Chapter 19 Panniculitis
1. What is panniculitis?
Panniculitis represents infiltration of subcutaneous tissue by inflammatory cells, neoplastic cells, or both. This condition presents clinically as a deep induration or swelling of the skin. Associated signs and symptoms may include erythema, ulceration, drainage, warmth, and pain. Under certain circumstances, induration or nodularity may be present without significant inflammation or may persist after the inflammation has largely subsided.
2. Name the various types of panniculitis. How are they classified?
Although no single classification seems to be totally satisfactory, disorders tend to be grouped by a combination of histopathologic features and etiologies (Table 19-1). Septal panniculitis refers to a predominance of inflammation involving the connective tissue septae between fat lobules, whereas lobular panniculitis indicates predominant involvement of the fat lobules themselves. Lipodystrophy and lipoatrophy may be end-stage changes of the fat brought about by several different etiologies, including inflammation, trauma, or metabolic or hormonal alterations.
3. What is erythema nodosum?
Traumatic Panniculitis
Infectious Panniculitis
Malignancy
Other Changes of the Fat
Lipodystrophy
Lipoatrophy
Lipohypertrophy
Erythema nodosum (Fig. 19-1) consists of an eruption of erythematous, tender nodules—typically over the pretibial areas but occasionally elsewhere—that is regarded as a hypersensitivity response to some antigenic challenge. It is typically an acute process lasting 3 to 6 weeks, but a more chronic form can occur. Some experts consider the condition termed subacute nodular migratory panniculitis (Vilanova’s disease) to be a chronic variant of erythema nodosum.
Table 19-1. Major Forms of Panniculitis
| Septal Panniculitis
Lobular and Mixed Panniculitis Metabolic Derangements |
Infectious Panniculitis
Malignancy
Other Changes of the Fat
Lipodystrophy
Lipoatrophy
Lipohypertrophy
4. What is the pathogenesis of erythema nodosum?
Erythema nodosum is usually considered to represent a delayed hypersensitivity response that reflects a common reaction pattern to a wide variety of eliciting factors. The subcutaneous septa in well-developed lesions often contain granulomas, and recent work has shown a strong correlation between genetic polymorphisms of tumor necrosis factor–α and erythema nodosum (TNF-α promotes granuloma formation). Reactive oxygen intermediates may be involved in the tissue damage and inflammation that accompany erythema nodosum.
5. List some of the common underlying conditions associated with erythema nodosum.
Streptococcal infection of the upper respiratory tract and medications (especially oral contraceptives, sulfonamides, penicillins, bromides, and iodides) are among the most common known causes. Other triggers include deep fungal infections (such as coccidioidomycosis), Yersinia infection, pregnancy, sarcoidosis, inflammatory bowel disease, and leukemia. Many episodes are idiopathic: A cause is not identified in one third to one half of cases.
6. How should a biopsy of erythema nodosum be obtained?
The specimen should be obtained from the most fully developed (central) portion of the lesion (Fig. 19-2). It is absolutely critical that the biopsy be deep enough to incorporate subcutaneous fat. Incisional biopsies that include a generous horizontal expanse of subcutis are preferred to small punch biopsies.
7. What are the characteristic microscopic features of erythema nodosum?
The typical histologic features include a predominantly septal panniculitis with a slight spillover of inflammatory cells into the fat lobules. Cell types may include lymphocytes, neutrophils, and eosinophils, especially in acute disease. In older lesions, small granulomas (Miescher’s granulomas) are sometimes observed within connective tissue septa. Perivascular infiltrates are common, but true vasculitis with destruction of vessel walls is not observed.
8. How is erythema nodosum treated?
Treatment of the underlying disorder, if known, is of primary importance. Salicylates or nonsteroidal antiinflammatory drugs, bed rest, and potassium iodide (particularly in chronic forms of the disease) are usually considered to be first-line therapies while colchicine, dapsone, hydroxychloroquine, and prednisone are second-line therapies used in recalcitrant cases.
9. What is nodular vasculitis?
This form of panniculitis most commonly occurs on the posterior lower legs (Fig. 19-3), as opposed to the classically anterior location of erythema nodosum. Ulceration and drainage sometimes occur.
10. What causes nodular vasculitis?
It was originally considered a hypersensitivity reaction to tuberculosis and termed erythema induratum of Bazin. Studies confirm that in many cases Mycobacterium tuberculosis DNA can be detected in the lesions by polymerase chain reaction (PCR); however, nodular vasculitis can also be idiopathic or associated with other infectious agents (Nocardia, hepatitis C) or drugs (propylthiouracil). These cases with nontuberculous etiologies are sometimes termed erythema induratum of Whitfield.
Figure 19-3. Erythema induratum demonstrating characteristic indurated subcutaneous nodules. Spontaneous ulceration is common.
(Courtesy of James E. Fitzpatrick, MD.)
Key Points: Panniculitis
1. Given the similar clinical appearance among panniculitides, histopathologic characterization is often critical for a correct diagnosis.
2. An incisional biopsy with a wide base in the fat is far more likely to be diagnostic than a deep shave or punch biopsy.
Key Points: Erythema Nodosum
3. Erythema nodosum can occur at any age and can be located at any site on the body; classically, however, it is a disease most frequently found in women in their 20s to 40s and is mainly located on the anterior shins.
Key Points: Lupus Panniculitis
1. Lupus panniculitis can be associated with systemic lupus erythematosus (SLE) in about 10% of cases and can occur before other systemic manifestations of SLE are clinically apparent. It is more commonly associated with discoid lupus erythematosus (30% to 33% of cases).
11. Describe the microscopic features of nodular vasculitis.
Nodular vasculitis presents as a lobular panniculitis with a mixed infiltrate that may be granulomatous. Vasculitis of a medium-sized artery or vein is present deep in the fat. Caseous necrosis is present in up to 50% of cases. Although necrosis can occur in cases not associated with tuberculosis, it may be more common in lesions that are positive for Mycobacterium tuberculosis–complex DNA.
12. What is the differential diagnosis of nodular vasculitis?
Clinical clues to an association with tuberculosis include constitutional symptoms, elevated erythrocyte sedimentation rate, an abnormal chest x-ray, or a positive tuberculin skin test. Both polyarteritis nodosa and superficial thrombophlebitis also show vasculitis involving medium-sized vessels in the subcutis. In both conditions, the inflammation is more specifically directed toward the vessel, and extensive lobular inflammation obscuring the vessel changes is uncommon. The clinical findings are also quite different in these two disorders (e.g., hypertension, renal, and central nervous system disease in systemic polyarteritis; association with internal malignancy in superficial migratory thrombophlebitis). In one author’s experience (JWP), true examples of nodular vasculitis are seldom seen, but this might change with the recent rise in number of cases of tuberculosis associated with human immunodeficiency virus.
13. How should nodular vasculitis be treated?
Treatment should be directed toward any underlying infection, especially tuberculosis. Studies have demonstrated the responsiveness of mycobacteria-associated lesions to multidrug antituberculous therapy. Symptomatic care includes bed rest, bandages, antiinflammatory agents, and avoidance of potential aggravating factors such as smoking. In more severe non-tuberculous cases, potassium iodide, dapsone, colchicine, antimalarials, tetracyclines, and prednisone can be used.
Mascaró JM Jr, Baselga E: Erythema induratum of Bazin, Dermatol Clin 26:439–445, 2008.
14. What are the clinical features of lupus panniculitis?
Lupus panniculitis, also termed lupus profundus, consists of erythematous or flesh-colored subcutaneous nodules. The lesions occur on the face, upper outer arms, shoulders, and trunk, including the breasts. They sometimes show overlying follicular plugging, epidermal atrophy, and hyperpigmentation—changes associated with cutaneous (discoid) lupus erythematosus (Fig. 19-4). The overlying skin can be “bound down” to the subcutaneous nodule or plaque, resulting in an obvious depression in the skin surface.
15. Describe the microscopic features of lupus panniculitis.
There is typically a mixed septal and lobular panniculitis with a predominance of lymphocytes in a patchy or diffuse and/or perivascular distribution. Nodular aggregates of lymphocytes surrounded by plasma cells may be present; there may even be formation of lymphoid follicles with germinal centers. Interstitial mucin deposition and hyalinization of the fat also occur. Overlying epidermal changes associated with cutaneous lupus erythematosus may be seen in close to one half of cases.
16. What is the significance of diagnosing lupus panniculitis?
Panniculitis may be a presenting finding of either cutaneous or systemic lupus erythematosus, or rarely of dermatomyositis or other autoimmune diseases. A small percentage of patients presenting with lupus panniculitis fulfill criteria for systemic lupus erythematous, and other complications have been reported, such as the development of antiphospholipid antibody syndrome. Antinuclear antibodies are common, and occasionally other circulating antibodies are detected, such as antineutrophil cytoplasmic antibodies. Because of the unusual clinical locations of lupus panniculitis, the true diagnosis may not be suspected for months or years. Early biopsy and direct immunofluorescence study of these lesions may provide the first clues to the diagnosis of lupus erythematosus and allow for early institution of appropriate therapy. Treatments for the panniculitis include intralesional corticosteroids, systemic antimalarials, and dapsone.
17. Are sclerema neonatorum and subcutaneous fat necrosis of the newborn the same thing?
No, but in both conditions, there are varying degrees of sclerosis of the subcutaneous fat of newborns. Sclerema neonatorum is very rare and occurs in premature, hypothermic infants with underlying medical problems. It is characterized by diffusely cold, rigid, boardlike skin; neonatal death is common. In subcutaneous fat necrosis of the newborn (Fig. 19-5A), relatively discrete, firm subcutaneous nodules develop several weeks after birth in an otherwise healthy baby. Hypercalcemia may be present, causing seizures and nephrocalcinosis, but the overall prognosis for survival and resolution of the lesions is excellent.
18. How similar are the microscopic features of sclerema neonatorum and subcutaneous fat necrosis of the newborn?
Both conditions show needle-shaped clefts within lipocytes, presumably representing triglyceride crystals that have been dissolved during tissue processing. Sclerema neonatorum tends to show thickened fibrous septa and little inflammation, while subcutaneous fat necrosis shows a substantial lobular panniculitis with a foreign body reaction to the needle-shaped clefts (Fig. 19-5B).
19. Why do these disorders occur in neonates and infants?
Neonatal fat has an increased ratio of saturated to unsaturated fatty acids, which results in higher melting and solidification points for stored fat. This, plus other possible metabolic defects, leads to crystal formation, fat necrosis, and inflammation when the fat is subjected to stresses such as ischemia or trauma.
20. What is pancreatic fat necrosis?
Subcutaneous nodules occur on the legs (Fig. 19-6) or elsewhere associated with acute or chronic pancreatitis or pancreatic carcinoma. Visceral fat may also be involved. Although immune mechanisms may play a role in producing this form of fat necrosis, the weight of evidence favors the effects of circulating pancreatic lipase, amylase, and trypsin on subcutaneous fat. The frequent co-occurrence of arthritis with joint fluid analysis revealing free fatty acids is a clinical reminder of the systemic effects of these pancreatic enzymes. Treatment is directed toward the underlying pancreatic disease.
22. What is the role of α-1 antitrypsin deficiency in the development of panniculitis?
Since the mid-1970s, it has become apparent that patients with this inherited proteinase inhibitor deficiency, especially those most severely affected and having the homozygous PiZZ phenotype, are prone to develop painful hemorrhagic subcutaneous nodules (Fig. 19-7) that ulcerate and drain. Without α-1 antitrypsin, the activity of neutrophil elastase is unchecked. It is believed that in such individuals a variety of triggering factors, such as trauma, may initiate a sequence of events that includes unchecked complement activation, inflammation, endothelial cell damage, and tissue injury. Microscopic clues to the diagnosis include diffuse neutrophilic infiltration of the reticular dermis, and liquefactive necrosis of the dermis and the subcutaneous septa, with resultant separation of fat lobules. Treatment options include dapsone, systemic corticosteroids, plasma exchange therapy, and, more recently, parenteral administration of a proteinase inhibitor.
Figure 19-7. Alpha-1 antitrypsin deficiency panniculitis showing foci of hemorrhage in the center of the lesion.
(Courtesy of Kenneth E. Greer, MD.)
Chowdhury MM, Williams EJ, Morris JS, et al: Severe panniculitis caused by ZZ alpha-1-antitrypsin deficiency treated successfully with human purified enzyme (Prolastin), Br J Dermatol 147:1258–1261, 2004.
23. Name some types of trauma that can produce panniculitis.
Numerous forms of trauma, either accidental or purposeful, can produce painful subcutaneous nodules or plaques. These include cold injury (“popsicle panniculitis” on the cheeks of children), injection of foreign substances such as oils or medications (Fig. 19-8), or blunt force trauma. There are some unique microscopic clues for each of these types of injury, so biopsy is particularly helpful when traumatic panniculitis is suspected. Polarization microscopy is one simple test for detecting the presence of refractile foreign material in tissue sections. The therapeutic challenge lies mainly in finding and removing the source of the injury that has produced the panniculitis.
24. Which infectious organisms can produce panniculitis?
Panniculitis can result from localized or generalized infection caused by gram-positive and gram-negative bacteria, mycobacteria (Fig. 19-9A), Nocardia, Cryptococcus (Fig. 19-9B), Candida, and Fusarium species. Other organisms that have been associated with panniculitis include streptococci, Toxocara, Trypanosoma, and Borrelia burgdorferi (as a manifestation of Lyme disease). Immunosuppressed patients appear to be particularly at risk for infection-induced panniculitis. Microscopic features vary and can occasionally mimic other forms of panniculitis. However, findings that should suggest the possibility of infection include mixed septal-lobular involvement, neutrophilic infiltration, vascular proliferation and hemorrhage, and sweat gland necrosis. Special stains and culture studies are crucial to making the correct diagnosis and instituting appropriate antimicrobial therapy.
Figure 19-8. Sclerosing panniculitis with lipoatrophy caused by repeated injection of pentazocine.
(Courtesy of Kenneth E. Greer, MD.)
25. Describe the role of malignancy in producing panniculitis.
Malignant infiltrates can sometimes produce subcutaneous nodules that mimic other forms of panniculitis. Malignancies that are capable of producing panniculitis-like lesions include poorly differentiated carcinomas, lymphomas (Fig. 19-10), multiple myeloma, and leukemias. Microscopic clues to the recognition of malignant infiltrates include a monotonous cell population and/or cytologic atypia, “lining up” of atypical cells between collagen bundles, and minimal alteration of connective tissue in the presence of dense cellular infiltration. Also, forms of more traditional inflammatory panniculitis can accompany malignancy, including erythema nodosum, migratory thrombophlebitis, and pancreatic fat necrosis. Therefore, diagnosis again is heavily dependent on biopsy.
26. What is lipodystrophy?
Lipodystrophy generally refers to a paucity or complete absence of subcutaneous fat, sometimes due to redistribution. It can be generalized or localized, inherited or acquired. Lipodystrophy can be idiopathic, but is often associated with inherited syndromes, endocrine abnormalities such as insulin-resistant diabetes mellitus, complement abnormalities (Fig. 19-11A), or autoimmune disease. It is well recognized that highly active antiretroviral therapy (highly active antiretroviral therapy [HAART], particularly protease inhibitors) causes a distinctive redistribution of subcutaneous fat with accumulation of fat in abdominal and cervical areas and wasting of the face and extremities.
27. What is lipoatrophy?
This term is sometimes used interchangeably with lipodystrophy, but it is more commonly used to describe a focal loss of subcutaneous fat. Probably the most common form of lipoatrophy is postinflammatory in nature and can occur following several types of panniculitis. Microscopically, lipoatrophy features “collapse” of fat lobules, with a reduced number of variably sized lipocytes and development of numerous capillaries in a mucinous background stroma. Localized lipoatrophy also occurs following injection of medications, especially corticosteroids (Fig. 19-11B). A variety of plastic surgical procedures has been used to improve or correct lipoatrophy.
28. What is lipohypertrophy?
Lipohypertrophy, which manifests as induration of involved skin, occurs in some individuals due to repeated injections of insulin. This effect is apparently independent of the source of insulin, and can even occur with human recombinant insulin. Growth hormone injections have also resulted in lipohypertrophy. In lipohypertrophy, lipocytes are enlarged and appear to encroach upon the midportion of the dermis. Rotation of insulin injection sites is a key to management of lipohypertrophy, both to prevent or minimize the hypertrophic changes and to assure adequate insulin absorption.
29. Discuss the approach to use when attempting to diagnose an “unknown” case of panniculitis.
• Careful history and physical examination are of greatest importance, emphasizing the location of the eruption, as well as its timing in relation to any possible drug ingestion, infection, or trauma.
• Laboratory studies should be guided by the clinical history but might include cultures of distant sites (e.g., for possible streptococcal pharyngitis in erythema nodosum), antinuclear antibody determination (to rule out lupus panniculitis), or measurement of α-1 antitrypsin levels (for evaluation of proteinase inhibitor–deficiency panniculitis).
