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CASE REPORT Table of Contents   
Year : 2009  |  Volume : 52  |  Issue : 1  |  Page : 65-68
Primary Langerhans cell histiocytosis of the vulva: Report of a case and brief review of the literature


1 Department of Pathology, Creighton University Medical Center, Omaha, Nebraska, USA
2 Department of Family Medicine, Creighton University Medical Center, Omaha, Nebraska, USA

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   Abstract 

Primary Langerhans cell histiocytosis (LCH) of the vulva is rare. Fifteen cases of primary cutaneous vulvar LCH have been reported in English literature. We report an additional case of LCH confined to the vulva. In this article, we describe the clinical presentation, histopathology and immunohistochemistry findings of vulvar LCH that are helpful to both gynecologists and pathologists in the diagnosis of this entity. We briefly discuss the pathogenesis of LCH. The debate whether LCH is a reactive or neoplastic entity is still ongoing.

Keywords: Langerhans cell histiocytosis, vulva

How to cite this article:
Pan Z, Sharma S, Sharma P. Primary Langerhans cell histiocytosis of the vulva: Report of a case and brief review of the literature. Indian J Pathol Microbiol 2009;52:65-8

How to cite this URL:
Pan Z, Sharma S, Sharma P. Primary Langerhans cell histiocytosis of the vulva: Report of a case and brief review of the literature. Indian J Pathol Microbiol [serial online] 2009 [cited 2019 Dec 14];52:65-8. Available from: http://www.ijpmonline.org/text.asp?2009/52/1/65/44968



   Introduction Top


Langerhans cell histiocytosis is characterized by the infiltration of Langerhans cells in one or more organs. Langerhans cell histiocytosis is primarily regarded as a pediatric disease. Childhood Langerhans cell histiocytosis has a reported incidence of 1 in 200,000. A fair number of adults may also be affected . Males are more commonly affected with a male:female ratio of 3.7:1. The clinical presentation and behavior of the disease varies greatly, ranging from mild to life-threatening.

Langerhans cell histiocytosis may affect any part of the body from the skin to the brain. The bone is the most common site of involvement. Involvement of the genital tract is unusual and involvement of vulvar skin is even less common. [1] A review of English literature revealed only 15 reported cases of primary vulvar Langerhans cell histiocytosis. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] Genital skin involvement by Langerhans cell histiocytosis is relatively more common in women than in men. The median age of presentation in women is 38 years old. We report a case of primary vulvar Langerhans cell histiocytosis with review of the literature.


   Case Report Top


A 49-year-old Caucasian female presented to a family physician with vulvar lesions noted approximately 1 year earlier. An examination revealed ulcerations on the periclitoral area that were thought to be of infectious etiology. She was treated with topical antibiotics. The treatment was unsuccessful and a few months later she presented with increased size of ulcers. An excisional biopsy was performed. The excision specimen measured 5.6 cm in greatest dimension and showed two ulcers, each measuring up to 2.0 cm in greatest dimension. A microscopic examination showed epidermal ulceration and nodular infiltrates of mononuclear cells in the dermis with extension into the subcutaneous tissue. The cells had a moderate amount of eosinophilic cytoplasm and grooved nuclei consistent with Langerhans cells [Figure 1A]. These cells were mixed with small lymphocytes and eosinophils [Figure 1B]. The Langerhans cells showed epidermotropism [Figure 1C]. The cells were positive for CD1a, S100 and CD4 immunohistochemical stains [Figure 1D],[Figure 1E],[Figure 1F]. The cells showed no staining with CD68 immunohistochemical stain. Lymphoma cutis, malignant melanoma and metastatic carcinoma were considered in the differential diagnosis in view of dense cellular infiltrate in the dermis. To exclude these entities, CD45 (leukocyte common antigen), CD20, HMB45, MelanA and Pankeratin immunohistochemical stains were performed. The lesional cells were negative for these markers. Histology in conjunction with positive staining for CD1a and S100 stains in Langerhans cells (LC) confirmed the diagnosis of Langerhans cell histiocytosis. The lesion was present at biopsy margins. This diagnosis led to a comprehensive evaluation of the patient including skeletal radiology, bone scintigraphy, an ultrasonography of the liver, computed tomography (CT) scan of the lung and metabolic panel. There was no evidence of disease beyond the vulva. The patient received local radiotherapy with complete response. There has been no evidence of local or systemic disease during the 5-month follow-up.


   Discussion Top


Langerhans cell histiocytosis is a rare disease with a wide variety of clinical presentations and course. The disease was initially categorized into eosinophilic granuloma, Hand-Schuller-Christian disease, or Letterer-Siwe disease depending on the site and degree of involvement. Later, these were found to be different manifestations of a single disease and were unified under one entity named Histiocytosis X. Currently, these disorders are grouped together under the name Langerhans' cell histiocytosis.

The Langerhans cells are peripheral dendritic, antigen processing cells of bone marrow origin. They are an important part of the localized immune response. These cells are found throughout the body but are primarily located in the suprabasal layer of the epidermis. They have also been found in the dermis, lymph nodes and stratified squamous epithelium of the tonsils and oral mucosa. In the genital tract, they have been documented in the vulva, vagina and cervix with a distinct preponderance in the transformation zone of the cervix and the vulva. Langerhans cells in these locations are modulated actively in response to chemical stimuli such as smoking and human papillomavirus infection. Therefore, Langerhans cell histiocytosis involvement of the lower genital tract is not surprising.

Although the disease has been known for a century, its etiopathogenesis has been obscure. Immune system dysfunction related to cytokines, infectious agents, genetic factors and neoplastic process have all been considered. LCH cells have been found to be clonal in both localized and multisystem forms of the disease. The clonal cells are the CD1a+ Langerhans cells that are presumed to play a pivotal role in the disease pathogenesis. The Langerhans cells and lesional lymphocytes have increased expression of the cytokines including tumor necrosis factor alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Cytokines are responsible for the proliferation and differentiation of Langerhans cells. Langerhans cell histiocytosis lesions have shown genetic abnormalities. Genetic instability may lead to histiocytic proliferation and disease progression. The role of viruses in initiating the disease remains under study. The possible involvement of Human Herpes virus Type-6 and Epstein-Barr virus infections in Langerhans cell histiocytosis has been suggested. The association with virus suggests that the disease could result from a viral induced proliferation of Langerhans cells. The exact pathogenesis is still unclear; it is likely that the etiology is multifactorial.

The disease most frequently manifests as osseous lesions, characteristically involving the flat bones of the skull, ribs, pelvis and scapula. The most common presentation of unifocal disease is a single lytic skull lesion. Involvement of the genital tract is usually seen as a part of multi-organ disease. Pure genital tract involvement is rare. At present, there are 51 published cases of Langerhans cell histiocytosis affecting the genital area and only 15 of these represent primary Langerhans cell histiocytosis of the vulva to the best of our knowledge [Table 1]. The vulva is the most common site of involvement by Langerhans cell histiocytosis in the female genital tract. [1] The disease has been reported in other sites of the genital tract including the vagina, cervix, uterus and ovaries. Four distinct patterns of the disease involvement of the female genital tract have been recognized: 1) pure genital Langerhans cell histiocytosis, in which the disease is restricted to the genital tract, 2) genital tract Langerhans cell histiocytosis with subsequent multi-organ involvement, 3) oral or cutaneous Langerhans cell histiocytosis with subsequent genital and multi-organ involvement and 4) diabetes insipidus with subsequent genital and multi-organ involvement. [1]

Clinically, most patients with vulvar involvement present with multiple ulcers. The lesions on the vulva may take the form of papules, a pruritic rash, nodules, or may appear as an area of induration. Due to such varied clinical appearance, genital Langerhans cell histiocytosis may mimic various neoplastic and non neoplastic conditions. Pruritic, erythematous lesions resemble eczema or seborrheic dermatitis. Papular and ulcerated lesions may resemble chancroid, granuloma inguinale, lymphogranuloma venereum, syphilitic chancres, tuberculosis, herpes genitalis, erythema multiforme, or Behcet's syndrome. It may be mistaken for cutaneous malignancies such as squamous cell carcinoma, malignant melanoma and sarcoma, particularly when presented as a mass lesion. Diffusely indurated lesions clinically mimic Paget's disease of the vulva. The gold standard for diagnosis is biopsy and histology.

The pathology of Langerhans cell histiocytosis is characteristic. The location and duration of the lesion may influence the histopathology of the disease to some extent. Early in the course of the disease, lesions tend to be cellular and show a mixture of Langerhans cells (LC), eosinophils, plasma cells and lymphocytes (mainly T lymphocytes) in varying proportions. As the disease progresses, the cellularity and number of Langerhans cells is reduced and macrophages and fibrosis become more prominent. LCs measure 10-12 µm in diameter with abundant eosinophilic cytoplasm and a medium-sized folded, indented, or reniform nucleus that has vesicular chromatin with one to three nucleoli and an elongated central groove, resulting in a coffee bean appearance. Phenotypically, LCs express CD1a thymocyte glycoprotein (Leu6), Langerin (CD207), HLA-DR and S100 glycoprotein. CD68 coexpression may be found in CD1a and Langerin-positive cells. Ultrastructurally, LCs have characteristic penta-laminar plate-like organelles called Birbeck granules (X bodies) in the cytoplasm and, rarely, in the nucleus. Birbeck granules are the products of the internalization of complexes originating from cell membrane antigens and corresponding antibodies. The Writing Group of the Histiocyte Society has identified three levels of confidence in the diagnosis of Langerhans cell histiocytosis. A definitive diagnosis requires the finding of Birbeck granules in the lesional cells by electron microscopy or the demonstration of CD1a antigenic determinants on the surface of lesional cells. The present case was diagnosed as "definitive Langerhans cell histiocytosis" by characteristic histology and immunohistochemical findings. The diagnosis of Langerhans cell histiocytosis may easily be overlooked in favor of other inflammatory processes particularly when Langerhans cells are sparse and or secondary chronic inflammatory cells predominate. The differential diagnosis at the microscopic level includes immunodeficiency syndromes with graft versus host disease, viral infection and infiltrative diseases such as leukemia or lymphoma, reticuloendothelial storage disease, congenital infections and papular xanthomas. Lesions showing dense cellular infiltrates, such as in the present case, may mimic malignant melanoma and metastatic carcinoma. Certain findings such as vasculitis, necrotizing granulomas and prominent plasma cell infiltrate are unusual in Langerhans cell histiocytosis. The presence of these findings should raise suspicion for an alternative diagnosis.

The treatment of genital Langerhans cell histiocytosis is not well defined and is highly individualized. Current treatment modalities include surgery, radiation, topical corticosteroids, topical nitrogen mustard, thalidomide, systemic chemotherapy and various combinations. Although no modality has been shown to yield a superior outcome, complete surgical excision is advocated as initial therapy. The assessment of the effectiveness of the current therapies is limited because of substantial variations in disease manifestation and spontaneous regression in 10-20% of patients. The prognosis is also difficult to determine with certainty. There appears to be no correlation between the histology and the outcome of the genital lesions. Important factors for predicting disease recurrence and poor prognosis include young age (<5 years) at presentation and the disease involving three or more body systems and/or organ dysfunction.

In conclusion, the occurrence of Langerhans cell histiocytosis of the vulva is very unusual. It should be considered in differential diagnosis of an atypical chronic lesion of the vulva. A biopsy of the lesion is necessary to confirm the diagnosis. It is important to exclude systemic disease in any patient with a diagnosis of vulvar Langerhans cell histiocytosis. The prognosis in a patient with disease limited to the vulvar skin is good. Surveillance is essential for early detection of local recurrence or systemic involvement.

 
   References Top

1.Axiotis CA, Merino MJ, Duray PH. Langerhans cell histiocytosis of the female genital tract. Cancer 1991;67:1650-60.  Back to cited text no. 1  [PUBMED]  
2.Mottl H, Rob L, Stary J, Kodet R, Drahokoupilova E. Langerhans cell histiocytosis of vulva in adolescent. Int J Gynecol Cancer 2007;17:520-4.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Venizelos ID, Mandala E, Tatsiou ZA, Acholos V, Goutzioulis M. Primary langerhans cell histiocytosis of the vulva. Int J Gynecol Pathol 2006;25:48-51.  Back to cited text no. 3  [PUBMED]  
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5.Ishigaki H, Hatta N, Yamada M, Orito H, Takehara K. Localized vulva Langerhans cell histiocytosis. Eur J Dermatol 2004;14:412-4.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Santillan A, Montero AJ, Kavanagh JJ, Liu J, Ramirez PT. Vulvar Langerhans cell histiocytosis: A case report and review of the literature. Gynecol Oncol 2003;91:241-6.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Padula A, Medeiros LJ, Silva EG, Deavers MT. Isolated vulvar Langerhans cell histiocytosis: Report of two cases. Int J Gynecol Pathol 2004;23:278-83.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Pather S, Moodley JM, Bramdev A. Isolated Langerhans cell histiocytosis of the vulva: A case report. J Obstet Gynaecol Res 2001;27:111-5.  Back to cited text no. 8  [PUBMED]  
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10.Prignano F, Domenici L, Carli P, Pimpinelli N, Romagnoli P. Langerhans cell histiocytosis of the vulva: An ultrastructural study. Ultrastruct Pathol 1999;23:127-32.  Back to cited text no. 10  [PUBMED]  
11.Savell V, Hanna R, Benda JA, Argenyi ZB. Histiocytosis X of the vulva with a confusing clinical and pathologic presentation: A case report. J Reprod Med 1995;40:323-6.  Back to cited text no. 11  [PUBMED]  
12.Blaauwgeers JL, Bleker OP, Veltkamp S, Weigel HM. Langerhans cell histiocytosis of the vulva. Eur J Obstet Gynecol Reprod Biol 1993;48:145-8.  Back to cited text no. 12  [PUBMED]  
13.Voelklein K, Horny HP, Marzusch K, Dietl J. Primary Langerhans cell histiocytosis of the vulva. Gynecol Obstet Invest 1993;36:189-90.  Back to cited text no. 13  [PUBMED]  
14.Rose PG, Johnston GC, O'Toole RV. Pure cutaneous histiocytosis X of the vulva. Obstet Gynecol 1984;64:587-90.  Back to cited text no. 14  [PUBMED]  
15.Weidman FD. The "eosinophilic granulomas" of the skin. Arch Derm Syphilol 1947;55:155-75.  Back to cited text no. 15    

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Correspondence Address:
Poonam Sharma
Department of Pathology, Creighton University Medical Center, 601 North 30th Street, Omaha, NE 68131
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.44968

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    Figures

  [Figure 1A], [Figure 1B], [Figure 1C], [Figure 1D], [Figure 1E], [Figure 1F]
 
 
    Tables

  [Table 1]

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