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
Corresponding author
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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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 9 | 15 |
| 2024 October | 99 | 38 | 137 |
| 2024 September | 117 | 25 | 142 |
| 2024 August | 134 | 49 | 183 |
| 2024 July | 124 | 36 | 160 |
| 2024 June | 107 | 35 | 142 |
| 2024 May | 99 | 38 | 137 |
| 2024 April | 91 | 19 | 110 |
| 2024 March | 105 | 25 | 130 |
| 2024 February | 106 | 31 | 137 |
| 2024 January | 70 | 36 | 106 |
| 2023 December | 87 | 26 | 113 |
| 2023 November | 146 | 41 | 187 |
| 2023 October | 105 | 31 | 136 |
| 2023 September | 108 | 29 | 137 |
| 2023 August | 122 | 27 | 149 |
| 2023 July | 170 | 40 | 210 |
| 2023 June | 153 | 31 | 184 |
| 2023 May | 323 | 35 | 358 |
| 2023 April | 158 | 24 | 182 |
| 2023 March | 105 | 29 | 134 |
| 2023 February | 100 | 25 | 125 |
| 2023 January | 95 | 33 | 128 |
| 2022 December | 104 | 39 | 143 |
| 2022 November | 59 | 29 | 88 |
| 2022 October | 72 | 27 | 99 |
| 2022 September | 123 | 36 | 159 |
| 2022 August | 82 | 34 | 116 |
| 2022 July | 59 | 36 | 95 |
| 2022 June | 46 | 25 | 71 |
| 2022 May | 96 | 31 | 127 |
| 2022 April | 90 | 29 | 119 |
| 2022 March | 71 | 52 | 123 |
| 2022 February | 53 | 25 | 78 |
| 2022 January | 69 | 34 | 103 |
| 2021 December | 63 | 36 | 99 |
| 2021 November | 70 | 49 | 119 |
| 2021 October | 63 | 56 | 119 |
| 2021 September | 51 | 35 | 86 |
| 2021 August | 36 | 45 | 81 |
| 2021 July | 53 | 35 | 88 |
| 2021 June | 41 | 22 | 63 |
| 2021 May | 58 | 36 | 94 |
| 2021 April | 121 | 70 | 191 |
| 2021 March | 90 | 31 | 121 |
| 2021 February | 61 | 28 | 89 |
| 2021 January | 30 | 30 | 60 |
| 2020 December | 28 | 18 | 46 |
| 2020 November | 35 | 26 | 61 |
| 2020 October | 23 | 7 | 30 |
| 2020 September | 38 | 24 | 62 |
| 2020 August | 30 | 14 | 44 |
| 2020 July | 19 | 15 | 34 |
| 2020 June | 41 | 32 | 73 |
| 2020 May | 53 | 11 | 64 |
| 2020 April | 43 | 18 | 61 |
| 2020 March | 41 | 21 | 62 |
| 2020 February | 5 | 0 | 5 |
| 2020 January | 4 | 0 | 4 |
| 2019 December | 5 | 0 | 5 |
| 2019 November | 6 | 0 | 6 |
| 2019 October | 1 | 0 | 1 |
| 2019 August | 4 | 0 | 4 |
| 2019 July | 4 | 0 | 4 |
| 2019 June | 4 | 0 | 4 |
| 2019 May | 6 | 2 | 8 |
| 2019 April | 2 | 3 | 5 |
| 2019 March | 2 | 0 | 2 |
| 2019 January | 2 | 0 | 2 |
| 2018 December | 1 | 0 | 1 |
| 2018 November | 2 | 0 | 2 |
| 2018 October | 5 | 0 | 5 |
| 2018 September | 17 | 0 | 17 |
| 2018 February | 156 | 6 | 162 |
| 2018 January | 149 | 11 | 160 |
| 2017 December | 64 | 6 | 70 |
| 2017 November | 49 | 7 | 56 |
| 2017 October | 50 | 8 | 58 |
| 2017 September | 27 | 3 | 30 |
| 2017 August | 42 | 14 | 56 |
| 2017 July | 33 | 13 | 46 |
| 2017 June | 43 | 14 | 57 |
| 2017 May | 29 | 8 | 37 |
| 2017 April | 38 | 10 | 48 |
| 2017 March | 30 | 15 | 45 |
| 2017 February | 31 | 13 | 44 |
| 2017 January | 20 | 8 | 28 |
| 2016 December | 59 | 40 | 99 |
| 2016 November | 17 | 25 | 42 |
| 2016 October | 0 | 4 | 4 |
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