indeterminate cell tumor (histiocytosis)

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109Saudi Journal of Medicine & Medical Sciences | Vol. 1 | Issue 2 | Jul-Dec 2013 | 109-112
Indeterminate Cell Tumor (Histiocytosis)
Ayesha Ahmed, Mohamed A. Shawarby, Dalal M. Al-Tamimi, Zainab A. Al-Ruwai, Tarek M. El-Sharkawy, Tarek M. Hashem, Eman F. Al-Saleh College of Medicine, University of Dammam, Kingdom of Saudi Arabia
Correspondence: Prof. Mohamed A. Shawarby, Department of Pathology, King Fahd Hospital of the University, Al-Khobar, P.O. Box 2208, Al-Khobar 31952, Kingdom of Saudi Arabia. E-mail: [email protected]
Indeterminate cell tumor (ICT) is a rare neoplastic dendritic cell disorder that has been ill-defined because of its rarity and poorly explicated histogenesis. The lesional “indeterminate” cells, as their name implies have a vague, yet undetermined origin, with overlapping features between Langerhans cells (LC) and dendritic cells. They resemble LC immunophenotypically (positive for CD1a and S-100 protein), but lack the characteristic Birbeck granules of LC ultrastructurally.[1] Such lesions are grouped under non-LC histiocytoses (non-LCH), that is, a group of disorders characterized by the accumulation of histiocytes that do not meet the phenotypic criteria necessary for
the diagnosis of LCs. Clinically the non-LCH can be divided into two groups, the cutaneous type, comprising predominantly cutaneous involvement, although systemic manifestations may be present, and the extracutaneous type which primarily involves extracutaneous sites.[2] The purpose of this article is to report a case of cutaneous ICT in a newborn and also to discuss its controversial histogenesis along with its evolving classifications and simplified, reproducible diagnostic strategies.
Clinical and gross findings A 6-month-old male infant presented with a left forearm skin lesion present since birth. Excision biopsy revealed a skin ellipse with a central hypopigmented area measuring 1 × 0.5 cm.
Microscopic and IHC findings Histologic examination revealed diffuse infiltration of the dermis by histiocytic cells with pale cytoplasm and focally cleft nuclei. Scattered mononuclear inflammatory cells were also present, along with rare neutrophils, eosinophils, lipidized cells, multinucleated giant cells,
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DOI: 10.4103/1658-631X.123647
Indeterminate cell tumor (ICT; histiocytosis) is a rare disorder characterized by accumulation of histiocytes that do not fulfill the phenotypic criteria designated for Langerhans cells (LC). The cells classified as “indeterminate” exhibit overlapping features between dendritic cells and histiocytic cells by showing variable reactivity for CD1a and positivity for S-100 protein and CD68. Ultrastructurally, absence of Birbeck granules, a feature consistent with LC, epitomizes the lesional cells. Herein, we report a case of ICT in a new born emphasizing its histogenesis and clinical, morphologic, immunohistochemical, and ultrastructural features.
Key words: Dendritic cells, histiocytes, indeterminate cells, Langerhans cells
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and occassional foci of necrosis. There was no significant nuclear pleomorphism or mitotic activity. No granulomas were discerned [Figure 1]. Immunohistochemically, the histiocytic cells showed strong reactivity for CD68 and S-100 protein and negativity for CD1a. Electron microscopy (EM) revealed absence of Birbeck granules in the histiocytic cells [Figure 2].
Histiocytic and dendritic cell neoplasms are a relatively rare and diverse group of disorders.[3] Tissue infiltration by cells of monocyte/macrophage lineage, admixed with other inflammatory cells typifies the lesions. Generally, no precipitating cause can be discerned.
Basically, these disorders comprise proliferation of two cell types: Antigen processing cells (monocytes/ macrophages) and antigen-presenting cells (dendritic cells). Both cell lineages share similar bone marrow precursor cells. Under the influence of various cytokines, these progenitor cells differentiate to become either antigen-processing or antigen-presenting cells.[3,4]
In the antigen-processing pathway, colony forming unit (CFU)-granulocytic/monocytic cells are differentiated into CFU-monocytic/dendritic cells, and subsequently into CFU- monocytic cells. Following this, a differentiation cascade leads to these progenitor cells forming immature and finally mature monocytes. The monocytes circulate in the blood and finally settle in multiple organs where they are designated as tissue histiocytes which are sometimes imparted a specific
name depending on the site of their permanent homage, for example, Kupffer cells of the liver, microglial cells of the brain, and type A synovial cells lining the joints.[5]
In the antigen presenting pathway, the CFU-monocytic/ dendritic cells differentiate into CFU-dendritic cells and then into immature dendritic cells also referred to by many as indeterminate cells. These indeterminate cells are thought to further differentiate into LC and interstitial dendritic cells.[3]
The dendritic cells are bone marrow-derived cells and reside in the skin, lymph nodes, and other organs. In the skin, the prominent dendritic cell is the Langerhans cell, characterized by simultaneous immunoexpression of S-100 and CD1a along with the presence of Birbeck granules (visualized by EM and initially described by Birbeck et al., in 1961[6,7]). LC are localized mostly in the epidermis and mucosal surfaces of various organs. Melanocytes also have a dendritic appearance but are not grouped into these cellular entities. Epidermal antigens are taken up by LC which then migrate through the dermis to lymphatics and finally to the lymph nodes. They carry out antigen presentation of processed antigens in conjunction with major histocompatibility molecules (MHC) to the T lymphocytes. The migrating LC is known as a veiled cell, while the antigen-presenting form is labeled as the interdigitating dendritic cell (IDC). The veiled cells and IDC differ from LC by absence of Birbeck granules in the veiled cells and lack of expression of CD1a in the IDC.[7]
The indeterminate cell, as its name implies, has an indeterminate, vague nature, not fitting precisely into any well-defined cellular category.[8] Not a single consensus
Figure 2: Electron microscopy (EM) showing absence of Birbeck granules in histiocyte
Figure 1: (a) Low power view showing a dermal histiocytic lesion (hematoxylin and eosin staining (H and E, ×10). (b) Histiocytes with pale cytoplasm and cleft nuclei (H and E, ×40). (c) Scattered inflammatory cells admixed with the histiocytes (H and E, ×20). (d) CD68 positivity (immunohistochemical staining (IHC), ×40). (e) S-100 positivity (IHC, ×40). (f) Negative CD1a staining (IHC, ×40)
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definition has been agreed upon, but the possibilities listed in recent literature comprise: • “Veiled cell”, that is, an LC migrating to the dermis. • LC precursor (exactly the opposite of a veiled cell). • Abnormal or dysregulated LC. • Cell with features of both a macrophage and LC”.[7]
The debate regarding indeterminate cells as pre-LC, has its basis on the fact that these cells may show CD1a and S-100 protein but lack Birbeck granules and should not demonstrate immunoreactivity for langerin. Ratzinger et al.,[9] in a study entitled “Indeterminate cell histiocytosis, facts or fiction” demonstrated variable reactivity for CD1a by these cells. However, positivity for macrophage markers, such as KP1 (CD68) and Ki-M1p, as well as for S-100 protein constituted the main feature of these cells. Birbeck granules could not be demonstrated ultrastructurally.[9]
As regards the Birbeck granules and langerin, the function of Birbeck granules yet remains to be deciphered, but a possible role in antigen capture has been postulated.[10] Birbeck granules are considered to originate from the plasmalemma by invaginations of endocytic structures, with langerin/CD207, a type II transmembrane protein, mediating their formation. Langerin expression has been reported to be limited to LC as analyzed by polymerase chain reaction (PCR) analysis and several other immunophenotypic techniques.[11,12]
The nature of the indeterminate cells is so controversial that lesions originating from them failed to gain entry into any of the histiocytic disorders classification systems till the year 2001. Before that, histiocytic disorders were traditionally compartmentalized into two main types, namely, “X’’ (Langerhans cell) and ‘‘non-X’’ histiocytoses. In 2001, histiocytic and dendritic cell neoplasms were classified according to their presumed normal cellular counterpart and were included among neoplasms of hematopoietic and lymphoid tissues in the World Health Organization (WHO) classification system. Indeterminate cell lesions/tumors were not categorized as a separate entity due to their poorly understood nature and histogenesis and they were grouped under the term ‘‘dendritic cell sarcoma, not otherwise specified’’.[13] Later on, indeterminate cell histiocytosis was included in the WHO Classification of tumors of the skin as an exclusive cutaneous neoplasm. [14] In the current revised WHO classification, it has gone back as a tumor of hematopoietic and lymphoid tissues and has been designated as “indeterminate cell tumor”.[1]
ICT has been described predominantly in adults with solitary or multiple cutaneous lesions, rarely with lymph node involvement. Most cases have a self-limited or indolent course.[15] However, leukemic trasnformstion has been reported. Histologically, the lesions show patterns recapitulating the pattern of xanthogranulomas, with the lesional cells showing a wide morphological spectrum comprising oncocytic, spindled, scalloped, or vacuolated cells. Lymphocytes, plasma cells, and eosinophils can be accompanying cells.[9]
In the histopathological workup of histiocytic lesions, a simplified approach has been recommended by Burgdorf et al.,[7] as depicted in Table 1. However, as an electron microscope necessary for the detection of Birbeck granules may not be available in many pathology laboratories, immunohistochemical positivity for langerin may substitute EM as a reliable marker of LC.
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Table 1: Simplified approach to histiocytoses Disorder S-100 CD1a Birbeck
granules Macrophage
+ − − +
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10. Valladeau J, Duvert-Frances V, Pin JJ, Dezutter-Dambuyant C, Vincent C, Massacrier C, et al. The monoclonal antibody DCGM4 recognizes Langerin, a protein specific of Langerhans cells, and is rapidly internalized from the cell surface. Eur J Immunol 1999;29:2695-704.
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How to cite this article: Ahmed A, Shawarby MA, Al-Tamimi DM, Al-Ruwai ZA, El-Sharkawy TM, Hashem TM, Al-Saleh EF. Indeterminate cell tumor (Histiocytosis). Saudi J Med Med Sci 2013;1:109-12. Source of Support: Nil. Conflict of Interest: None declared.