**3. Langerhans cell sarcoma**

## **3.1. Clinical presentation**

by screening may be allowed for protocol or clinical trial entry with use of Zelboraf (vemura‐ finib), an FDA approved therapy. Recently, a variant BRAF V600D mutation has been reported in congenital, benign, self-regressive LCH [14]. E-cadherin expression was found as a marker of good prognosis and limited disease, however, the results have not been validated in separated studies [10, 45]. The role of Ki67 as a prognostic marker is limited. One of the most common abnormalities seen in LCH is TP53 over-expression (FIGURE 6); however, TP53

mutations have not been identified [7, 9, 46].

34 Skin Biopsy - Diagnosis and Treatment

**Figure 6.** TP53 over-expression in Langerhans Cell Histiocytosis (LCH)

Patients require complete clinical history, physical examination, and a comprehensive laboratory and radiographic evaluation [47]. The Histiocyte Society recommends that in order to determine the adequate research protocol, patients should be stratified based upon exten‐ sion of the disease (unifocal, multifocal/multysistemic), involvement of risk organs (hemato‐ lymphoid including spleen and liver) and central nervous system risk lesions [48-49]. Patients with unifocal disease limited to the skin require follow up-and usually no additional treatment

**2.6. Treatment**

Thirty one cases of LCS have been reported to date [53]. Skin can be a single site involved by LCS or can be seen as part of widespread disease. Cutaneous involvement is present in more than half of cases. Multiorgan involvement includes lymph node, lungs, liver, spleen and bone. Skin biopsy is an accessible and a useful way to demonstrate malignant LC. LCS occurs in all age groups with a male:female ratio 1:1. LCS can appear as an increasingly progressive malignant disease followed by multiple LCH recurrences, *de novo* and with underlying myeloproliferative disease [53-55]. *De novo* or primary LCS has been reported exclusively in adults, without previous evidence of LCH. In a recent publication, a case of trans-differentia‐ tion of acute B-lymphoblastic leukemia into a LCS has been documented, as both show identical IGH@ gene rearrangements [54].

#### **3.2. Histopathology**

Skin biopsy usually shows an infiltrative and poorly defined high grade malignant neoplasm composed of large cells with grooved nuclei, granular chromatin, prominent nucleoli and high mitotic rate. Although inflammatory infiltrate can be present and abundant, especially if there is associated necrosis, eosinophils are usually scattered. Epidermis can be ulcerated and epidermotropism is seen [2, 55]. (FIGURE 7)

#### **3.3. Immunoprofile and electron microscopy**

Malignant LC are usually positive for CD1a, S100 and Langerin (CD207) (FIGURE 8). There is lack of reactivity for T and B cell antigens. Neoplastic cells have a high proliferative Ki67 index and overexpress p53. CD56 /neural cell adhesion molecule (NCAM) positivity has been found expressed in LCS [56]. A broad panel of immunohistochemical stains is used to confirm LC due to the atypical features of the neoplasm, and electron microscopy is usually performed for identification of intracytoplasmic Birbeck granules.

**3.4. Differential diagnosis**

(MPO) positivity in tumor cells.

Because of the marked pleomorphism and cytologic atypia, hematologic and nonhematologic entities must be considered in the differential diagnosis including malignant melanoma, carcinoma, mesenchymal malignant neoplasms and lymphomas with anaplastic features. Pleomorphic large cells may be mistaken for malignant melanoma, which shares S100 positivity but also expresses other melanocytic markers. LCS comprises cells with bizarre pleomorphic nuclei and abundant cytoplasm mimicking hematolymphoid neoplasms including anaplastic large cell lymphoma, anaplastic diffuse large B-cell lymphoma, plasma cell neoplasm with anaplastic features, lymphomatoid papulosis, peripheral T cell lymphoma and myeloid sarcoma (FIGURE 9) (TABLE 1) [55]. In those cases, immunohistochemical and

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37

**Figure 9.** Myeloid Sarcoma. A. Skin shows a diffuse dermal infiltrate composed of malignant cells. B. Features of neo‐ plastic cells with promyelocytic differentiation. C. CD34 stain is positive in the majority of cells. D. Myeloperoxidase

molecular features are useful to distinguish the cell of origin.

**Figure 7.** Histological appearance of Langerhans Cell Sarcoma (LCS). A. Dermal infiltrate of large atypical cells with epidermotrophism. B. Bizarre and pleomorphic cells with abundant mitotic figures and lack of cohesiveness. C. De‐ tailed figure of LCS cells with prominent intranuclear inclusions.

**Figure 8.** Immunoprofile of Langerhans Cell Sarcoma (LCS). A. Langerin (CD207) expression in cells with malignant features. Numerous mitotic figures are identified. B. Malignant cells retain CD1a expression.

### **3.4. Differential diagnosis**

**Figure 8.** Immunoprofile of Langerhans Cell Sarcoma (LCS). A. Langerin (CD207) expression in cells with malignant

**Figure 7.** Histological appearance of Langerhans Cell Sarcoma (LCS). A. Dermal infiltrate of large atypical cells with epidermotrophism. B. Bizarre and pleomorphic cells with abundant mitotic figures and lack of cohesiveness. C. De‐

tailed figure of LCS cells with prominent intranuclear inclusions.

36 Skin Biopsy - Diagnosis and Treatment

features. Numerous mitotic figures are identified. B. Malignant cells retain CD1a expression.

Because of the marked pleomorphism and cytologic atypia, hematologic and nonhematologic entities must be considered in the differential diagnosis including malignant melanoma, carcinoma, mesenchymal malignant neoplasms and lymphomas with anaplastic features. Pleomorphic large cells may be mistaken for malignant melanoma, which shares S100 positivity but also expresses other melanocytic markers. LCS comprises cells with bizarre pleomorphic nuclei and abundant cytoplasm mimicking hematolymphoid neoplasms including anaplastic large cell lymphoma, anaplastic diffuse large B-cell lymphoma, plasma cell neoplasm with anaplastic features, lymphomatoid papulosis, peripheral T cell lymphoma and myeloid sarcoma (FIGURE 9) (TABLE 1) [55]. In those cases, immunohistochemical and molecular features are useful to distinguish the cell of origin.

**Figure 9.** Myeloid Sarcoma. A. Skin shows a diffuse dermal infiltrate composed of malignant cells. B. Features of neo‐ plastic cells with promyelocytic differentiation. C. CD34 stain is positive in the majority of cells. D. Myeloperoxidase (MPO) positivity in tumor cells.


[4] Anjuere, F. del Hoyo GM, Martin P, Ardavin C. Langerhans cells develop from a

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39

[5] Park, H. J, Jeon, Y. K, Lee, A. H, Oh, Y. H, Park, S. H, & Jung, K. C. Use of the JL1 epitope, which encompasses the nonglycosylation site of CD43, as a marker of imma‐

[6] Willman, C. L, Busque, L, Griffith, B. B, Favara, B. E, Mcclain, K. L, Duncan, M. H, et al. Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. N

[7] Badalian-very, G, Vergilio, J. A, & Degar, B. A. MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. (2010).

[8] Mcelligott, J, Mcmichael, A, Sangueza, O. P, Anthony, E, Rose, D, & Mclean, T. W. Spontaneous regression of langerhans cell histiocytosis in a neonate with multiple

[9] Badalian-very, G, Vergilio, J. A, Degar, B. A, Rodriguez-galindo, C, & Rollins, B. J. Recent advances in the understanding of Langerhans cell histiocytosis. Br J Haema‐

[10] Kapur, P, Erickson, C, Rakheja, D, Carder, K. R, & Hoang, M. P. Congenital self-heal‐ ing reticulohistiocytosis (Hashimoto-Pritzker disease): ten-year experience at Dallas

[11] Elder, D. E E. R, Johnson, B, Ioffreda, M, Miller, J, & Miller, O. F. editor. Lever's His‐ topathology of the skin. 9th edition ed. Philadelphia: Lippincott Williams & Wilkins;

[12] Edelbroek, J. R, Vermeer, M. H, Jansen, P. M, Stoof, T. J, Van Der Linden, M. M, Hor‐ vath, B, et al. Langerhans cell histiocytosis first presenting in the skin in adults: fre‐ quent association with a second hematological malignancy. Br J Dermatol. (2012). Jul

[13] Hashimoto, K, & Pritzker, M. S. Electron microscopic study of reticulohistiocytoma. An unusual case of congenital, self-healing reticulohistiocytosis. Arch Dermatol.

[14] Kansal, R, Quintanilla-martinez, L, Datta, V, Lopategui, J, Garshfield, G, & Nathwa‐ ni, B. N. Identification of the mutation in Exon 15 of the BRAF oncogene in congeni‐ tal, benign langerhans cell histiocytosis. Genes Chromosomes Cancer. (2012). Sep 21.,

[15] Sahm, F, Capper, D, Preusser, M, Meyer, J, Stenzinger, A, Lasitschka, F, et al. BRAFV600E mutant protein is expressed in cells of variable maturation in Langer‐

hans cell histiocytosis. Blood. (2012). Sep 20;120(12):e, 28-34.

Children's Medical Center. J Am Acad Dermatol. (2007). Feb;, 56(2), 290-4.

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(1973). Feb;, 107(2), 263-70.

(2004).

27.

600D

**Table 1.** Langerhans Cell Sarcoma (LCS) - Differential Diagnosis

#### **3.5. Prognosis and treatment**

Currently, no specific marker has demonstrated to predict prognosis in LCS. In a study, CD56 expression was associated to poor prognosis and the results have not been validated in a different set of patients [56]. Despite combination chemotherapy/radiotherapy and surgery, LCS is an aggressive high grade malignancy with poor prognosis, frequent recurrences and short survival, usually resulting in death within 1 year [2, 53, 55].
