Case and Research Letter
Milroy Disease or Primary Congenital Lymphedema Associated With Invasive Squamous Cell Carcinoma
Enfermedad de Milroy o linfedema primario congénito asociado a carcinoma espinocelular invasor
O. Cheirif-Wolosky
, L. Ramírez-Hobak, S. Toussaint-Caire, L. Lammoglia-Ordiales
Autor para correspondencia
Departamento de Dermatología y Dermatopatología del Hospital General Dr. Manuel Gea González, Ciudad de México, México
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Cheirif-Wolosky, L. Ramírez-Hobak, S. Toussaint-Caire, L. Lammoglia-Ordiales" "autores" => array:4 [ 0 => array:4 [ "nombre" => "O." "apellidos" => "Cheirif-Wolosky" "email" => array:2 [ 0 => "dra.dermaorly@gmail.com" 1 => "Orly.cheirif@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Ramírez-Hobak" ] 2 => array:2 [ "nombre" => "S." "apellidos" => "Toussaint-Caire" ] 3 => array:2 [ "nombre" => "L." "apellidos" => "Lammoglia-Ordiales" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Departamento de Dermatología y Dermatopatología del Hospital General Dr. Manuel Gea González, Ciudad de México, México" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Enfermedad de Milroy o linfedema primario congénito asociado a carcinoma espinocelular invasor" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 915 "Ancho" => 1500 "Tamanyo" => 299197 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Histologic sections of skin showing the formation of squamous whorls and corneal pearls, large atypical keratinocytes with pleomorphic hyperchromatic nuclei and abundant eosinophilic cytoplasm, and atypical mitoses. Hematoxylin and eosin, original magnification A<span class="elsevierStyleHsp" style=""></span>×10 and B<span class="elsevierStyleHsp" style=""></span>×40.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Milroy disease or primary congenital lymphedema was first described in 1892. It is characterized by congenital lymphedema of the lower limbs. Associations have been observed between chronic lymphedema and a number of neoplasms, including angiosarcoma, Kaposi sarcoma, lymphoma, basal cell carcinoma, melanoma, and squamous cell carcinoma (SCC).<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">A 58-year-old man with a history of congenital lymphedema, with aplasia of lymph vessels in both lower limbs demonstrated on lymphoscintigraphy in childhood and a hereditary family history of the same disease (father), had undergone numerous operations to improve lymphatic circulation. He was seen in the dermatology department for a deterioration of the lesions that affected both lower limbs symmetrically and the genitalia since birth. In the pretibial region, the calves, and the dorsum of the feet, the patient presented papillomatous verrucous plaques, areas of fibrosis and atrophy, retracted scars, and small circular ulcers with erythematous borders and a seropurulent exudate. The thighs presented marked, hard edema, with surgical scars, and there was massive edema of the testicles that deformed the region, associated with verrucous plaques (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, A and B).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">A multilobulated tumor measuring 14<span class="elsevierStyleHsp" style=""></span>cm in diameter was observed in the left inguinal region. The exophytic tumor had a friable erythematous surface covered by fibrin (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A). A poorly defined erythematous exophytic tumor with hyperkeratotic areas and elevated pigmented borders was observed on the shaft of the penis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">On a suspicion of SCC or angiosarcoma, incisional biopsies were taken from the lesions in the left inguinal region and on the penis, and computed tomography (CT) of the abdomen, pelvis, and lower limbs was requested.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Histopathology revealed a poorly differentiated, invasive squamous cell carcinoma with a thickness of 4.22<span class="elsevierStyleHsp" style=""></span>mm, Clark level V, with 11 mitoses per mm<span class="elsevierStyleSup">2</span>, and, on the penis, a well-differentiated invasive SCC with a thickness of 1.2<span class="elsevierStyleHsp" style=""></span>mm, Clark level IV, with 15 mitoses per mm<span class="elsevierStyleSup">2</span>. Neither tumor presented perineural or lymphovascular invasion or association with human papillomavirus (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>, A and B). On CT, numerous lymph nodes with a diameter less than 1<span class="elsevierStyleHsp" style=""></span>cm were visible in the mediastinum and more than 15 lymph nodes of up to 12<span class="elsevierStyleHsp" style=""></span>mm diameter in the right axilla. The patient was referred to another hospital where he has received chemotherapy with paclitaxel, cisplatin, and ifosfamide; he has completed 4 cycles but has shown no clinical or radiological improvement.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Lymphedema is a progressive edema of the tissues secondary to a dysfunction of the lymphatic system. It can be primary or secondary. Primary lymphedema is due to abnormal development of the lymphatic system and the secondary form is due to trauma, lymph-node resection, tumors, or infections such as filariasis. Secondary lymphedema accounts for 99% of cases.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Primary lymphedema is usually idiopathic, with no hereditary family history. The incidence is 1.15 per 100<span class="elsevierStyleHsp" style=""></span>000 population.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Non-idiopathic causes include a number of diseases with an autosomal dominant pattern of transmission, such as Milroy disease, which is characterized by congenital lymphedema of the lower limbs.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–5</span></a> The locus has been mapped to 5q35.3 and the mutated gene is <span class="elsevierStyleItalic">FLT4</span>, which codes for endothelial growth factor receptor 3. It presents with lymphedema of the lower limbs affecting the dorsum of the feet, knees, and thighs; the edema has a woody texture.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4–7</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Diagnosis is made in patients with symmetrical bilateral congenital edema of the lower limbs, but other factors must be taken into account, such as a positive family history and mutation of endothelial growth factor receptor 3 (present in 42% of patients).<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The lymphedematous region becomes an immunocompromised territory due to altered migration of dendritic cells, T cells, and macrophages to the dermal lymph vessels.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">7,8</span></a> One of the most common tumors to arise in Milroy disease is angiosarcoma (Stewart-Trevès syndrome), which, despite being more common in patients after surgery for breast cancer, has also been reported in lymphedema of the lower limbs. Other associated tumors are Kaposi sarcoma, lymphoma, basal cell carcinoma, melanoma, and SCC. The time over which the neoplasm develops can vary from years to decades.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6–10</span></a> The most relevant risk factors for SCC in patients with primary lymphedema are common warts, angiosarcoma, widespread vitiligo, chronic ulcers, chronic verrucous hyperplasia, dystrophic epidermolysis bullosa, and a history of UV-B therapy.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">9,10</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Only 15 cases of SCC associated with chronic lymphedema have been reported, and only 3 of these were associated with primary lymphedema. All these cases occurred in men. The mean age was 40.5 years and the most common site was on the lower limbs.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">8–10</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The treatment of choice is resection of the tumor, combined with lymphadenectomy when lymph-node metastases are present. Adjuvant radiotherapy and chemotherapy may be administered.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The importance of this case derives from the low frequency of these tumors in the context of primary lymphedema and the few cases reported in the literature. Knowledge of this association will favor early diagnosis and appropriate treatment.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Cheirif-Wolosky O, Ramírez-Hobak L, Toussaint-Caire S, Lammoglia-Ordiales L. Enfermedad de Milroy o linfedema primario congénito asociado a carcinoma espinocelular invasor. Actas Dermosifiliogr. 2016;107:865–867.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1276 "Ancho" => 1340 "Tamanyo" => 160685 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A, Marked bilateral lymphedema. B, Detail of the dorsum of the right foot.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 796 "Ancho" => 1730 "Tamanyo" => 166694 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A, Tumor in the groin. B, Tumor on the shaft of the penis.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 915 "Ancho" => 1500 "Tamanyo" => 299197 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Histologic sections of skin showing the formation of squamous whorls and corneal pearls, large atypical keratinocytes with pleomorphic hyperchromatic nuclei and abundant eosinophilic cytoplasm, and atypical mitoses. Hematoxylin and eosin, original magnification A<span class="elsevierStyleHsp" style=""></span>×10 and B<span class="elsevierStyleHsp" style=""></span>×40.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A guide to lymphedema" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K. Gordon" 1 => "P.S. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 6 | 9 | 15 |
| 2024 Octubre | 99 | 38 | 137 |
| 2024 Septiembre | 117 | 25 | 142 |
| 2024 Agosto | 134 | 49 | 183 |
| 2024 Julio | 124 | 36 | 160 |
| 2024 Junio | 107 | 35 | 142 |
| 2024 Mayo | 99 | 38 | 137 |
| 2024 Abril | 91 | 19 | 110 |
| 2024 Marzo | 105 | 25 | 130 |
| 2024 Febrero | 106 | 31 | 137 |
| 2024 Enero | 70 | 36 | 106 |
| 2023 Diciembre | 87 | 26 | 113 |
| 2023 Noviembre | 146 | 41 | 187 |
| 2023 Octubre | 105 | 31 | 136 |
| 2023 Septiembre | 108 | 29 | 137 |
| 2023 Agosto | 122 | 27 | 149 |
| 2023 Julio | 170 | 40 | 210 |
| 2023 Junio | 153 | 31 | 184 |
| 2023 Mayo | 323 | 35 | 358 |
| 2023 Abril | 158 | 24 | 182 |
| 2023 Marzo | 105 | 29 | 134 |
| 2023 Febrero | 100 | 25 | 125 |
| 2023 Enero | 95 | 33 | 128 |
| 2022 Diciembre | 104 | 39 | 143 |
| 2022 Noviembre | 59 | 29 | 88 |
| 2022 Octubre | 72 | 27 | 99 |
| 2022 Septiembre | 123 | 36 | 159 |
| 2022 Agosto | 82 | 34 | 116 |
| 2022 Julio | 59 | 36 | 95 |
| 2022 Junio | 46 | 25 | 71 |
| 2022 Mayo | 96 | 31 | 127 |
| 2022 Abril | 90 | 29 | 119 |
| 2022 Marzo | 71 | 52 | 123 |
| 2022 Febrero | 53 | 25 | 78 |
| 2022 Enero | 69 | 34 | 103 |
| 2021 Diciembre | 63 | 36 | 99 |
| 2021 Noviembre | 70 | 49 | 119 |
| 2021 Octubre | 63 | 56 | 119 |
| 2021 Septiembre | 51 | 35 | 86 |
| 2021 Agosto | 36 | 45 | 81 |
| 2021 Julio | 53 | 35 | 88 |
| 2021 Junio | 41 | 22 | 63 |
| 2021 Mayo | 58 | 36 | 94 |
| 2021 Abril | 121 | 70 | 191 |
| 2021 Marzo | 90 | 31 | 121 |
| 2021 Febrero | 61 | 28 | 89 |
| 2021 Enero | 30 | 30 | 60 |
| 2020 Diciembre | 28 | 18 | 46 |
| 2020 Noviembre | 35 | 26 | 61 |
| 2020 Octubre | 23 | 7 | 30 |
| 2020 Septiembre | 38 | 24 | 62 |
| 2020 Agosto | 30 | 14 | 44 |
| 2020 Julio | 19 | 15 | 34 |
| 2020 Junio | 41 | 32 | 73 |
| 2020 Mayo | 53 | 11 | 64 |
| 2020 Abril | 43 | 18 | 61 |
| 2020 Marzo | 41 | 21 | 62 |
| 2020 Febrero | 5 | 0 | 5 |
| 2020 Enero | 4 | 0 | 4 |
| 2019 Diciembre | 5 | 0 | 5 |
| 2019 Noviembre | 6 | 0 | 6 |
| 2019 Octubre | 1 | 0 | 1 |
| 2019 Agosto | 4 | 0 | 4 |
| 2019 Julio | 4 | 0 | 4 |
| 2019 Junio | 4 | 0 | 4 |
| 2019 Mayo | 6 | 2 | 8 |
| 2019 Abril | 2 | 3 | 5 |
| 2019 Marzo | 2 | 0 | 2 |
| 2019 Enero | 2 | 0 | 2 |
| 2018 Diciembre | 1 | 0 | 1 |
| 2018 Noviembre | 2 | 0 | 2 |
| 2018 Octubre | 5 | 0 | 5 |
| 2018 Septiembre | 17 | 0 | 17 |
| 2018 Febrero | 156 | 6 | 162 |
| 2018 Enero | 149 | 11 | 160 |
| 2017 Diciembre | 64 | 6 | 70 |
| 2017 Noviembre | 49 | 7 | 56 |
| 2017 Octubre | 50 | 8 | 58 |
| 2017 Septiembre | 27 | 3 | 30 |
| 2017 Agosto | 42 | 14 | 56 |
| 2017 Julio | 33 | 13 | 46 |
| 2017 Junio | 43 | 14 | 57 |
| 2017 Mayo | 29 | 8 | 37 |
| 2017 Abril | 38 | 10 | 48 |
| 2017 Marzo | 30 | 15 | 45 |
| 2017 Febrero | 31 | 13 | 44 |
| 2017 Enero | 20 | 8 | 28 |
| 2016 Diciembre | 59 | 40 | 99 |
| 2016 Noviembre | 17 | 25 | 42 |
| 2016 Octubre | 0 | 4 | 4 |
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