Tammie Ferringer

Granuloma annulare

Granuloma annulare typically involves the upper- to mid-reticular dermis. The mucin in palisading lesions is usually apparent with routine staining as faint feathery blue material; however, colloidal iron or other mucin stains can be used for confirmation. Sparse multinucleate histiocytes are typically identified and eosinophils occur in approximately half of cases. Rarely, perforation of the process through the epidermis (transepidermal elimination) occurs.

The subcutaneous tissue can be involved. Subcutaneous or deep granuloma annulare typically consists of histiocytes palisading around fibrin rather than mucin. It may be indistinguishable from rheumatoid nodule, resulting in its designation as pseudorheumatoid nodule. This subtype of granuloma annulare typically occurs on the lower legs, hands, head, and buttock in young individuals without rheumatoid disease.

The microscopic differential diagnosis of granuloma annulare and other palisading granulomas includes epithelioid sarcoma. Clues to this malignant neoplasm include necrosis and mild cytologic atypia. Epithelioid sarcoma demonstrates a biphasic pattern with transition between epithelioid and spindle cells. Cells stain for both keratin and vimentin.

Table 10.1 shows distinctions between granuloma annulare and necrobiosis lipoidica.

Actinic granuloma

These lesions occur on areas of chronic sun damage such as the face, neck, hands, and arms. They have a raised border and atrophic finely wrinkled center. The granulomas consume actinically damaged elastic tissue. Other names have included Miescher’s facial granuloma, atypical necrobiosis lipoidica of the face and scalp, and annular elastolytic giant cell granuloma. Some consider it to be a variant of granuloma annulare on sun-damaged skin. The central loss of elastic tissue, absence of mucin, and conspicuous multinucleated histiocytes are the primary basis for distinguishing these lesions.

Necrobiosis lipoidica

A large proportion of patients with necrobiosis lipoidica have diabetes, thus the original name necrobiosis lipoidica diabeticorum. However, fewer than 1% of patients with diabetes have necrobiosis lipoidica. The pretibial area is the most common site but other areas of the lower extremities, arms, hands, and trunk can rarely be involved.

Necrobiosis lipoidica is considered a palisading granulomatous dermatitis. The palisade is horizontally arranged in tiers like the layers of lasagna. The full thickness of the dermis and often the subcutis is involved.

The term “necrobiosis” refers to alteration of dermal connective tissue with loss of definition, pale staining, and absence of nuclei.

Rheumatoid nodule

The histology mimics subcutaneous granuloma annulare and rheumatic fever nodules. Rarely similar nodules occur in systemic lupus erythematosus.

Lupus miliaris disseminatus faciei (LMDF: acne agminata)

Despite its histologic resemblance to miliary tuberculosis, LMDF is a variant of rosacea. LMDF can be distinguished from miliary tuberculosis by the absence of acid-fast bacilli.

Caseation has a dull, pale pink amorphous appearance, unlike the deeply staining fibrin of a rheumatoid nodule.

Sarcoidosis

Cutaneous lesions are present in up to one-quarter of patients with systemic sarcoidosis, but cutaneous lesions can occur in the absence of systemic disease in one-quarter of patients.

Asteroid bodies and Schaumann bodies can be found in sarcoidosis but are not specific and have been observed in other granulomas such as tuberculosis, leprosy, and berylliosis. An eosinophilic star-burst inclusion within a giant cell is an asteroid body. Schaumann bodies are cytoplasmic, laminated calcifications.

Sarcoidosis is a diagnosis of exclusion requiring clinicopathologic correlation. Infectious etiologies, including acid-fast bacilli and fungi, should be sought with special stains. The granulomas should be polarized to rule out foreign body. However, the presence of small crystalline refractile silica material does not exclude the possibility of sarcoidosis. In fact, silica granulomas may be the earliest manifestation of sarcoidosis (“scar sarcoid”).

Necrobiotic xanthogranuloma

If the layered appearance of necrobiosis lipoidica is likened to strips of bacon, then the appearance of necrobiotic xanthogranuloma resembles “pepper bacon” or “dirty cholesterol-laden bacon,” with karyorrhectic debris making up the “pepper” or “dirt.” The differentiation from necrobiosis lipoidica can be made clinically by the periorbital predominance and associated immunoglobulin (Ig) G (usually kappa) paraproteinemia in necrobiotic xanthogranuloma. Necrobiotic xanthogranuloma is more cellular, has a greater proportion of foamy histiocytes, and contains more giant cells than necrobiosis lipoidica.

Touton giant cells have a ring of nuclei and a peripheral rim of foamy cytoplasm. Touton giant cells are also common in juvenile xanthogranuloma, dermatofibroma, and necrobiotic xanthogranuloma.

Xanthogranuloma

Xanthogranulomas can be seen at any age but are most common in children, giving rise to the name juvenile xanthogranulomas.

Early xanthogranulomas are clinically red and consist of numerous histiocytes with abundant cytoplasm, giving the impression of a sea of lavender histologically. Over time, the histiocytes become lipidized and the lesion clinically becomes yellow-orange. At this point, Touton giant cells, with a wreath of nuclei surrounded by foamy cytoplasm, are identified. Regressing lesions show a proliferation of fibroblasts and fibrosis. In contrast to those in dermatofibromas, the Touton giant cells in xanthogranulomas never contain hemosiderin.

In children with multiple xanthogranulomas, an eye exam should be considered as ocular involvement can result in glaucoma or anterior-chamber hemorrhage. Visceral xanthogranulomas with pericarditis have been reported. An association between xanthogranuloma, neurofibromatosis I, and juvenile chronic myelogenous leukemia has been identified.

Reticulohistiocytic granuloma (solitary reticulohistiocytoma)

Multinucleate cells typically have irregularly arranged vesicular nuclei containing prominent nucleoli. There are admixed lymphocytes and lesser numbers of eosinophils and neutrophils. Older lesions are less inflammatory and reveal cells with artifactual halos around them due to retraction.

Lesions can be solitary or multiple. When multiple they may be associated with systemic findings. Multicentric reticulohistiocytosis consists of multiple lesions with deforming arthritis, coral beading around the nail folds, and an associated internal malignancy in 10% of cases.

Rosai–Dorfman disease (sinus histiocytosis with massive lymphadenopathy)

Rosai–Dorfman disease typically occurs in the first two decades of life as painless cervical adenopathy and fever. There is extranodal involvement in one-third of cases. Skin lesions are found in approximately 10% with a predilection for the eyelids and the malar area. Occasionally, the skin is the only site of involvement. Emperipolesis is a phenomenon where lymphocytes and plasma cells pass through histiocytes, but are not found within phagolysosomes.

Langerhans cell histiocytosis (histiocytosis X)

The infiltrate can be a perivascular, band-like, or periappendageal pattern. Variable eosinophils, lymphocytes, and sparse neutrophils accompany the characteristic large cells with lobulated, notched, or grooved nuclei that resemble kidney beans. Due to the edema, these cells appear to be “floating in the sea.” Acute Langerhans cell histiocytosis is described in further detail in Chapter 15.

In the past, Langerhans cell histiocytosis was subclassified into Letterer–Siwe disease, Hand–Schüller–Christian disease, or eosinophilic granuloma, based on the clinical findings. Eosinophilic granuloma is typically localized to one site, such as bone or skin, whereas the other two affect several organ systems. Hand–Schüller–Christian disease is typically associated with the triad of diabetes insipidus, exophthalmos, and lytic bone lesions. Letterer–Siwe disease is more disseminated and involves multiple organs. As many patients do not clearly fit into these categories, the prognosis is currently based on the patient’s age, number of organs involved, and the degree of organ dysfunction. Children are most commonly affected but adult cases have been observed. The scalp, ears, and intertriginous areas are preferred cutaneous sites.

Similar to Langerhans cells of normal skin, Birbeck granules, with the appearance of a tennis racket, are pathognomonic ultrastructural markers.

Congenital self-healing “reticulohistiocytosis” is a form of Langerhans cell histiocytosis that generally presents with one or several cutaneous nodules, at or shortly after birth, and resolves spontaneously.

Xanthomas

Xanthomas represent the accumulation of lipid in histiocytes, known as foam cells or xanthoma cells. Xanthomas can be subdivided by clinical morphology, anatomic location, and mode of development into: tuberous, tendinous, eruptive, planar, and verruciform. Many are associated with inherited or acquired disorders of lipoprotein metabolism but normolipemic planar xanthoma is related to plasma cell dyscrasia.

Planar xanthomas are further subdivided on the basis of their location into xanthelasma, intertriginous xanthomas, xanthoma striatum palmaris, and diffuse (generalized) plane xanthomas.

Intertriginous xanthomas are pathognomonic of homozygous familial hypercholesterolemia. Xanthoma striatum palmaris is characteristic of familial dysbetalipoproteinemia (type III) and, as the name describes, are identified in the palmar creases. The great majority of patients with diffuse plane xanthomas are normolipemic, and there is an association with IgG paraproteinemia and progression to myeloma.

Further reading