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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Melanoma is a potentially lethal skin neoplasm that requires an accurate diagnosis to ensure that the patient will receive optimal treatment&#46; Despite the advent of large-scale&#44; high-resolution genomics&#44; histopathological analysis remains the reference for diagnosis and the primary classification tool in correlation with clinical characteristics<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Melanoma can exhibit a variety of histopathological patterns&#44; mimicking other malignant tumors&#46; Based on their histopathological characteristics&#44; several morphological subtypes have been described in addition to the classical forms&#44; such as polypoid&#44; verrucous&#44; desmoplastic&#44; myxoid&#44; balloon-cell&#44; rhabdoid&#44; amelanotic&#44; and spitzoid melanoma&#44; among others<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; It may also rarely show heterologous differentiation patterns&#44; including fibroblastic&#44; smooth muscle&#44; rhabdomyoblastic&#44; osteocartilaginous&#44; Schwannian&#44; and ganglionic&#46; Osteocartilaginous differentiation is one of the most uncommon patterns<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Osteocartilaginous differentiation is characterized by the formation of osteoid&#44; bone&#44; and cartilaginous tissue by the neoplastic cells&#46; Its rarity and overlapping characteristics with those of other neoplasms make it difficult to diagnose&#44; especially in small biopsies or when clinical&#47;radiological information is limited&#46; It may be confused with osteosarcomas or chondrosarcomas<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The mechanisms responsible for heterologous differentiation are not well understood&#46; This report describes a case of melanoma with osteocartilaginous differentiation that developed on the distal region of the left upper limb&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In August 2019&#44; a 52-year-old woman came to the Orthopedics outpatient clinic with a history of a darkened lesion in the subungual region of the left thumb&#44; with an evolution of approximately three years&#46; On physical examination&#44; edema&#44; local phlogosis&#44; and signs suggestive of fungal infection were observed&#46; She underwent specific treatment for the infection but did not show a complete response&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The subungual lesion was submitted to an incisional biopsy&#44; and the histopathological and immunohistochemical study confirmed the diagnosis of melanoma&#46; The patient was then referred to the Oncological Surgery service for specific treatment&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In November of the same year&#44; after evaluation&#44; she underwent amputation of the affected finger&#46; Histopathological analysis confirmed the diagnosis of nodular melanoma&#44; with the presence of lymphovascular invasion and a proliferative index of 17 mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#46; After surgery&#44; she had regular follow-up consultations at the Clinical Oncology department&#46; After eight months&#44; tumor growth was observed on the surgical scar&#46; Computed tomography assessment showed a lesion suggestive of recurrence&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">She underwent surgical resection once again&#44; with en bloc removal of the lesion&#46; Histopathological analysis of the specimen showed local recurrence of the melanoma&#44; with the presence of vascular and neural invasion&#44; in addition to compromised surgical margins&#46; Follow-up imaging studies demonstrated the presence of axillary involvement and the presence of pulmonary lesions suggestive of metastasis&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patient was referred for adjuvant local and axillary radiotherapy in February 2021&#46; She also started therapy with Dacarbazine and immunotherapy with Pembrolizumab in April 2021&#46; In the same month&#44; she had a new tumor growth in the area of &#8203;&#8203;the previous resection&#46; Computed tomography showed extensive expansive&#47;infiltrative soft tissue lesions in the distal region of the left arm and hand&#44; and palliative surgery was chosen&#44; with surgical disarticulation at the elbow and left axillary lymphadenectomy&#44; performed in July 2021&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Macroscopically&#44; the surgical specimen showed a large tumor in the distal region of the left upper limb &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Histopathology showed the presence of melanoma with areas of heterologous osteocartilaginous differentiation &#40;<a class="elsevierStyleCrossRefs" href="#fig0010">Figs&#46; 2&#8211;4</a>&#41;&#44; invading soft tissues and bone&#44; with free surgical margins&#46; The diagnosis of melanoma was confirmed by immunoreactivity with SOX10 and HMB45 &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46; Axillary dissection showed metastatic melanoma in a left axillary lymph node&#46; Molecular screening for the V600E mutation in the BRAF gene was negative&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Due to advanced and metastatic disease&#44; the patient remained hospitalized&#44; progressing with clinical worsening&#44; signs of respiratory distress&#44; and hemodynamic instability&#46; With no possibility of disease-modifying therapy&#44; she started exclusive palliative care&#44; passing away in October 2021&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Osteocartilaginous differentiation in melanoma was first observed over 45 years ago<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&#44; but fewer than 40 reports have been published since then<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Osteoid&#44; chondroid and mixed patterns have been described as appearing in predominantly acral and subungual sites&#46; However&#44; osteocartilaginous differentiation is not restricted to these regions&#44; as it has been previously described in mucosal lesions&#44; as well as in skin that is chronically or intermittently exposed to the sun<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The mechanism for the formation of the osteoid&#47;chondroid matrix in these melanomas is unknown&#46; Many are associated with a history of previous local trauma and the osteoid&#47;chondroid matrix may be a form of host response to the lesion<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46; Another hypothesis is that osteoid&#47;chondroid differentiation is a result of reactive responses induced by the melanoma in the surrounding stromal fibroblasts&#46; However&#44; there is often a lack of stromal cells in the matrix areas&#44; which may arise from the neoplastic cells themselves<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Hypothetical intrinsic melanoma factors that could drive the production of this matrix include the expression of the &#8220;Melanoma inhibitory activity &#40;MIA&#41;&#8221; and &#8220;Runt-related transcription factor 2&#8221; &#40;RUNX2&#41; genes&#44; transcriptional regulators of chondrogenesis and osteogenesis<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Although these genes can be expressed by most melanomas&#44; studies have already shown that MIA and RUNX2 require the expression of other cofactors to drive osteoid&#47;chondroid differentiation&#44; and the lack of these genes may explain the rarity of osteocartilaginous melanoma despite frequent gene expression<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The diagnosis of melanoma can be supported by the presence of an &#8220;<span class="elsevierStyleItalic">in situ</span>&#8221; component&#44; the presence of melanin pigment&#44; or immunoreactivity with markers such as S100&#44; Melan-A&#44; HMB45&#44; or SOX10<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; In melanomas with cartilaginous differentiation&#44; the use of S100 is limited&#44; as cartilaginous tissues and chondrosarcomas also express positivity<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In the molecular analysis&#44; the presence of the V600E mutation in the BRAF gene can also support the diagnosis of melanoma&#44; in addition to being crucial for planning its treatment<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">It is not yet entirely clear whether the osteocartilaginous melanoma harbors only mutations and differentiation markers typical of melanoma or of the osteocartilaginous lesions it mimics as well<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Based on the literature review&#44; the authors highlight the importance of applying an immunohistochemical panel with the inclusion of melanocytic differentiation markers in cases of neoplasms with osteoid&#47;chondroid differentiation&#44; mainly in acral lesions&#44; and of including melanoma with heterologous differentiation among the differential diagnoses&#46; Due to the rarity of the case&#44; the development of guidelines for early diagnosis&#44; management and prognosis for this cancer variant remains challenging&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial support</span><p id="par0110" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authors&#39; contributions</span><p id="par0115" class="elsevierStylePara elsevierViewall">Bennett Barroso de Carvalho&#58; drafting and editing of the manuscript or critical review of important intellectual content&#59; critical review of the literature&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Diogo Batista dos Santos Medeiros&#58; Effective participation in research orientation&#59; drafting and editing of the manuscript or critical review of important intellectual content&#59; approval of the final version of the manuscript&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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Letter - Dermatopathology
Melanoma with osteocartilaginous differentiation
Bennett Barroso de Carvalho
Autor para correspondência
bennettcarvalho@gmail.com

Corresponding author.
, Diogo Batista dos Santos Medeiros
Division of Pathology, Hospital de Base do Distrito Federal, Brasília, DF, Brazil
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Melanoma cells showing atypia&#44; pleomorphism&#44; evident nucleoli&#44; and frequent mitotic figures &#40;Hematoxylin &#38; eosin&#44; &#215;400&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Melanoma is a potentially lethal skin neoplasm that requires an accurate diagnosis to ensure that the patient will receive optimal treatment&#46; Despite the advent of large-scale&#44; high-resolution genomics&#44; histopathological analysis remains the reference for diagnosis and the primary classification tool in correlation with clinical characteristics<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Melanoma can exhibit a variety of histopathological patterns&#44; mimicking other malignant tumors&#46; Based on their histopathological characteristics&#44; several morphological subtypes have been described in addition to the classical forms&#44; such as polypoid&#44; verrucous&#44; desmoplastic&#44; myxoid&#44; balloon-cell&#44; rhabdoid&#44; amelanotic&#44; and spitzoid melanoma&#44; among others<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; It may also rarely show heterologous differentiation patterns&#44; including fibroblastic&#44; smooth muscle&#44; rhabdomyoblastic&#44; osteocartilaginous&#44; Schwannian&#44; and ganglionic&#46; Osteocartilaginous differentiation is one of the most uncommon patterns<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Osteocartilaginous differentiation is characterized by the formation of osteoid&#44; bone&#44; and cartilaginous tissue by the neoplastic cells&#46; Its rarity and overlapping characteristics with those of other neoplasms make it difficult to diagnose&#44; especially in small biopsies or when clinical&#47;radiological information is limited&#46; It may be confused with osteosarcomas or chondrosarcomas<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The mechanisms responsible for heterologous differentiation are not well understood&#46; This report describes a case of melanoma with osteocartilaginous differentiation that developed on the distal region of the left upper limb&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In August 2019&#44; a 52-year-old woman came to the Orthopedics outpatient clinic with a history of a darkened lesion in the subungual region of the left thumb&#44; with an evolution of approximately three years&#46; On physical examination&#44; edema&#44; local phlogosis&#44; and signs suggestive of fungal infection were observed&#46; She underwent specific treatment for the infection but did not show a complete response&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The subungual lesion was submitted to an incisional biopsy&#44; and the histopathological and immunohistochemical study confirmed the diagnosis of melanoma&#46; The patient was then referred to the Oncological Surgery service for specific treatment&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In November of the same year&#44; after evaluation&#44; she underwent amputation of the affected finger&#46; Histopathological analysis confirmed the diagnosis of nodular melanoma&#44; with the presence of lymphovascular invasion and a proliferative index of 17 mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#46; After surgery&#44; she had regular follow-up consultations at the Clinical Oncology department&#46; After eight months&#44; tumor growth was observed on the surgical scar&#46; Computed tomography assessment showed a lesion suggestive of recurrence&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">She underwent surgical resection once again&#44; with en bloc removal of the lesion&#46; Histopathological analysis of the specimen showed local recurrence of the melanoma&#44; with the presence of vascular and neural invasion&#44; in addition to compromised surgical margins&#46; Follow-up imaging studies demonstrated the presence of axillary involvement and the presence of pulmonary lesions suggestive of metastasis&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patient was referred for adjuvant local and axillary radiotherapy in February 2021&#46; She also started therapy with Dacarbazine and immunotherapy with Pembrolizumab in April 2021&#46; In the same month&#44; she had a new tumor growth in the area of &#8203;&#8203;the previous resection&#46; Computed tomography showed extensive expansive&#47;infiltrative soft tissue lesions in the distal region of the left arm and hand&#44; and palliative surgery was chosen&#44; with surgical disarticulation at the elbow and left axillary lymphadenectomy&#44; performed in July 2021&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Macroscopically&#44; the surgical specimen showed a large tumor in the distal region of the left upper limb &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Histopathology showed the presence of melanoma with areas of heterologous osteocartilaginous differentiation &#40;<a class="elsevierStyleCrossRefs" href="#fig0010">Figs&#46; 2&#8211;4</a>&#41;&#44; invading soft tissues and bone&#44; with free surgical margins&#46; The diagnosis of melanoma was confirmed by immunoreactivity with SOX10 and HMB45 &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46; Axillary dissection showed metastatic melanoma in a left axillary lymph node&#46; Molecular screening for the V600E mutation in the BRAF gene was negative&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Due to advanced and metastatic disease&#44; the patient remained hospitalized&#44; progressing with clinical worsening&#44; signs of respiratory distress&#44; and hemodynamic instability&#46; With no possibility of disease-modifying therapy&#44; she started exclusive palliative care&#44; passing away in October 2021&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Osteocartilaginous differentiation in melanoma was first observed over 45 years ago<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&#44; but fewer than 40 reports have been published since then<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Osteoid&#44; chondroid and mixed patterns have been described as appearing in predominantly acral and subungual sites&#46; However&#44; osteocartilaginous differentiation is not restricted to these regions&#44; as it has been previously described in mucosal lesions&#44; as well as in skin that is chronically or intermittently exposed to the sun<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The mechanism for the formation of the osteoid&#47;chondroid matrix in these melanomas is unknown&#46; Many are associated with a history of previous local trauma and the osteoid&#47;chondroid matrix may be a form of host response to the lesion<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46; Another hypothesis is that osteoid&#47;chondroid differentiation is a result of reactive responses induced by the melanoma in the surrounding stromal fibroblasts&#46; However&#44; there is often a lack of stromal cells in the matrix areas&#44; which may arise from the neoplastic cells themselves<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Hypothetical intrinsic melanoma factors that could drive the production of this matrix include the expression of the &#8220;Melanoma inhibitory activity &#40;MIA&#41;&#8221; and &#8220;Runt-related transcription factor 2&#8221; &#40;RUNX2&#41; genes&#44; transcriptional regulators of chondrogenesis and osteogenesis<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Although these genes can be expressed by most melanomas&#44; studies have already shown that MIA and RUNX2 require the expression of other cofactors to drive osteoid&#47;chondroid differentiation&#44; and the lack of these genes may explain the rarity of osteocartilaginous melanoma despite frequent gene expression<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The diagnosis of melanoma can be supported by the presence of an &#8220;<span class="elsevierStyleItalic">in situ</span>&#8221; component&#44; the presence of melanin pigment&#44; or immunoreactivity with markers such as S100&#44; Melan-A&#44; HMB45&#44; or SOX10<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; In melanomas with cartilaginous differentiation&#44; the use of S100 is limited&#44; as cartilaginous tissues and chondrosarcomas also express positivity<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In the molecular analysis&#44; the presence of the V600E mutation in the BRAF gene can also support the diagnosis of melanoma&#44; in addition to being crucial for planning its treatment<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">It is not yet entirely clear whether the osteocartilaginous melanoma harbors only mutations and differentiation markers typical of melanoma or of the osteocartilaginous lesions it mimics as well<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Based on the literature review&#44; the authors highlight the importance of applying an immunohistochemical panel with the inclusion of melanocytic differentiation markers in cases of neoplasms with osteoid&#47;chondroid differentiation&#44; mainly in acral lesions&#44; and of including melanoma with heterologous differentiation among the differential diagnoses&#46; Due to the rarity of the case&#44; the development of guidelines for early diagnosis&#44; management and prognosis for this cancer variant remains challenging&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial support</span><p id="par0110" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authors&#39; contributions</span><p id="par0115" class="elsevierStylePara elsevierViewall">Bennett Barroso de Carvalho&#58; drafting and editing of the manuscript or critical review of important intellectual content&#59; critical review of the literature&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Diogo Batista dos Santos Medeiros&#58; Effective participation in research orientation&#59; drafting and editing of the manuscript or critical review of important intellectual content&#59; approval of the final version of the manuscript&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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