shape(P = 0.0002), dense cytoplasm(P = 0.0001), and cytoplasmic microvacuoles(P = 0.0001). In our material, cases of squamous cell carcinoma were often difficult to distinguish from MM. Useful discriminatory features present in squamous cell carcinoma included ink dot nuclei(P = 0.0003), a “dirty” cystic, necrotic background (P = 0.0027) and tumor balls with peripheral spindling(P = 0.0041). Conclusion Most cases of MM have a consistent appearance in core biopsy touch preps and FNAs. Distinguishing MM from adenocarcinoma and squamous cell carcinoma can be facilitated by evaluating a few key morphologic features. Diagn. Cytopathol. 2016;44:14–19. © 2015 Wiley Periodicals, Inc.

Cervical cancer epitomizes the success of cancer prevention through the human papillomavirus (HPV) vaccine, but significant challenges remain in the treatment of advanced disease. We report the first three cases of cervical carcinoma harboring an FGFR3–TACC3 fusion, which serves as a novel therapeutic target. The fusion, identified by comprehensive genomic profiling, activates the FGFR pathway that has been implicated in HPV-driven carcinogenesis. One of the patients whose tumor contained the FGFR3–TACC3 fusion was treated with an investigational FGFR tyrosine kinase inhibitor. Concomitant molecular alterations involving the PI3K/AKT/mTOR and RAF/MEK pathways were also identified and suggest other treatment strategies that deserve investigation. This case series highlights the role of comprehensive genomic profiling in the identification of new therapeutic targets and in targeted therapy selection for patients with cervical cancer., Highlights • The first cases of cervical carcinoma harboring an FGFR3–TACC3 fusion • One of patients whose tumor contained the FGFR3–TACC3 fusion received an investigational FGFR tyrosine kinase inhibitor • Manuscript highlights the role of genomic profiling identifying new therapeutic targets and targeted therapies

Lung cancer is the leading cause of cancer-related mortality in both sexes, accounting for over one quarter of cancer deaths. Non-small-cell lung cancer (NSCLC) comprises 85%–90% of lung cancer diagnoses and despite advances in multimodality therapies, 5-year survival rates remain dismal with a median survival for patients with metastatic disease of 1 year. The positive outcomes of targeted therapies against the kinase domain of epidermal growth factor receptor in NSCLC triggered consistent efforts to identify the so-called driver mutations as other potential targets. Anaplastic large-cell kinase (ALK) gene rearrangements were identified and targeted resulting in promising response rates in early studies. Unfortunately, most of the patients treated with crizotinib, the first-generation ALK inhibitor, progressed within 9 months. Ceritinib is a second-generation ALK inhibitor that has demonstrated activity in crizotinib-resistant patients, becoming a promising treatment option in this population. Furthermore, additional novel ALK inhibitors and agents targeting alternative pathways have been recruited to rechallenge this evasive disease post-crizotinib resistance.

Background It is unclear why human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has improved clinical behavior compared to HPV-negative HNSCC. We sought to better characterize the immune microenvironment of tongue cancers by examining the CD3 and CD8 TIL pattern in HPV-positive and -negative tumors. Methods Histologic sections from 40 oral tongue and oropharyngeal cases were analyzed (n= 21 HPV DNA-positive, n= 19 HPV DNA-negative). CD3 and CD8 T cell immunostaining was performed on whole slide sections to quantify tumor infiltrating lymphocyte (TIL) density and assess its morphology. Results A subset of cases (HPV-positive), displayed a unique TIL pattern consisting of circumferential peritumoral population T cells, which was absent in the HPV-negative cases. The presence of peritumoral cuffing was strongly predictive of improved recurrence free survival compared to cases that lacked this morphologic pattern of immune infiltrate. Four HPV-positive cases lacked the pattern, including two cases with disease recurrence. Conclusions For the first time, we show an architectural pattern of immune infiltrate in HNSCC is seen exclusively in HPV-positive patients with improved recurrence free survival and suggests an organized host immunological response contributes to disease control. This article is protected by copyright. All rights reserved.

Context.—Uterine serous carcinoma is biologically more aggressive than the endometrioid carcinoma. Because uterine serous carcinoma has a high propensity for lymphovascular invasion and intraperitoneal and extra-abdominal spread, accurate diagnosis of this tumor type in endometrial biopsies/curettings is critical for appropriate clinical management. Objective.—To share our experience in the evaluation of endometrial biopsy specimens in type I and type II endometrial adenocarcinoma. Design.—We retrospectively reviewed 358 biopsies containing endometrial carcinoma during a recent 3 year period of our consultation records. In cases in which our interpretation differed from the submitting diagnosis, a panel of immunostains was performed. The performance characteristics of each antibody in our panel was calculated in this group of challenging cases. Results.—Among the endometrial carcinomas we examined, a diagnosis of type I carcinoma accounted for 91% of cases (327 of 358) and type II carcinoma for 9% of cases (31 of 358); 41 cases (11.5%) were ambiguous or discordant (differing from submitted diagnoses and reviewed) based on histology alone. All 41 ambiguous and discordant cases were further evaluated with a battery of immunohistochemical markers. Of the 41 cases, 36 (88%) were ultimately classified (10 cases [24%] were endometrioid carcinoma; 18 cases [44%] were uterine serous carcinoma; 8 cases [20%] resulted in various other outcomes) and 5 cases (12%) remained indeterminate. Conclusions.—Making the distinction between type I and II endometrial carcinoma remains a common problem in general practice. Although no one biomarker provides excellent statistical performance, a panel of immunohistochemical markers is often useful in difficult cases.

BACKGROUND The diagnosis of malignant mesothelioma (MM) in effusion specimens is controversial. At the study institution (Northwestern University), a primary diagnosis of MM is made on fluid cytology specimens. In an effort to estimate the practice at other institutions, a survey was disseminated regarding cytologic diagnosis of MM. The authors also evaluated their own institution's experience with primary cytologic diagnosis of MM. METHODS Patients with MM at the study institution were identified from 1992 through 2011. Fluid cytology specimens preceding histologic diagnoses were reviewed. A survey was sent to a number of cytology laboratories to assess practice patterns regarding the diagnosis of MM. RESULTS At the study institution, 20 cases of MM had effusion specimens preceding the diagnostic histologic material. In 6 cases (30%), a definitive diagnosis of MM was rendered via cytology alone. There were no false-positive diagnoses of MM. Of 55 laboratories that responded to the survey, 36 reported making a definitive diagnosis of MM after cytologic analysis. Almost all laboratories (35) willing to diagnose MM in effusions reported performing immunohistochemistry to distinguish adenocarcinoma from MM. A smaller proportion (18) of these laboratories reported doing additional immunohistochemistry or fluorescence in situ hybridization for p16 to help distinguish benign from malignant mesothelial proliferations. Those who do not definitively diagnose MM in fluid specimens state inability to identify invasion and overlap with reactive mesothelial proliferation as factors supporting their practice. Most respondents (32) felt that the clinicians at their institution would manage a patient based on a cytologic diagnosis of MM. CONCLUSIONS The majority of respondents reported making a definitive diagnosis of MM in effusion cytology specimens. The diagnosis of MM in effusions, although not sensitive, is extremely specific. Cancer (Cancer Cytopathol) 2013;121:703–707. © 2013 American Cancer Society.

Cardiac papillary fibroelastoma, a rare entity, is the second most common benign primary cardiac tumor. Commonly involving the cardiac valves, this entity is increasingly diagnosed using different imaging modalities. We present a rare case of simultaneous involvement of both the aortic and pulmonary valves in an asymptomatic patient who underwent different imaging modalities, including transthoracic and transesophageal echocardiography, nongated and gated computed tomography, and magnetic resonance imaging. We will discuss the imaging findings and differential diagnosis.

Background & Aims Despite the widespread use of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to sample pancreatic lesions and the standardization of pancreaticobiliary cytopathologic nomenclature, there are few data on inter-observer agreement among cytopathologists evaluating pancreatic cytologic specimens obtained by EUS-FNA. We developed a scoring system to assess agreement among cytopathologists in overall diagnosis and quantitative and qualitative parameters, and evaluated factors associated with agreement. Methods We performed a prospective study to validate results from our pilot study that demonstrated moderate to substantial inter-observer agreement among cytopathologists for the final cytologic diagnosis. In the first phase, 3 cytopathologists refined criteria for assessment of quantity and quality measures. During phase 2, EUS-FNA specimens of solid pancreatic lesions from 46 patients were evaluated by 11 cytopathologists at 5 tertiary care centers using a standardized scoring tool. Individual quantitative and qualitative measures were scored and an overall cytologic diagnosis was determined. Clinical and EUS parameters were assessed as predictors of unanimous agreement. Inter-observer agreement (IOA) was calculated using multi-rater kappa (κ) statistics and a logistic regression model was created to identify factors associated with unanimous agreement. Results The IOA for final diagnoses, based on cytologic analysis, was moderate (κ = 0.56; 95% CI, 0.43–0.70). Kappa values did not increase when categories of suspicious for malignancy, malignant, and neoplasm were combined. IOA was slight to moderate for individual quantitative (κ = 0.007; 95% CI, –0.03 to –0.04) and qualitative parameters (κ = 0.5; 95% CI, 0.47–0.53). Jaundice was the only factor associated with agreement among all cytopathologists on multivariate analysis (odds ratio for unanimous agreement, 5.3; 95% CI, 1.1–26.89). Conclusions There is a suboptimal level of agreement among cytopathologists in the diagnosis of malignancy based on analysis of EUS-FNA specimens obtained from solid pancreatic masses. Strategies are needed to refine the cytologic criteria for diagnosis of malignancy and enhance tissue acquisition techniques to improve diagnostic reproducibility among cytopathologists.

Flt3 (fms-like tyrosine kinase 3) ligand, a cytokine that stimulates increases in the number of dendritic cells (DC) in vivo, has been shown to have antitumor activity in murine models via an immune-mediated mechanism. Therefore, we examined the clinical activity of this cytokine in patients with an immunologic-responsive cancer, metastatic renal cell carcinoma. Flt3 ligand (25 μg/kg subcutaneous) was administered daily for the first 14 days of a 28-day cycle. Although the treatment was well tolerated and was confirmed to induce expansion of lineage (Lin) - /HLA-DR + /CD11c + myeloid DC and Lin - /HLA-DR + /CD123 + plasmacytoid DC, no clinical activity was observed. Reasoning that DC expanded by Flt3 ligand might potentiate the clinical activity of low-dose interleukin-2, a second study was conducted of sequential administration of 25 μg/kg of Flt3 ligand daily for 7 days was followed by 11 x 10 6 IU of subcutaneous interleukin-2 for 4 consecutive days x 4 weeks. In this study, increased numbers of circulating DC were again observed, which was followed by increased numbers of activated T cells, confirming a biologic effect of each cytokine. However, toxicity and clinical efficacy were similar to what has been seen with low-dose interleukin-2 alone, with two minor responses observed. These results demonstrate that Flt3 ligand, although capable of inducing expansion of circulating myeloid and plasmacytoid DC in patients with metastatic renal cell carcinoma, lacks significant clinical activity at the doses and schedules examined.

Widespread adoption of the Pap test as a screening tool for cervical cancer is arguably one of the most significant advances in public health in human history. While much of the basic performance of the Pap test has remained the same over the years, the addition of liquid-based cytology, automated image analysis, and concomitant testing for high-risk human papillomaviruses have had a substantial impact on the screening and treatment paradigm and the way the Pap test has been used over the last decade. These technologies have helped advance the detection of cervical cancer and its precursors.

ObjectiveMost endometrial cancers are detected early and have a good prognosis, while some endometrial cancers are highly invasive, metastasize early, and respond suboptimally to therapy. Currently, appropriate model systems to study the aggressive nature of these tumors are lacking. The objective of this study was to establish a mouse xenograft model of endometrial tumors derived from patients in order to study the biological aggressive characteristics that underlie invasion and metastasis.MethodsEndometrial tumor tissue fragments (1.5 mm × 1.5 mm) from patients undergoing surgery, were transplanted under the renal capsule of NOD scid gamma mice. After 6-8 weeks, tumors were excised and serially transplanted into additional mice for propagation. Immunohistochemical analysis of the tumors was done for various tumor markers.ResultsFour cases of different subtypes of endometrial cancer were grown and propagated in mice. Three of the four tumor cases invaded into the kidneys and to adjacent organs. While all tumors exhibited minimal to no staining for estrogen receptor α, progesterone receptor staining was observed for tumor grafts. In addition, levels and localization of E-cadherin, cytokeratin and vimentin varied depending on subtype. Finally, all tumor xenografts stained positively for urokinase plasminogen activator while 3 tumor xenografts, which showed invasive characteristics, stained positively for urokinase plasminogen activator receptor.ConclusionEndometrial tumors transplanted under the renal capsule exhibit growth, invasion and local spread. These tumors can be propagated and used to study aggressive endometrial cancer.

The introduction of aspiration cytology has revolutionized the workup of many human tumors. In the head and neck, it has streamlined the evaluation of the thyroid and salivary glands tumors, cervical lymphadenopathy, orbital lesions, and other head and neck masses. The technique has evolved and is frequently the first step in the initial in-office evaluation of head and neck tumors. Fine needle aspiration biopsy is safe, accurate, practical, and very cost-effective. Despite its wide acceptance, many aspects relating to the utility and interpretation of cytologic specimens remain controversial. The purpose of this chapter is to familiarize the oncologist with the role of cytology and fine needle biopsy in head and neck neoplasms and their use in clinical practice.

Triple negative breast cancers (TNBCs) are often aggressive neoplasms that are poorly differentiated, making confirmation that a metastasis is from a TNBC challenging. Many immunohistochemical (IHC) breast markers are specific but not sensitive, particularly in TNBCs. SOX10 is a nuclear transcription factor that is primarily used in diagnosing neuroectodermal tumors but that …

Given the lack of recent literature regarding the aspiration cytology of immunohistochemically confirmed malignant mesothelioma (MM), we were interested in reviewing the experience of our institution and establishing useful morphologic criteria.Seventeen aspiration and touch preparation specimens with a diagnosis of MM obtained between 2002-2013 were reviewed along with 20 cases of adenocarcinoma and 16 cases of squamous cell carcinoma. The utility of a number of morphologic features was evaluated.In most cases of MM, a consistent pattern emerged. Aspirates and touch preps were cellular with irregularly shaped 2 and 3 dimensional clusters. The individual cells were predominantly angulated and had dense cytoplasm with eccentric nuclei. In every case, a minority of tumor cells contained prominent microvacuoles. The chromatin pattern tended to be fine with small nucleoli. While most cases were cytologically monotonous, five cases displayed striking pleomorphism and three cases contained occasional large atypical cells. Two cases contained metachromatic background material. Features which were most useful in discriminating MM from adenocarcinoma were angulated cell shape(P = 0.0002), dense cytoplasm(P = 0.0001), and cytoplasmic microvacuoles(P = 0.0001). In our material, cases of squamous cell carcinoma were often difficult to distinguish from MM. Useful discriminatory features present in squamous cell carcinoma included ink dot nuclei(P = 0.0003), a "dirty" cystic, necrotic background (P = 0.0027) and tumor balls with peripheral spindling(P = 0.0041).Most cases of MM have a consistent appearance in core biopsy touch preps and FNAs. Distinguishing MM from adenocarcinoma and squamous cell carcinoma can be facilitated by evaluating a few key morphologic features.