Merkel cell carcinoma: an update.

Merkel cell carcinoma (MCC) is an uncommon primary cutaneous neuroendocrine carcinoma associated with an adverse prognosis. In recent years, our understanding of MCC biology has markedly progressed. Since the discovery of the Merkel cell polyomavirus, it has become clear that MCC represents an ontogenetically dichotomous group of neoplasms with overlapping histopathology. Specifically, most MCCs arise secondary to viral oncogenesis, while a smaller subset is the direct result of UV-associated mutations. The distinction of these groups bears relevance in their immunohistochemical and molecular characterization, as well as in disease prognosis. Further recent developments relate to the landmark utilization of immunotherapeutics in MCC, providing optimistic options for the management of this aggressive disease. In this review, we discuss both fundamental and emerging concepts in MCC, with a particular focus on topics of practical relevance to the surgical or dermatopathologist.

Periocular invasive melanoma manifestation in a patient using bimatoprost: case report and literature review.

Prostaglandin F2a analogs (PGAs) are considered efficacious in the first-line treatment of glaucoma. They have however been associated with a number of periocular side effects. We present a case of periocular hyperpigmentation and progression to lentigo maligna melanoma (LMM) in a patient using bimatoprost eye drops. We conducted a literature review regarding the etiology and pathophysiology of periocular pigmentation in this setting.A 71-year-old female Caucasian patient with open-angle glaucoma using bimatoprost exclusively in her right eye noticed an ipsilateral lower eyelid/upper cheek area dark lesion after commencing treatment. Examination demonstrated a heterogeneously pigmented lesion. Excisional biopsy demonstrated extensive lentigo maligna (melanoma in situ) with superficially invasive malignant melanoma in the lesion center. The patient underwent successful staged excision and reconstruction. Literature review has demonstrated case reports supporting periocular hyperpigmentation; however, there has been no description of progression to periocular lentigo maligna and melanoma in a patient using bimatoprost.

RB1-deficient squamous cell carcinoma: the proposed source of combined Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine (NE) carcinoma arising from integration of Merkel cell polyomavirus (MCPyV) DNA into a host cell or from ultraviolet light-induced genetic damage (proportions vary geographically). Tumors in the latter group include those with "pure" NE phenotype and those "combined" with other elements, most often squamous cell carcinoma (SCC). We performed comprehensive genomic profiling (CGP) of MCPyV+ and MCPyV- (pure and combined) tumors, to better understand their mutational profiles and shed light on their pathogenesis. Supplemental immunohistochemistry for Rb expression was also undertaken. After eliminating low quality samples, 37 tumors were successfully analyzed (14 MCPyV+, 8 pure MCPyV- and 15 combined MCPyV-). The SCC and NE components were sequenced separately in 5 combined tumors. Tumor mutational burden was lower in MCPyV+ tumors (mean 1.66 vs. 29.9/Mb, P < 0.0001). MCPyV- tumors featured frequent mutations in TP53 (95.6%), RB1 (87%), and NOTCH family genes (95.6%). No recurrently mutated genes were identified in MCPyV+ tumors. Mutational overlap in the NE and SCC components of combined tumors was substantial ('similarity index' >24% in 4/5 cases). Loss of Rb expression correlated with RB1 mutational (P < 0.0001) and MCPyV- status (P < 0.0001) in MCCs and it was observed more frequently in the SCC component of combined MCC than in a control group of conventional cutaneous SCC (P = 0.0002). Our results (i) support existing evidence that MCPyV+ and MCPyV- MCCs are pathogenetically distinct entities (ii) concur with earlier studies linking the NE and SCC components of combined MCCs via shared genetic profiles and (iii) lend credence to the proposal that an Rb-deficient subset of SCC's is the source of phenotypically divergent combined MCCs.

Morphological patterns of metastases from combined Merkel cell carcinomas: study of an eastern Canadian cohort of cases.

Combined Merkel cell carcinomas are hybrid tumors composed of neuroendocrine and other phenotypic (usually squamous) elements. They form a minority of Merkel cell carcinomas (MCCs) as a whole, are usually Merkel cell polyomavirus-negative, and have rarely been segregated for specific study. Sporadic reports have indicated that metastases from these tumors can show a combined phenotype. We retrospectively studied 38 cases (24 men [63%], 14 women [37%], mean age 78 years [range, 46-99 years]) of combined MCC. Metastases occurred in 20 patients (53%) (at presentation and/or in follow-up [mean 38 months (range, 0.6-185 months)]). Those from 17 individuals (45%) were examined microscopically. These were mainly nodal in distribution. In 12 patients (71%), the secondary deposits were of pure neuroendocrine type, whereas in 5 (29%), combined deposits were identified. Squamous elements were the most common divergent component, in the primary and secondary tumors. The combined metastases varied from obvious squamous nests in a neuroendocrine background to scattered bizarre tumor giant cells expressing CK5/6 on immunohistochemistry. In one case, individual nodes within a single basin displayed purely squamous or purely neuroendocrine deposits. The mean overall survival in the cohort was 48 months (range, 30-67 months) and the mortality was 82%. Our work sheds light on the frequency and patterns of metastases in combined MCCs. In concert with the poor outcome data documented by others, it also raises a question as to the potential prognostic significance of a combined phenotype per se, independent of a virus-negative status and other variables. This issue deserves further study.

Relationship between p63 and p53 expression in Merkel cell carcinoma and corresponding abnormalities in TP63 and TP53: a study and a proposal.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma. Oncogenesis occurs via Merkel cell polyomavirus-mediated (MCPyV+) and/or ultraviolet radiation-associated (MCPyV-) pathways. Advanced clinical stage and an MCPyV- status are important adverse prognostic indicators. There is mounting evidence that p63 expression is a negative prognostic indicator in MCC and that it correlates with MCPyV- status. p63 is a member of the p53 family of proteins among which complex interactions occur. It has two main isoforms (proapoptotic TAp63 and oncogenic ΔNp63). Paradoxically, TAp63 predominates in MCC. To explore this quandary, we examined relationships between p63 and p53 expression and corresponding abnormalities in the TP63 and TP53 genes in MCC. A cohort of 26 MCCs (12 MCPyV+ and 14 MCPyV-) was studied. Comparative immunohistochemical expression of p63 and p53 was evaluated semiquantitatively (H scores) and qualitatively (aberrant patterns). The results were compared with genetic abnormalities in TP63 and TP53 via next-generation sequencing. p63 was positive in 73% of cases. p53 showed "wild-type" expression in 69%, with "aberrant" staining in 31%. TP63 mutations (predominantly low-level copy gains; 23% of cases) and mainly pathogenic mutations in TP53 (50% of cases) featured in the MCPyV- subset of cases. p63 expression correlated quantitatively with p53 expression and qualitatively with aberrant patterns of the latter. Increased expression of p63 and p53 and aberrant p53 staining correlated best with TP53 mutation. We propose that p63 expression (ie, proapoptotic TAp63) in MCC is most likely functionally driven as a compensatory response to defective p53 tumor suppressor activity.

The use of noninvasive imaging techniques in the diagnosis of melanoma: a prospective diagnostic accuracy study.

BACKGROUND: Early detection of melanoma is crucial to improving the detection of thin curable melanomas. Noninvasive, computer-assisted methods have been developed to use at the bedside to aid in diagnoses but have not been compared directly in a clinical setting. OBJECTIVE: We conducted a prospective diagnostic accuracy study comparing a dermatologist's clinical examination at the bedside, teledermatology, and noninvasive imaging techniques (FotoFinder, MelaFind, and Verisante Aura). METHODS: A total of 184 patients were recruited prospectively from an outpatient dermatology clinic, with lesions imaged, assessed, and excised. Skin specimens were assessed by 2 blinded pathologists, providing the gold standard comparison. RESULTS: Fifty-nine lesions from 56 patients had a histopathologic diagnosis of melanoma, whereas 150 lesions from 128 patients were diagnosed as benign. Sensitivities and specificities were, respectively, MelaFind (82.5%, 52.4%), Verisante Aura (21.4%, 86.2%), and FotoFinder Moleanalyzer Pro (88.1%, 78.8%). The sensitivity and specificity of the teledermoscopist (84.5% and 82.6%, respectively) and local dermatologist (96.6% and 32.2%, respectively) were also compared. LIMITATIONS: There are inherent limitations in using pathology as the gold standard to compare sensitivities and specificities. CONCLUSION: This study demonstrates that the highest sensitivity and specificity of the instruments were established with the FotoFinder Moleanalyzer Pro, which could be a valuable tool to assist with, but not replace, clinical decision making.

p63 expression in Merkel cell carcinoma: comparative immunohistochemistry invokes TAp63 as the dominant isoform involved.

The literature suggests that p63 expression in Merkel cell carcinoma (MCC) is associated with a poor prognosis. p63 immunohistochemistry marks the 2 main isoforms of this transcriptional protein: TAp63 (tumor suppressor-like properties) and ∆Np63 (oncogenic properties). Little information about the isoform of relevance in MCC exists. p40 immunohistochemistry specifically marks ∆Np63, and using comparative, semiquantitative expression of p63 and p40, we sought to clarify the issue. Our cohort of 53 cases (28 men and 25 women, median age 79 years, interquartile range 71-88) was stratified by morphology and viral status. Immunohistochemistry (p63, p40, and cytokeratin 5/6) was performed, H-scores for nuclear expression of p63 and p40 were derived (2 observers; positivity ≥ 10), and interobserver agreement was evaluated. Clinical, pathological, and outcome data were documented. The results were analyzed statistically. Mortality amounted to 57% (median follow-up 686 days, interquartile range 292-1599). Positivity for Merkel cell polyomavirus was observed in 29 (55%) of cases. Expression of p63 and p40 was present in 36 (69%) and 4 (8%) of cases, respectively. Increased age (P = .0241), negative Merkel cell polyomavirus status (P = .0185), and p63 positivity (P = .0012) were significantly associated with mortality. The latter 2 variables were highly correlated (P = .004). The interclass correlation between the 2 sets of H-scores was 0.95. Our findings support an association between p63 expression and reduced overall survival in MCC and show consistency in scoring this prognostic parameter. TAp63 is the dominant isoform of the protein involved. The paradoxical tumor suppressor-like activity of this isoform in p63-positive MCCs with reduced overall survival requires further study.

Global PD-L1 Signals and Tumor-Infiltrating Lymphocytes: Markers of Immunogenicity in Different Subsets of Merkel Cell Carcinoma and Potential Therapeutic Implications.

We previously studied the genetic and immunohistochemical profiles of subsets of Merkel cell carcinoma (MCC) stratified by morphology and Merkel cell polyomavirus (MCPyV) status. Recent advances in the immunotherapy of this disease prompted us to examine markers of immunogenicity [PD-L1 expression and tumor-infiltrating lymphocytes (TILS) in these subsets]. The observed clinical responses to checkpoint inhibition of the PD-1/PD-L1 pathway have not correlated with PD-L1 expression by MCC cells, and recent evidence suggests that functions of this pathway within the immune tumor microenvironment may be relevant. We conducted a semiquantitative (high, moderate, and minimal) immunohistochemical evaluation of the global PD-L1 signal in 52 cases of MCC, segregated in 3 subsets [pure MCPyV-positive (n = 28), pure MCPyV-negative (n = 9), and combined MCPyV-negative (n = 15)]. TILS were categorized as brisk, nonbrisk, or absent. Intersubset comparisons revealed that high global PD-L1 signals were exclusively associated with pure MCPyV-positive MCCs contrasted with virus-negative cases (P = 0.0003). Moderate signals were seen across all 3 groups. Brisk TILS were significantly associated with MCPyV-positive MCCs compared with MCPyV-negative cases (P = 0.029). Neither parameter (PD-L1 or TILS) was significantly different between the MCPyV-negative groups. Of potential clinical relevance, MCPyV seems to convey greater immunogenicity to MCCs than the high mutational burden/greater neoantigen load of MCPyV-negative cases. Interesting too is the fact that subset-related profiles of these markers mirrored those noted at genetic and immunohistochemical levels, separating pure MCPyV-positive MCCs from the virus-negative subsets.

Immunohistochemical profiles of different subsets of Merkel cell carcinoma.

The literature records many examples of Merkel cell carcinoma (MCC) exhibiting aberrant immunohistochemical profiles. These can lead to diagnostic difficulty. The objectives of the current study were (1) to examine the immunohistochemical profile of different subsets of MCC to determine whether predictable subset-specific patterns exist and (2) to establish whether shared immunophenotypic patterns might reveal links between individual subsets, as demonstrated previously at a genetic level. In 52 cases of MCC, stratified by viral status and morphology, we studied 5 markers commonly used in the diagnostic evaluation of these tumors (CK20, CK7, chromogranin, neurofilament and TTF-1). Expression of these proteins was recorded as quantitative (H-scores) and absolute (positive vs negative) variables. In general, our data indicate that the "classical" or expected panel (CK20+, NF+, Chromo+, TTF-1, CK7-) is observed significantly more often in pure Merkel cell polyomavirus (MCPyV)-positive than in MCPyV-negative cases (78% vs 25%; P = .002). Neurofilament was less frequently encountered in MCPyV-negative than in MCPyV-positive tumors (66.7% vs 100%; P = .001) and expression of TTF-1 (37.5% vs 3.6%; P = .003) and CK7 (45.8 vs 14.3; P = .02) was more frequent. No significant immonophenotypic differences were observed between pure and combined MCPyV-negative tumors. Recognition of the more aberrant immunohistochemical profile of MCPyV-negative MCC should inform the diagnostic approach to this tumor. Moreover, the shared aberrant immunophenotype in pure and combined MCPyV-negative tumors supports a link between these entities and serves to separate them from MCPyV-positive tumors.

Recurrent and Fixed Neutrophilic Dermatosis Associated With Dasatinib.

BACKGROUND: Dasatinib is a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia (CML). Skin rashes are common, occurring in about a quarter of patients treated, and are generally mild. The commonest rash is a keratosis pilaris-like eruption. A neutrophilic dermatosis has rarely been reported. OBJECTIVE: We report a patient whose CML was successfully treated with dasatinib and who several years later developed episodes of a neutrophilic dermatosis recurring at the same sites. CONCLUSION: This report extends the clinical spectrum of neutrophilic dermatoses to include dasatinib-induced recurrent and fixed erythematous plaques.

Dyshidrotic Bullous Pemphigoid: Case Report and Review of Literature.

BACKGROUND: Dyshidrotic pemphigoid (DP) is a rare variant of bullous pemphigoid (BP) that affects the hands and feet and may resemble an acute vesicular eczema. While it can remain confined to hands and feet, spread that involves the entire body is described. BP and DP are associated with autoantibodies directed against hemidesmosomal proteins BP180 (collagen XVII) and BP230 (dystonin), which are transmembrane and intracellular proteins in the basement membrane zone, respectively. CASE SUMMARY: We present a case of DP in a 78-year-old woman who was diagnosed based on histopathologic and immunofluorescence findings and subsequently successfully treated. CONCLUSION: DP is an unusual form of localized BP. While the pathogenesis is still unclear, it may involve differential expression of BP antigens in the cutaneous basement membrane of the hands and feet. The clinical presentation is a diagnostic challenge, and skin biopsies with immunofluorescence studies are required for diagnosis.

Genetic profiles of different subsets of Merkel cell carcinoma show links between combined and pure MCPyV-negative tumors.

Tumorigenesis in Merkel cell carcinoma (MCC) is driven by (1) clonal integration of the Merkel cell polyomavirus (MCPyV) in neoplastic cells and/or (2) genetic damage by ultraviolet (UV) light. A higher mutational burden, a UV-mutational signature, and many mutations in the TP53 and RB1 genes characterize the virus-negative subset. MCPyV-negative MCCs include combined (often squamous and neuroendocrine) and pure (neuroendocrine) tumors. Because a combined morphology could elude detection microscopically, we sought a genetic link between combined and pure virus-negative tumors. From a global cohort of 46 cases, 9 pure MCPyV-positive, 9 pure MCPyV-negative, and 10 combined MCPyV-negative MCCs were studied by genome-wide microarray in search of copy number aberrations. The entire cohort (n=46) was evaluated by next-generation sequencing for mutations in selected tumor suppressor genes and oncogenes. More copy number aberrations and a greater fraction of the genome were changed in combined and pure MCPyV-negative tumors relative to MCPyV-positive cases (P<.01 for all comparisons). No difference in these parameters was found between the 2 MCPyV-negative groups. Copy number loss of RB1 or an inactivating RB1 mutation (either or both) was common in combined (8/10, 80%) and pure (7/9, 78%) MCPyV-negative tumors but not MCPyV-positive cases (1/9, 11%). A similar trend was seen for TP53 (combined [2/10, 20%] and pure virus-negative tumors [5/9, 56%] showed gene copy number loss or mutations contrasted with pure virus-positive cases [0/9, 0%]). The shared genetic profiles of combined and pure MCPyV-negative tumors link these subsets and separate them from MCPyV-positive tumors.

AL Amyloidoma of the Skin/Subcutis: Cutaneous Amyloidosis, Plasma Cell Dyscrasia or a Manifestation of Primary Cutaneous Marginal Zone Lymphoma?

It is unclear whether AL amyloidoma of the skin/subcutis represents a distinct entity, an indolent precursor of systemic amyloidosis, or a manifestation of cutaneous marginal zone lymphoma (cMZL). We collected 10 cases of cutaneous AL amyloidoma in order to better characterize the clinicopathologic features of this elusive entity (M:F=4:6; median age: 62.5 y, range: 31 to 82 y). Nine patients had a solitary nodule or plaque on the lower extremity (n=7), upper extremity (n=1), or chin (n=1). One patient had an AL amyloidoma on the right thigh and a second lesion on the right arm showing histopathologic features of cMZL without amyloid deposits. Clinical investigations excluded relevant systemic disease in all cases. Microscopically, dermal/subcutaneous deposits of amyloid were associated with sparse to moderate perivascular infiltrates of lymphocytes and monotypic plasma cells (7 with kappa and 3 with lambda light chain restriction). The plasma cells expressed CD56 in one of 9 studied cases. One case was characterized by a t(14;18)(q32;q21)/IGH-MALT1 translocation. Follow-up was available in 8 cases. All remain systemically well after a median time of 86.5 months (range: 40 to 144 mo). Local recurrence of disease was observed in 3 patients. A fourth patient presented with a cMZL without amyloid deposits 8 years after excision of the cutaneous AL amyloidoma. Although our series is small, careful categorization and follow-up of the cases, together with updated information in the literature, show clinical and biological links between AL amyloidomas of the skin/subcutis and cMZL, suggesting that at least a subset of cutaneous AL amyloidoma may represent an unusual manifestation of cMZL (cutaneous mucosa-associated lymphoid tissue lymphomas).

Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors.

Merkel cell polyomavirus is of oncogenic significance in approximately 80% of Merkel cell carcinomas. Morphological subcategories of the tumor differ in regard to viral status, the rare combined type being uniformly virus negative and the predominant pure type being mainly virus positive. Indications that different biological subsets of the tumor exist led us to explore this diversity. In an Eastern Canadian cohort of cases (75 patients; mean age, 76 years [range, 43-91]; male/female ratio, 43:32; 51 [68%] pure and 24 [34%] combined tumors), we semiquantitatively compared the immunohistochemical expression of 3 cellular proteins (p53, Bcl-2, and c-kit) in pure versus combined groups. Viral status was known in a subset of cases. The significant overexpression of p53 in the combined group (mean [SD], 153.8 [117.8] versus 121.6 [77.9]; P = .01) and the increased epidermal expression of this protein (p53 patches) in the same group lend credence to a primary etiologic role for sun damage in these cases. Expression of Bcl-2 and c-kit did not differ significantly between the 2 morphological groups. A relative increase in c-kit expression was significantly associated with a virus-negative status (median [interquartile range], 100 [60-115] versus 70 [0-100]; P = .03). Emerging data reveal divergent biological pathways in Merkel cell carcinoma, each with a characteristic immunohistochemical profile. Virus-positive tumors (all pure) exhibit high retinoblastoma protein and low p53 expression, whereas virus-negative cases (few pure and all combined) show high p53 and relatively high c-kit expression. The potential biological implications of this dichotomy call for consistent stratification of these tumors in future studies.

Support for p63 expression as an adverse prognostic marker in Merkel cell carcinoma: report on a Canadian cohort.

Recent evidence has invoked immunohistochemical expression of p63 in Merkel cell carcinoma as an adverse prognostic factor. Conflicting data led us to evaluate this. An Eastern Canadian cohort diagnosed between 1990 and 2012 was studied. Demographic and clinical data were obtained from pathology records and Provincial Cancer Registries. Pathological features were evaluated by the investigators. Merkel cell polyomavirus status was known in a subset of cases. Clinicopathological features were correlated with overall survival. The cohort consisted of 83 patients (mean age, 75.8 ± 11.7 years) with a male/female ratio of 1.24:1. In a mean follow-up period of 175 weeks (±177), 51 patients died (61.4%). Of several parameters examined, 6 showed significant adverse associations with survival on univariate analysis: age (hazard ratio [HR], 1.05 [1.02-1.08]), clinical stage (III/IV versus I/II; HR, 2.24 [1.18-4.27]), tumor size (HR, 1.16 [1.05-1.28]), combined versus pure morphology (HR, 1.82 [1.04-3.18]), minimal tumor-infiltrating lymphocytes (HR, 2.23 [1.04-4.78]), and expression of p63 (positive in 49.4%; HR, 1.93 [1.09-3.43]). In the stage I/II subgroup, p63 expression was associated with a trend toward poor survival. On multivariate analysis, p63 expression was not significantly associated with reduced survival. Our data support existing evidence that p63 expression in Merkel cell carcinoma carries adverse implications for survival. That it was not an independent prognostic factor may be due to study size and/or its potential as a confounding variable with clinical stage. Of clinical importance is its association with a trend toward a poor outcome in early stage disease.

The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites.

Most Merkel cell carcinomas display pure neuroendocrine differentiation (pure Merkel cell carcinoma), whereas a minority show combined neuroendocrine and nonneuroendocrine elements (combined Merkel cell carcinoma). Recent identification of Merkel cell polyomavirus DNA and Merkel cell polyomavirus large T antigen expression in a proportion of Merkel cell carcinomas has suggested viral-induced oncogenesis. To date, Merkel cell polyomavirus immunohistochemistry has shown an absence of viral large T antigen expression in combined Merkel cell carcinoma as well as select non-Merkel cell carcinoma cutaneous lesions and visceral neuroendocrine tumors. In our series, we aimed to further characterize the frequency and pattern of Merkel cell polyomavirus large T antigen expression by CM2B4 immunohistochemistry in primary and metastatic Merkel cell carcinoma (pure Merkel cell carcinoma and combined Merkel cell carcinoma) and various non-Merkel cell carcinoma lesions from patients with Merkel cell carcinoma, patients without Merkel cell carcinoma, and individuals with altered immune function. Merkel cell polyomavirus large T antigen was detected in 17 (63%) of 27 pure Merkel cell carcinomas and absent in all 15 (0%) combined Merkel cell carcinomas. Furthermore, complete concordance (100%) of Merkel cell polyomavirus large T antigen expression was observed in 10 cases of primary Merkel cell carcinoma and subsequent tumor metastases. We also evaluated 70 non-Merkel cell carcinoma lesions including 15 cases each of pulmonary and gastrointestinal neuroendocrine tumors. All 70 non-Merkel cell carcinoma lesions were negative for Merkel cell polyomavirus by CM2B4 immunohistochemistry, irrespective of any known Merkel cell carcinoma diagnosis and immune status. In summary, our identification of Merkel cell polyomavirus large T antigen expression in a subset of Merkel cell carcinoma and lack of findings in combined Merkel cell carcinomas and non-Merkel cell carcinoma lesions concur with earlier findings and implicate Merkel cell polyomavirus-independent pathogenesis in these cases. Overall, CM2B4 immunohistochemistry appears to be a specific method for Merkel cell polyomavirus detection and has the potential to play an important role in the diagnosis and classification of Merkel cell carcinoma in the future.

Fine-needle aspiration cytology of mammary fibroadenoma: a comparison of ThinPrep® and cytospin preparations.

Mammary fibroadenoma (FA) is a lesion frequently sampled and diagnosed by fine-needle aspiration (FNA). Accurate cytologic diagnosis of this common benign lesion is important as this can lead to non-surgical, conservative management when breast imaging and clinical examination are concordant. In most instances, a confident diagnosis of FA is possible because of a characteristic cytologic appearance that includes hypercellularity, large epithelial cell groups, staghorn epithelial configurations, stromal fragments, and numerous background stripped nuclei. Nevertheless, FAs can be diagnostically challenging because of shared cytomorphologic features with other benign lesions and low-grade carcinoma. As such, FA is a well-recognized source of false results on FNA cytology. Furthermore, there are reports that newer thin layer cytopreparatory techniques, including the ThinPrep® (TP) system (Hologic Corp., Bedford, MA), alter the appearance of FA on FNA compared to conventional preparations and may compromise accurate cytologic diagnosis.