Granulomatous and histiocytic diseases

Tammie Ferringer

Granulomas are discrete collections of histiocytes with or without multinucleate giant cells. Histiocytes are bone marrow-derived or mesenchymal. In granulomas, their cytoplasmic membranes touch with no intervening connective tissue. Infectious etiologies, especially fungal and mycobacterial, should be excluded with special stains in any granulomatous process without obvious etiology. Examination under polarized light is required to exclude birefringent foreign material.

Granulomas can be categorized into: sarcoidal, tuberculoid, palisading, and suppurative. Sarcoidal granulomas, composed of epithelioid histiocytes, are “naked” granulomas with a paucity of surrounding infiltrate. Tuberculoid granulomas are associated with a peripheral mononuclear infiltrate and may show central caseous necrosis. Palisading granulomas surround devitalized collagen (necrobiosis), mucin, or foreign material. Suppurative granulomas have a central collection of neutrophils (stellate abscess).

Granuloma annulare

Key features

Interstitial pattern

• Patchy interstitial histiocytes, lymphocytes, and mucin give the appearance of a “busy dermis” at low power

Palisading pattern

• Histiocytes surround altered dermal collagen and mucin

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.

Table 10-1

Features of granuloma annulare and necrobiosis lipoidica

Feature	Granuloma annulare	Necrobiosis lipoidica
Distribution	Focal and patchy	Diffuse and full-thickness
Granuloma	Palisaded or interstitial	Horizontal tiers (layers)
Mucin	Yes	No
Shape of punch biopsy	Tapered	Rectangular
Plasma cells	Rare	Common
Cholesterol clefts	No	Occasional

Fig 10-1 Interstitial granuloma annulare

Fig 10-2 Interstitial granuloma annulare

Fig 10-3 Interstitial granuloma annulare (colloidal iron)

Fig 10-4 Palisading granuloma annulare

Fig 10-5 Palisading granuloma annulare

Differential Diagnosis

The microscopic differential for a “busy dermis” includes:

• Blue nevus

• Dermatofibroma

• Dermal Spitz nevus

• Metastatic breast carcinoma

• Kaposi’s sarcoma (patch stage)

• Granuloma annulare

• Scleromyxedema

• Neurofibroma

Actinic granuloma

Key features

• Solar elastosis

• Elastic fibers are engulfed by palisading giant cells and histocytes (elastolysis)

• Central loss of elastic tissue

Fig 10-6 Actinic granuloma

Fig 10-7 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

Key features

• Horizontal acellular, pale, degenerated collagen between layers of granuloma

• Top-to-bottom and side-to-side involvement

• Plasma cells common in the deep dermis

• No mucin

• Rectangular punch due to sclerosis

• May see cholesterol clefts or lymphoid nodules

• Very early lesions can resemble interstitial granuloma annulare

Fig 10-8 Necrobiosis lipoidica

Fig 10-9 Necrobiosis lipoidica (medium-power)

Fig 10-10 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.