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Hisiocytosis X
(Langerhans Histiocytosis)
Histiocytosis X has remained a process of uncertain nature; the possibilities include both reaction and neoplasm. While it is possible to marshal some evidence favoring a notion
that the process is neoplastic, the exact nature has remained controversial.
The name, histiocytosis X, generally is attributed to Lichenstein; it is a generic compromise in which concessions are made by the simple assignment of the “X.” It was anticipated
that, with time, a proper characterization of the nature of the process would also prompt an assignment of a more appropriate designation. Molecular patholologists and immunopathologists, being impressed with their
ability to identify cell markers and experiencing some degree of historical confusion, have presumptuously discarded the “X.” They have inappropriately credited Langerhans, not because of any aggreement that
Langerhans might have had an understanding of the disease (which in fact was nil), but simply because they had identified a cell sharing cell markers with the cells of histiocytosis X. The scientists had a cell line
and a battery of immunoreactions, but no disease; by attributing significance to Langerhans’s observations and by ignoring the contributions of Lichenstein, they managed to find a disease for their cell markers.
They assumed that, by making this incorrect historical attribution, the assignment would be legitimized; the “X” could be discarded.
The cells of histiocytosis X harbor the antigens, S-100 protein and CD1a. Great emphasis is placed on the demonstration of these antigens in the diagnosis of histiocytosis X. On the
other hand, these two antigens can be demonstrated in a population of histiocytic cells outside the clinical and histologic setting of histiocytosis X. Birbeck granules are cited as the prime requisite for diagnosis
but, in practice, a characteristic infiltrate in a characteristic clinical setting is sufficient for a definitive diagnosis; Birbeck granules are not a unique attribute of the cells of histiocytosis X.
The cells of histiocytosis X are rounded; they have pale cytoplasm with an eccentric nucleus. The nuclear configurations generally provide an important clue; the nuclei of many of
the cells are deeply indented. The nuclear characteristics are not diagnostic; similar nuclei may be encountered in some examples of juvenile xanthogranuloma.
Chromatin patterns are variable in the cells of the infiltrate of histiocytosis X; they often are delicate. In rare cases, the nuclei vary in size and outline, and chromatin is
dense. Lesions with such cells in the infiltrates qualify as atypical histiocytosis X. Such lesions may behave in the pattern of a malignant tumor and be associated with regional node involvement. On the other hand,
nodal involvement, in itself, is not evidence of a variant that is biologically more aggressive. Solitary bone lesions (eosinophilic granulomas of bone) may be associated with nodal involvement and the association is of no prognostic significance.
In the evaluation of the biologic significance of a lesion of histiocytosis X, the observation that a lesion may regress spontaneously, or may regress after a biopsy is an obstacle,
particularly for observers who promote the notion that the process is neoplastic. In providing prognostications, clinical staging and age of onset are cited as important factors.
The classic categories of histiocytosis X include: 1.) chronic localized disease (eosinophilic granuloma), 2.) chronic disseminated disease (a category which, if associated with
certain clinical and radiologic findings, would embrace the concept of Hand-Shuller-Christian disease), and 3.) acute disseminated disease (corresponding to the older definition of Letterer-Siwe disease; some
observers have been hesitant to accept Letterer-Siwe disease as a variant).
Eosinophils are commonly a feature of the infiltrates of histiocytosis X, but are not a requisite for the diagnosis. Some lesions, particularly those of bone, may be associated with
prominent lymphoplasmacytic infiltrates. Neutrophils may also be a feature of the infiltrates.
Localized infiltrates, which satisfy the criteria for the diagnosis of histiocytosis X, may be encountered in the stroma of neoplasms (i.e., thyroid carcinoma), or in lymph nodes
draining the site of a malignant neoplasm. Subpleural bullous emphysematous lesions of the lung may be associated with infiltrates of histiocytic cells which resemble those of histiocytosis X.
Histiocytosis X is properly characterized as a borderline process.
Congenital regressing histiocytosis is a rare skin disease characterized by infiltrates that are cytologically similar to those of histiocytosis X. Nuclear characteristics are bland.
The lesions of histiocytosis X in the skin often are band-like in the upper portion of the dermis; some of the cells may be found in the epidermis. In congenital regressing
histiocytosis, the infiltrates tend to be perivenular in distribution and nodules may be found in the dermis, but away from the dermal-epidermal interface. Often, the lesions of congenital regressing histiocytosis
have an inflammatory quality and may be covered by an inflammatory crust. The clinical presentation
and the onset of disease in infancy are features which should alert the clinician to the possibility that the process is something other than classic histiocytosis X.
The role of the histiocyte in neoplasia has been controversial. For years, many large cell lymphomas were characterized as histiocytic lymphomas (this was a morphologic convenience;
many plump, round cells were characterized as histiocytes prior to the availability of cell markers). To compensate for the loss of this morphologic convenience, the designation, “histiocytoid,” has been
popularized. The “malignant fibrous histiocytoma” is a good example of the confusion surrounding a definition, in the absence of cell markers, of a neoplastic histiocyte. This characterization was also a
compromise. By promoting the concept, much service was paid to the needs of oncologists but, from a different perspective, a generation, or more, of pathlogists simply failed to develop an appreciation for the
morphologic features of pleomorphic soft tissue tumors, such as pleomorphic rhabdomyosarcomas and dedifferentiated liposarcomas.
In the 1970’s, two pathologists, who were recognized as experts in bone pathology, reviewed sections of a lesion which I had classified as malignant fibrous histiocytoma. Both
recorded
that they were not familiar with such a lesion in bone. It seems that now malignant fibrous histiocytoma of bone is more common than osteosarcoma. It is now the popular thing to diagnose a lesion of bone as a malignant fibrous histiocytoma. Our diagnoses often become a response to fads. Much of the controversy surrounding the concept of fibrous histiocytoma relates to a definition of the histiocyte as a facultative fibroblast ( a definition based on unwarranted extensions of weak observations). The category of fibrohistiocytic lesions finds untility in regard to relationships between fibroblastic cells (including myofibroblastic variants) and dendritic histiocytes (“reticular cells”). In the latter approach, the nature of the categories and of the relationships between histiocytes and fibroblasts have been modified.
One additional example of a borderline histiocytic process has been included in this section, namely sinus histiocytosis X with massive lymphadenopathy. Azoury and Reed described a
case from Charity Hospital of New Orleans as an unusual form of histiocytosis. In this report, the lesion in the lymph node was characterized as a “sinus histiocytosis;” this approach was based on Robb-Smith’s
efforts to relate zonal distribution of primary lesions of lymph nodes to a classification of the respective disorders. Rosai and Dorfman, in a study of collected cases, defined the nature of the process. The
histiocyte of sinus histiocytosis harbors the antigen, S-100 protein, as do some of the dendritic histiocytes of a normal lymph node, particularly those of the paracortical zone (T cell domain). The histiocytes of
sinus histiocytosis with massive lymphadenopathy apparently do not harbor the antigen, CD1a.
Sinus histiocytosis (Rosai & Dorfman) may involve the skin and subcutaneous fat. In the skin, a portion of the infiltrates of Rosai-Dorfman disease presents a non-specific
pattern with lymphoid cells, plasma cells, and a variable admixture of neutrophils. The large, pale histiocytes are distinctive, particularly when clustered. They have round, plump nuclei with marginated
chromatin and a central, large
nucleolus. Lymphoid cells and neutrophils may be found in the cytoplasm of such cells. Some of the intracytoplasmic cells are outlined by a clear space. Lesions of sinus histiocytosis with massive lymphadenopathy are variable in distribution; apparently, any organ system can be involved.
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