Indeterminate cell histiocytosis—a clinicopathological entity with features of both X- and non-X histiocytosis

An otherwise healthy 50-year-old woman presented with a 6-month history of having developed more than 100 generalized, non-confluent, reddish-brown, partially yellow-coloured papules. A non-epidermotropic, monomorphous infiltrate of vacuolated mononuclear, and occasionally multinuclear, histiocytes, positive for factor XIIIa and macrophage markers HAM56 and KiM1p, was consistent with the clinical impression of generalized eruptive histiocytomas. However, the additional reactivity for S100 protein, in the absence of features of histiocytosis X, suggested a diagnosis of indeterminate cell histiocytosis (ICH). Further immunohistochemical studies, performed on snap-frozen material, characterized the lesions as being diffusely positive with LN3 (HLA-UR). Leu4 (CD3) and Leu3 (CD4). the infiltrate in the upper dermis as reactive for OKT6 (CD1) and IOT6c (CD1c), and the infiltrate in the lower dermis as reactive for a variety of macrophage markers. Ultrastructural studies showed various non-specific features of histocytic disorders, but no Birbeck granules Our findings confirm those of previous reports suggesting that ICH is a distinct histiocytic entity, characterized by immunophenotypic features of both X- and non-X histiocytoses. Generalized eruptive histiocytoma seems to be an early indeterminate stage of various non-X histiocytic syndromes including ICH, multicentric reticulohistiocytosis, xanthogranuloma and xanthoma disseminatum. The distribution pattern of the various X/non-X histiocytic markers suggests dermal arrest of antigen-presenting cells during their physiological trafficking from the skin to the lymph nodes.     

Cutaneous indeterminate cell histiocytosis: a new spindle cell variant resembling dendritic cell sarcoma

BACKGROUND: Cutaneous indeterminate cell histiocytosis is a rare neoplastic disorder. Its varied histological presentation and rarity have limited efforts to determine its pathogenic relationship with other histiocytic lesions and possibly, its recognition. METHODS: We report on an unusual histologic pattern of indeterminate cell histiocytosis that resembled follicular dendritic sarcoma. A battery of immunohistochemical stains and electron microscopy were performed to elucidate the phenotype of the "histiocytic" cells. Based on a review of the literature, reported cases of indeterminate cell histiocytosis are presented and the diagnostic differential of spindle-cell lesions is discussed. RESULTS: Spindling histiocytes were positive for S-100 and CD1a. The monocytic/macrophage marker, CD68, and the dendritic cell marker, CD21, were negative. Electron microscopy failed to reveal Birbeck granules. CONCLUSIONS: Relatively few reports of indeterminate cell histiocytosis exist, some of which include discussion of potential overlaps with the non-X histiocytoses. Although the presence of prominent spindling in our case expanded the differential to include non-histiocytic disorders, the identified histiocytes unequivocally fulfilled the criteria of S-100 and CD1a positivity without demonstrable Birbeck granules.     

Acral histiocytic nodules: a possible new variant of non-X histiocytosis

Many types of histiocytoses have been described. We present a case of a 56-year-old woman who presented with multiple nodules on the hands. On histological examination of an excision biopsy, a mainly dermal lesion was seen, with scattered mononuclear inflammatory cells and occasional multinucleated cells in the background. The tumour was composed of short spindle-shaped histiocyte-like cells with vesicular nuclei and small nucleoli. These cells were positive for CD68 and focally positive for smooth-muscle actin. There was no lipid or haemosiderin pigment, and no cholesterol clefts. Further investigations did not find evidence of bony or systemic involvement. The non-Langerhans cell histiocytoses, also known as non-X histiocytoses, are rare and of unknown aetiology. Clinicopathologically, this case does not seem to fit with any of the recognized subtypes, and we propose that it may represent a previously undescribed variant of the disease.     

Cutaneous non-X histiocytosis: clinical and histologic features and response to dermabrasion

A 22-year-old man presented with a progressive cutaneous eruption consisting of reddish-yellow papules and plaques on his face, which was histopathologically characteristic of a non-X histiocytosis. No systemic involvement was present. Monoclonal antibody staining of the tissue infiltrate was strongly positive for only OKT6. On electron microscopy, Langerhans (Birbeck) granules were not found. Four years of conservative treatment was unsuccessful. Spontaneous involution did not occur. Dermabrasion not only produced excellent cosmetic results, but on rebiopsy the histiocytic infiltrate was absent. There has been no recurrence in treated areas after 18 months.     

An immunohistochemical and ultrastructural study of an unusual case of multiple non-X histiocytoma

An immunohistochemical and ultrastructural study of an atypical case of multiple non-X histiocytoma was done. There was involvement of the skin, lungs, and liver in a 3-month-old male infant. Microscopic examination of the cutaneous tumors revealed a dense infiltration of cells with polymorphous large nuclei and abundant eosinophilic cytoplasm in the entire dermis. Both immunohistochemical and electron microscopic studies suggested that the tumors were non-X histiocytomas. The patient's condition deteriorated with dyspnea due to rapid enlargement of tumor masses in the liver and lungs. However, at 5 months of age, the cutaneous nodules and pulmonary and hepatic lesions showed a tendency to involute. Furthermore, at 12 months of age, they were no longer detectable. The patient at 24 months of age was well with normal development. To date, no recurrence of the disease has been observed.     

An infiltrative variant of non-neural granular cell tumor: a case report

Dermal non-neural granular cell tumors are rare tumors of indeterminate lineage that typically present as well-circumscribed tumors with nuclear pleomorphism and mitotic activity. We describe a dermal non-neural granular cell tumor with a distinctive growth pattern with granular cells interspersed between collagen bundles. This asymptomatic papule arose on the scapula of a 46-year-old woman and consisted of a mixture of epithelioid and spindled granular cells. The immunohistochemical characteristics were similar to those of previously reported dermal non-neural granular cell tumors. Despite mild nuclear pleomorphism and dispersion of lesional cells among collagen bundles, mitoses were not present and Ki-67 staining indicated a low proliferative rate. In addition to being S-100 protein negative and NKI/C3 positive, our case was positive for PGP9.5 and weakly positive for neuron-specific enolase, a staining pattern similar to what has been observed for cellular neurothekeomas. Our case could represent a dermal non-neural granular cell tumor with unique architecture, a granular cellular neurothekeoma or a granular cell dermatofibroma. As both dermal non-neural granular cell tumor and cellular neurothekeoma are of indeterminate lineage, our case with features characteristic of both entities may suggest a common precursor or lineage for dermal non-neural granular cell tumor and cellular neurothekeoma.     

Generalized eruptive histiocytosis

The histiocytic disorders can be broadly categorized into histiocytosis X (Langerhans cell-derived) and non-X types. There are several variants of non-X histiocytoses that tend to occur in a generalized distribution on the body; these include xanthoma disseminatum, generalized eruptive histiocytosis (GEH), progressive nodular histiocytosis, and multicentric reticulohistiocytosis. Clinical and pathologic correlation are required for differentiating among these 4 disorders. We report a case of a middle-aged man in whom small, scattered, symmetrical lesions on the trunk and proximal extremities developed that, after correlating with biopsy specimen and laboratory results, were best classified as a non-X histiocytosis with features of GEH. GEH is a rare generalized non-X histiocytosis that occurs mainly in adults. It is characterized by multiple, scattered, symmetric lesions on the trunk and proximal extremities that are benign in nature and tend to resolve spontaneously. Recent literature has suggested that GEH may be a part of a continuous spectrum of non-X histiocytic disorders.     

Skin tumor of T accessory cells (interdigitating reticulum cells) with high content of T lymphocytes

A case of T-accessory cell tumor of the skin in a 67-year-old man is reported. The limbs, shoulders, and face were affected, but no visceral involvement is evident 6 years after onset. Tumor cells are nonphagocytic mononuclear cells with folded irregular nuclei. Immunologically, cells were positive for S100 protein, HLA-DR, Ki-M1, Leu 3a (CD4), Leu 6 (CD1); that is, they are identical to the phenotype of Langerhans or interdigitating reticulum cells (IDCs). Birbeck granules were absent. The clinical course appears to be less aggressive than that of the reported IDC sarcomas in other anatomical sites. The similarity of our case to some cases of so-called "non-X histiocytosis" of the skin is discussed. It is suspected that the "non-X histiocytosis of the skin" reported in the literature might have included T-accessory cell tumors, especially those of IDC origin. More immunological studies on the histiocytic disorders of the skin are necessary to clarify their cytogenesis.     

Histiocytic syndromes: a review

Histiocytoses represent a large, puzzling group of rare skin diseases. The purpose of this review is to schematically outline the clinical, histologic, and ultrastructural features of the most important histiocytic syndromes and to provide the pertinent differential diagnoses. For convenience, we have followed the criterion suggested by Winkelmann, distinguishing these conditions into X and non-X. Among the non-X histiocytoses the self-healing forms have been treated first; the progressive forms follow.     

Multiple self-healing indeterminate cell lesions of the skin in an adult

We report a case of multiple cutaneous indeterminate cell proliferative lesions in an adult without any other organ involvement. All lesions regressed spontaneously over 5 years without recurrence over a 4-year period of follow-up. The electron-microscopic and immunohistochemical features of the cellular infiltrate were those of the indeterminate cells. This case supports the hypothesis that indeterminate cell proliferative disorder is a wide spectrum of conditions with variegated clinicopathologic presentation and with different biological behavior.     

Long-lasting "christmas tree rash" in an adolescent: isotopic response of indeterminate cell histiocytosis in pityriasis rosea?

A 13-year-old girl developed a non-pruritic pityriasis rosea-like rash, which did not respond to topical corticosteroids or UV therapy but persisted for 2 years. The lymphohistiocytic infiltrate in the upper dermis showed mononuclear cells immunoreactive with S100, CD68, factor XIIIa and CD1a. Electron microscopic evaluation of these cells demonstrated lamellated dense bodies but no Birbeck granules, lipid vacuoles or cholesterol crystals. Two diagnoses were made: a primarily clinical diagnosis of generalized eruptive histiocytosis and a more cell-biology-based diagnosis of an indeterminate cell histiocytosis. Three years later, the lesions are showing spontaneous resolution, with loss of erythema and flattening. Our patient's indeterminate cells fulfil Rowden's classical definition (dendritically shaped epidermal non-keratinocytes without identifying cytoplasmic features), as well as Zelger's newer definition (cells with features of both macrophages and dendritic cells). A Christmas tree pattern has not been previously described in indeterminate cell histiocytosis. Development of indeterminate cell histiocytosis in the lesions of a healing pityriasis rosea might explain the unusual distribution pattern. The development of a skin disorder at the site of an unrelated, already healed skin disease is known as an isotopic response. Key     

T6 is superior to Ia (HLA-DR) as a marker for Langerhans cells and indeterminate cells in normal epidermis: a monoclonal antibody study

Previous studies in our laboratory using immunoelectron microscopy have shown that anti-T6 monoclonal antibody reacts with all epidermal Langerhans cells in normal skin. Comparison of the number of T6-positive (+) epidermal cells with Ia (HLA-DR) (+) cells, as defined by the monoclonal antibodies, anti-I1 and anti-I2, disclosed that these latter markers significantly underestimated Langerhans cell and indeterminate cell numbers (p less than 0.01 and p less than 0.001, respectively) when employed in a sensitive 4-step immunoperoxidase procedure. Thus, it appears that all epidermal Langerhans cells and indeterminate cells are not Ia-positive as defined in this system and that Ia(+)/T6(+) and Ia(-)/T6(+) subsets exist. These subsets may be analogous to the Ia(+) and IA(-) subsets of macrophages, in which the former are responsible for antigen interaction with T cells.     

Lymphomatoid papulosis expresses immunophenotypes associated with T cell lymphoma but not inflammation

Twelve skin biopsy specimens of lymphomatoid papulosis from nine patients were studied immunohistologically. The large atypical cells morphologically resembled Reed-Sternberg cells in six cases and large cerebriform mononuclear cells in three cases. These cells expressed pan-T cell antigens (Leu-4 and/or Leu-5) and helper T cell antigen (Leu-3) in each case. They also expressed activation antigens: HLA (human lymphocyte antigen)-DR, HLA-DQ, Tac, and T9. Reactivity of many nuclei with Ki-67 indicated a high proliferative index. Phenotypic abnormality of the large atypical cells was evident by their deficiency of T cell antigens Leu-1 and/or Leu-9 in eight of nine cases. Neither Ki-1 nor Leu-M1 were reliable markers for lymphomatoid papulosis in this series, since large atypical cells were Ki-1-positive in only three of eight cases and were Leu-M1-negative in all eight cases tested. The remainder of the cutaneous infiltrate consisted of small T cells, macrophages, Langerhans cells, and granulocytes. The small T cells expressed a normal phenotype except in some cases associated with mycosis fungoides in which they were deficient in various T cell antigens. Comparison of concurrent lymphomatoid papulosis and mycosis fungoides skin biopsy specimens in two patients revealed that they were composed of phenotypically distinct T cell subpopulations. These results indicate that the large atypical cells of lymphomatoid papulosis are a proliferating population of activated helper T cells that are deficient in certain T cell antigens. Such abnormal T cell phenotypes are common in T cell lymphoma but are rarely, if ever, observed in cutaneous inflammation. In conjunction with the cytologic atypia, aneuploidy, and association with other lymphomas documented in this or previous reports, these data suggest that lymphomatoid papulosis represents a T cell lymphoproliferative disorder rather than an inflammatory disorder.     

Acrochordon-like basal cell carcinomas in patients with basal cell nevus syndrome

Basal cell nevus syndrome is an autosomal dominant disorder characterized by multiple basal cell carcinomas, along with numerous other documented clinical features. Acrochordons (or skin tags) are common benign neoplasms that are appropriately left untreated in most patients. We describe two patients with known BCNS who were found to have multiple BCCs that clinically resembled acrochordons. Our findings support the biopsy of acrochordon-like growths in patients with basal cell nevus syndrome to rule out basal cell carcinoma.     

Histiocytic sarcoma with secondary involvement of the skin and expression of CD1a: evidence of indeterminate cell differentiation?

BACKGROUND: Histiocytic sarcoma is an exceedingly rare malignant neoplasm composed of cells with a monocyte/macrophage phenotype. In the current nosology of histiocytic neoplasms, histiocytic sarcoma is separate from indeterminate cell histiocytosis, a generally benign disorder characterized by proliferation of a CD1a+ and S-100+ population of cells lacking Birbeck granules usually limited to the skin. METHODS: We present a case of histiocytic sarcoma in a 64-year-old man presenting as a peritonsillar mass and secondarily involving the skin. RESULTS: The malignant cells in the extracutaneous foci of disease expressed macrophage-associated antigens including S-100 but were CD1a-. The malignant cells in the skin coexpressed CD1a and S-100 but lacked ultrastructural features of Langerhans cells, findings indicative of indeterminate cells. CONCLUSIONS: We discuss the clinical and histopathologic differential diagnosis in association with prior reported cases of histiocytic sarcoma, particularly in cases involving the skin and cases expressing the Langerhans cell-associated antigen CD1a.     

Acquired mucosal indeterminate cell histiocytoma

Indeterminate cell histiocytosis is an exceptional and controversial entity with variable clinical, histopathologic or immunohistochemical findings, sharing morphologic and immunophenotypic features from both Langerhans and non-Langerhans cell histiocytoses. Neoplastic cells express S-100 and CD1a antigens, but lack Birbeck granules. It has been reported in both adults and children, as solitary or multiple cutaneous lesions with rare extracutaneous involvement. We describe a 12-year-old boy with an indeterminate cell histiocytosis manifesting as a solitary verrucous papule on the mucosa of the glans penis. The morphologic features and diagnostic criteria of cutaneous indeterminate cell histiocytic proliferations are reviewed. The possible relationship between indeterminate cell and Langerhans cell histiocytoses is discussed.     

Ia antigens on indeterminate cells of the epidermis: immunoelectronmicroscpic studies of surface antigens

An antiserum against human B-lymphoblastoid cell membrane alloantigens (Ia-like antigens) was used to study the presence of such antigens on dendritic cells in human epidermis. Only Langerhans cells and the majority (85%) of so-called indeterminate cells were positively stained, as shown by immuno-electron microscopy. Fifteen percent of the indeterminate cells were negative and were considered to be immature melanocytes. A relationship exists between the indeterminate cell and the Langerhans cell. A proposal is made concerning emigration of Langerhans cells in response to haptenic stimulation, and the immigration of indeterminate cells to restore the status quo.     

Post-scabetic nodules: a lymphohistiocytic reaction rich in indeterminate cells

We studied six infants and two adult cases of nodular scabies with immunostains and electron microscopy. All eight cases have had either direct (KOH) or family histories of scabies and were treated with lindane 1% cream or permethrin 5% cream. Family members responded very well, but our patients developed multiple papulo-nodular lesions which were initially very pruritic and, in some cases, persisted from several months to over one year. H & E stain of biopsied tissue sections revealed a heavy perivascular and periappendageal lymphohistiocytic cell infiltration. Immunophenotype of these cells was compatible with Langerhans cells, i.e. CD1A (+), S-100 (+) and HLA-DR (+). Electron microscopy showed that these histiocytic cells satisfied all the ultrastructural criteria of Langerhans cells except for the absence of Birbeck's granules. Lag, a monoclonal antibody for Birbeck's granules, was negative. "Persistent nodules in scabies" or "nodular scabies" seems to represent a prolonged response of indeterminate cells-lymphocytes to mite antigens.     

Benign Cephalic Histiocytosis: Report of Four Cases

We cared for four patients with benign cephalic histiocytosis, a self-healing non-X, nonlipid cutaneous histiocytosis of children. The age of onset of the disease was 5 to 9 months, with papules and erythematous macules involving the head (mainly the cheeks), and posterior spread to the trunk and limbs in three patients. Microscopic examination of skin biopsies revealed a histiocytic infiltrate in the superficial dermis that was S100 protein-negative by immunoperoxidase (PAP method). One patient showed comma-shaped bodies and desmosomelike junctions on electron microscopy. No Birbeck's granules were present. Benign cephalic histiocytosis is a self-limiting condition that requires no treatment.     

Malignant Langerhans cell tumour

We report the case of a 49-year-old woman suffering from a malignant neoplasm of Langerhans cells (LC), documented by immunohistochemical and ultrastructural analysis, and review the literature to examine and characterize the clinical and laboratory features, therapy, and prognosis of malignant neoplasms of LC. Langerhans cell histiocytosis is now regarded as a disorder of immune regulation or an inflammatory process, rather than as a malignant neoplasm. Although LC share certain features in common with ordinary histiocytes or interdigitating dendritic cells, they also differ significantly from these cells in other respects. Therefore, we propose designating a malignant neoplasm of LC 'malignant Langerhans cell tumour' and that it should be considered as a separate entity from Langerhans cell histiocytosis or other malignant histiocytoses.