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which was described by Carlson<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> and is included in the World Health Organization classification of skin tumors&#44; is a similar tumor&#44; but with pigmented dendritic melanocytes &#40;i&#46;e&#46;&#44; it has a dual population of epithelial and melanocytic cells&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present the case of a 75-year-old woman with a history of basal cell carcinoma and actinic keratoses who presented with an asymptomatic papular lesion on her forehead that had been growing progressively for several weeks and was clinically suggestive of basal cell carcinoma &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; The lesion was excised&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Histopathologic examination showed a small nodular tumor in the dermis with a diameter of approximately 2<span class="elsevierStyleHsp" style=""></span>mm&#44; a uniform proliferation of basaloid cells&#44; frequent mitotic figures &#40;some of which showed atypia&#41;&#44; and no evidence of peripheral palisading or stromal retraction &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#8211;D&#41;&#46; Immunohistochemistry was positive for cytokeratin AE1&#47;AE3&#44; and there was also focal staining for p63 and BER-EP4&#46; Epithelial membrane antigen&#44; cytokeratin 7&#44; androgen receptor&#44; chromogranin&#44; synaptophysin&#44; and CD56 were negative&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Based on the above findings&#44; the main entity considered in the differential diagnosis was an adnexal tumor of follicular origin&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Immunohistochemistry for &#946;-catenin showed a cytoplasmic staining pattern&#44; similar to that seen in the epidermis&#59; nuclear positivity was absent &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#8211;C&#41;&#46; These findings were interpreted as nonspecific&#44; and it was decided to send a sample to Friedrichshafen for LEF-1 staining&#46; Although this immunostain is not completely specific &#40;it can be observed in other basaloid skin tumors<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a>&#41;&#44; positive nuclear staining in this particular setting would support a matrical origin&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">7&#44;8</span></a> The tumor cells expressed LEF-1 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#8211;D&#41;&#46; Based on the mitotic activity and degree of atypia observed&#44; the lesion could be considered within the group of proliferative pilomatricomas described by Kaddu et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a> although&#44; given its unilobular silhouette and solid appearance&#44; the definitive diagnosis was matricoma&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Occurrence in the sun-damaged of an elderly individual and the presence of atypical mitoses are unusual proliferative features for a benign matricoma tumor&#44; and perhaps lie more in the middle of the spectrum toward malignancy&#46; Several of the features described in the current report&#44; however&#44; indicate benign biologic behavior&#44; such as the small size and clear demarcation of the tumor&#44; absence of necrosis and&#44; above all&#44; absence of recurrences and new lesions during 10 months of follow-up&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">7&#44;10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">A number of immunostains are considered useful for the diagnosis of matrical tumors&#44; the best known being &#946;-catenin&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> Interpretation&#44; however&#44; is challenging in this setting&#44; as immunostaining should only be considered positive and relevant in the presence of nuclear positivity&#46; In addition&#44; &#946;-catenin staining can yield false negatives if the histopathologic sample does not include basaloid areas or if the tumor arose following activation of the WNT signaling pathway upstream of &#946;-catenin&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1&#44;8</span></a> Tumors originating in the hair matrix cell may be secondary to hyperactivation of the WNT pathway&#44; which has a crucial role in maintaining the normal hair cycle&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> In this pathway&#44; dephosphorylated &#946;-catenin is translocated to the cell nucleus&#44; where its presence&#44; evidenced by immunohistochemistry&#44; indicates activation of the pathway&#44; which is characteristic of&#44; though not specific to&#44; matrical tumors&#46; Nuclear &#946;-catenin translocation would activate transcription factors such as LEF-1&#44; which would drive the expression of several genes involved in this pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> Overexpression of LEF-1 in hair follicle bulge stem cells could also lead to nuclear &#946;-catenin translocation&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> The activated pathway is shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">LEF-1 is more sensitive than nuclear &#946;-catenin for the diagnosis of skin tumors originating in the hair follicle matrix &#40;100&#37; vs&#46; 75&#37; for benign tumors and 100&#37; vs 92&#37; for malignant tumors&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Matrical tumors formed by immature cells and connected to the epidermis or hair follicle are challenging to diagnose&#46; Histopathologic features typically seen in these tumors may be absent&#44; such as transitional cells or the characteristic shadow cells seen in pilomatricomas&#44; because the only cells present are proliferative matrix cells&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Familiarity with the main activation pathway involved in pilomatrical tumors and thoughtful use and interpretation of diagnostically helpful immunostains led to a correct diagnosis in the current case&#46; It is important to recall that LEF-1 immunostaining&#44; apart from having greater diagnostic sensitivity than &#946;-catenin&#44; is purely nuclear&#44; and its results are therefore easier to interpret&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest in relation to this article&#46; Dr&#46; Llamas-Velasco has received consultancy and speakers&#8217; fees and participated in studies and&#47;or clinical trials with the following pharmaceutical companies&#58; Abbvie&#44; Almirall&#44; Biogen&#44; Celgene&#44; Galderma&#44; Janssen&#44; Leo&#44; Lilly&#44; Novartis&#44; and UCB&#46;</p></span></span>"
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        "texto" => "<p id="par0065" class="elsevierStylePara elsevierViewall">We thank Dr&#46; Javier Fraga and Dr&#46; Arno R&#252;tten for sharing their enormous experience and passion for dermatopathology with us every day&#46; We are also grateful to Dr&#46; R&#252;tten&#44; an expert in cutaneous adnexal tumors&#44; for helping us to confirm the diagnosis in our case by providing us access to LEF-1 staining&#46;</p>"
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Case and Research Letter
Usefulness of LEF-1 Immunostaining for the Diagnosis of Matricoma
Utilidad de la inmunotinción con LEF-1 para el diagnóstico de matricoma
A. Reymundo-Jiméneza,1, L. Martos-Cabreraa,1, P. Muñoz-Hernándezb, M. Llamas-Velascoa,
Corresponding author
mar.llamasvelasco@gmail.com

Corresponding author.
a Servicio de Dermatología, Hospital Universitario de la Princesa, Madrid, Spain
b Servicio de anatomía Patológica, Hospital Universitario de la Princesa, Madrid, Spain
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which was described by Carlson<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> and is included in the World Health Organization classification of skin tumors&#44; is a similar tumor&#44; but with pigmented dendritic melanocytes &#40;i&#46;e&#46;&#44; it has a dual population of epithelial and melanocytic cells&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present the case of a 75-year-old woman with a history of basal cell carcinoma and actinic keratoses who presented with an asymptomatic papular lesion on her forehead that had been growing progressively for several weeks and was clinically suggestive of basal cell carcinoma &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; The lesion was excised&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Histopathologic examination showed a small nodular tumor in the dermis with a diameter of approximately 2<span class="elsevierStyleHsp" style=""></span>mm&#44; a uniform proliferation of basaloid cells&#44; frequent mitotic figures &#40;some of which showed atypia&#41;&#44; and no evidence of peripheral palisading or stromal retraction &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#8211;D&#41;&#46; Immunohistochemistry was positive for cytokeratin AE1&#47;AE3&#44; and there was also focal staining for p63 and BER-EP4&#46; Epithelial membrane antigen&#44; cytokeratin 7&#44; androgen receptor&#44; chromogranin&#44; synaptophysin&#44; and CD56 were negative&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Based on the above findings&#44; the main entity considered in the differential diagnosis was an adnexal tumor of follicular origin&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Immunohistochemistry for &#946;-catenin showed a cytoplasmic staining pattern&#44; similar to that seen in the epidermis&#59; nuclear positivity was absent &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#8211;C&#41;&#46; These findings were interpreted as nonspecific&#44; and it was decided to send a sample to Friedrichshafen for LEF-1 staining&#46; Although this immunostain is not completely specific &#40;it can be observed in other basaloid skin tumors<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a>&#41;&#44; positive nuclear staining in this particular setting would support a matrical origin&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">7&#44;8</span></a> The tumor cells expressed LEF-1 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#8211;D&#41;&#46; Based on the mitotic activity and degree of atypia observed&#44; the lesion could be considered within the group of proliferative pilomatricomas described by Kaddu et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a> although&#44; given its unilobular silhouette and solid appearance&#44; 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however&#44; is challenging in this setting&#44; as immunostaining should only be considered positive and relevant in the presence of nuclear positivity&#46; In addition&#44; &#946;-catenin staining can yield false negatives if the histopathologic sample does not include basaloid areas or if the tumor arose following activation of the WNT signaling pathway upstream of &#946;-catenin&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1&#44;8</span></a> Tumors originating in the hair matrix cell may be secondary to hyperactivation of the WNT pathway&#44; which has a crucial role in maintaining the normal hair cycle&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> In this pathway&#44; dephosphorylated &#946;-catenin is translocated to the cell nucleus&#44; where its presence&#44; evidenced by immunohistochemistry&#44; indicates activation of the pathway&#44; which is characteristic of&#44; though not specific to&#44; matrical tumors&#46; Nuclear &#946;-catenin translocation would activate transcription factors such as LEF-1&#44; which would drive the expression of several genes involved in this pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> Overexpression of LEF-1 in hair follicle bulge stem cells could also lead to nuclear &#946;-catenin translocation&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> The activated pathway is shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">LEF-1 is more sensitive than nuclear &#946;-catenin for the diagnosis of skin tumors originating in the hair follicle matrix &#40;100&#37; vs&#46; 75&#37; for benign tumors and 100&#37; vs 92&#37; for malignant tumors&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Matrical tumors formed by immature cells and connected to the epidermis or hair follicle are challenging to diagnose&#46; Histopathologic features typically seen in these tumors may be absent&#44; such as transitional cells or the characteristic shadow cells seen in pilomatricomas&#44; because the only cells present are proliferative matrix cells&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Familiarity with the main activation pathway involved in pilomatrical tumors and thoughtful use and interpretation of diagnostically helpful immunostains led to a correct diagnosis in the current case&#46; It is important to recall that LEF-1 immunostaining&#44; apart from having greater diagnostic sensitivity than &#946;-catenin&#44; is purely nuclear&#44; and its results are therefore easier to interpret&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest in relation to this article&#46; Dr&#46; Llamas-Velasco has received consultancy and speakers&#8217; fees and participated in studies and&#47;or clinical trials with the following pharmaceutical companies&#58; Abbvie&#44; Almirall&#44; Biogen&#44; Celgene&#44; Galderma&#44; Janssen&#44; Leo&#44; Lilly&#44; Novartis&#44; and UCB&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical and histopathologic findings&#46; Clinical findings&#46; A&#44; Flesh-colored&#44; 3-mm papule on the forehead&#46; B&#44; Hematoxylin&#8211;eosin staining &#40;original magnification &#215;2&#41;&#46; Panoramic view showing a small&#44; well-defined nodule in the dermis&#46; C&#44; Hematoxylin&#8211;eosin&#44; original magnification &#215;10&#41;&#46; Higher-magnification view showing a well-delimited lesion&#44; without palisading and surrounded by some stroma without artifactual retraction&#46; D&#44; Hematoxylin&#8211;eosin&#44; original magnification &#215;20&#41;&#46; Higher-magnification view showing basaloid cells with a vesicular nucleus&#46; Note the mitoses in the field shown&#46;</p>"
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        "texto" => "<p id="par0065" class="elsevierStylePara elsevierViewall">We thank Dr&#46; Javier Fraga and Dr&#46; Arno R&#252;tten for sharing their enormous experience and passion for dermatopathology with us every day&#46; We are also grateful to Dr&#46; R&#252;tten&#44; an expert in cutaneous adnexal tumors&#44; for helping us to confirm the diagnosis in our case by providing us access to LEF-1 staining&#46;</p>"
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