Necrobiotic Xanthogranuloma

Lethal Non-Langerhans Cell Histiocytoses: Necrobiotic Xanthogranuloma and Xanthoma Disseminatum

Synonyms:

NXG—Necrobiotic xanthogranuloma with

paraproteinemia

XD—Montgomery's syndrome

Etiology:

NXG—Unknown

XD—Unknown

Associations:

NXG—Myeloma, Grave's disease, primary biliary

cirrhosis, paraproteins

XD—Myeloma, Waldenstrom's macroglobulinemia,

paraproteins

Clinical:

NXG—Ulcerating red-orange plaques, particularly of the

periorbital area

XD—Disseminated red brown papules into plaques

Histology:

NXG—Palisading granulomatous dermatitis with bizarre

giant cells

XD—Diffuse epithelioid histiocytes, foam cells, and

siderosis

IHC repertoire:

NXG—CD-68(+), S-100(-), CD-1(-)

XD—CD-68(+), S-100(-),CD-1(-)

Staging:

NXG—None

XD—None

Prognosis:

NXG—Overall 5% 5-year mortality

XD—Overall 2% 5-year mortality

Adverse variables:

NXG—Cases associated with myeloma

XD—Cases associated with myeloma and Waldenstrom's

Treatment:

NXG—Corticosteroids, alkylating agents

XD—Corticosteroids

The histiocytic disorders encompass a broad range of malignant and nonmalignant entities capable of presenting in a variety of clinical and pathologic guises. The histiocytic disorders are generally classified by the cell of the origin, and specifically as bone marrow tissue-derived monocytes that migrate secondarily to the skin serving as either phagocytic macrophages or antigen-presenting dendritic or Langerhans cells. Langerhans cells typically reside closely to the epithelium and traffic to the lymph nodes. They are important in immunologic surveillance and are defined by the presence of Birbeck granules on ultrastructural examination, as well as S-100 and CD-1a immunopositivity. This discussion will focus upon the entities comprised of the phagocytic non-Langerhans cell macrophages and specifically the disorders within this category capable of producing or being associated with significant morbidity or mortality.

The two most important entities associated with serious systemic disorder including hematopoetic malignancy are necrobiotic xanthogranuloma (NXG) and xanthoma disseminatum (XD). Despite a marked difference in their clinical and histologic appearance, both share a common histogenesis, an association with abnormal amounts or types of circulating immunoglobulins (paraproteins) and hematopoetic malignancies including multiple myeloma.

Necrobiotic Xanthogranuloma

This rare non-Langerhans cell histiocytosis was first described in 1980 by Winkelman and Kossard, who correctly surmised its association with paraproteinemia and risk for development of multiple myeloma (1). Since its initial description, over 60 cases have been described with nearly all patients presenting as adults. There is no gender or ethnic predisposition (2). The etiology of the disorder is unknown but various theories regarding its development have been proposed, including abnormal immunoglobulin or lipid storage leading to the formation of xanthomatous histiocytic cells and faulty phagocytic mechanisms leading to the characteristic clinical and pathologic findings. Each of the theories, however, fails to wholly account for its rarity, associated laboratory findings, or peculiar anatomic predisposition.

NXG is associated with a variety of unrelated disorders including, most importantly, multiple myeloma (10% of patients), Hodgkin's disease, arthropathy, hypertension, neuropathy, primary biliary cirrhosis, and Grave's disease (3).

The clinical findings consist of firm red-orange to violaceous papules that typically enlarge into plaques, finally undergoing central atrophy and ulceration. The plaques may attain dimensions of greater than 25 cm and can be solitary or multiple. The lesions typically develop on the head and neck area, particularly the periorbital region (Figure 20.1). Lesions have been described on the trunk and extremities. Involvement in the oral mucosa has also been reported. The lesions themselves are typically asymptomatic although an antecedent pruritic and/or burning sensation has been documented. Other physical findings include hepato-splenomegaly, which has been documented in approximately 20% of patients. Although the skin is the principal organ involved, the eye, lungs, heart, and CNS may be afflicted.

The histopathologic features are distinctive and consist of a deep dermal and subcutaneous fat granulomatous inflammation with intervening zones of collagen degeneration, lymphoid follicles, and foam cells (Figure 20.2) (4). The granulomas take the form of palisading mono-and multinucleate giant cells with the latter often assuming irregular silhouettes and containing increased numbers of atypical nuclei as well as epithelioid granulomas, Touton-type wreath-like giant cells, and foreign body-type giant cells (Figures 20.3 and 20.4). The degenerated collagen foci often contain zones of cholesterol clefting (Figure 20.5). The histiocytes of NXG immuno-stain with CD-68, CD-15 and are negative with S-100 and CD-1a.

Necrobiotic XanthogranulomaNxg Pathology
Figure 20.2. Low power photomicrograph depicting deep dermal palisading granuloma.

The most important diagnoses to consider in the histologic differential diagnosis are necrobiosis lipoidica, granuloma annulare, and rheumatoid nodule. Although each of the foregoing show palisading granulomatous foci, the collagen degeneration seen in NXG is more extensive, often extending deep into the panniculus, and is associated with cholesterol clefting.

Laboratory findings include paraproteinemia, found in approximately 90% of patients (usually IgG with mostly kappa or occasionally lambda light chains), cryoglobulins (~40% of cases), decreased complements, hyper/hypolip-idemia, neutropenia, and elevated erythrocyte sedimentation rate. Bone marrow biopsy often yields increased numbers of atypical plasma cells.

Necrobiotic Cell
Figure 20.3. Medium power photomicrograph depicting central necrobiotic material replete with cholesterol clefts and peripheral palisade of granulomatous inflammation.
Deep Clefts Lymphocytes

Figure 20.4. Medium power photomicrograph depicting nodular aggregates of lymphocytes with interspersed giant cells.

Figure 20.4. Medium power photomicrograph depicting nodular aggregates of lymphocytes with interspersed giant cells.

Photomicrograph

The course of NXG is usually chronic with episodic lesional development followed by healing and remission. Important complications involve its proximity to the eye and include conjunctivitis, keratitis, scleritis uveitis, cornel ulceration, and exceptionally, blindness. The development of multiple myeloma is particularly ominous and may present prior to, concomitant with, or following the diagnosis of NXG. The overall 5-year mortality of multiple myeloma is 40%.

The treatment consists of corticosteroids and low-dose alkylating agents such as chlorambucil and melphalan.

Figure 20.5. High power detail of lymphoid aggregates. Note central giant cell.

Figure 20.5. High power detail of lymphoid aggregates. Note central giant cell.

Xanthoma Disseminatum

Temporary remission has also been reported with radiation therapy and plasmapheresis.

Xanthoma Disseminatum

This uncommon systemic non-Langerhans cell histiocytosis was first described by Montgomery and Osterberg in 1938. Since its initial description, over 100 cases have been described. The disorder is slightly more common among males and most patients described with this condition have been children (5). There is no ethnic predisposition. The etiology and pathogenesis of this disorder is unknown. Like NXG, it is associated with multiple myeloma, Waldenstrom's macroglobulinemia, and paraproteinemia (6,7). Notably, each of these disorders is typically exceptional among children.

The clinical findings consist of disseminated red-brown papules that have a tendency to become yellow and coalesce, forming plaques. Similar lesions are often found in approximately 50% of patients involving the mucous membranes of the mouth, pharynx, conjuctiva, and cornea. Lesions of the pharynx and larynx may produce symptoms of dysphagia, and an altered voice. Diabetes insipidus secondary to involvement of the hypothalamus and vasopressin deficiency is observed in approximately 50% of patients.

The histologic features of well-developed lesions are suggestive of the disorder and consist of diffuse dermal aggregates of foam cells with interspersed Touton-type wreath giant cells (8). Early lesions usually show an admixture of characteristically scalloped histiocytes with acute and chronic inflammatory cells. Extension into the subcutaneous fat or epidermal ulceration is exceptional. The lesional cells are CD-68 (+), S-100(-), CD-1a (-).

Laboratory findings usually show normal lipid levels. Serum vasopressin levels are typically depressed. The overall prognosis is favorable with the exception of those patients who develop hematopoetic malignancy. The dermatologie manifestations may pursue three clinical courses: spontaneous resolution; remain persistent; or rarely, progress. Important complications include diabetes insipidus and obstructive upper aerodigestive tract disease. Treatment consists of symptomatic removal of mucosal lesions and vasopressin administration in cases complicated by diabetes insipidus. The cutaneous lesions do not usually respond to topical or systemic medication.

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