Panniculitis: Recognition and diagnosis

INTRODUCTION — Panniculitis (inflammation of the subcutaneous fat) is a relatively uncommon condition that usually presents with inflammatory nodules or plaques. A wide variety of subtypes of panniculitis exist, including panniculitides related to infection, external insults, malignancy, and inflammatory diseases (table 1).

The diagnosis of panniculitis can be challenging because different forms of panniculitis may present with similar clinical findings, and many types of panniculitis are rare. A careful clinical assessment that includes an evaluation of patient risk factors, lesion distribution, and associated clinical findings (eg, ulceration, sclerosis, atrophy) can provide valuable clues for diagnosis.

Although histopathologic examination of the affected area can be of benefit, interpretation of the biopsy findings must be approached with discretion. In the absence of careful clinical correlation and thorough consideration of the clinical and pathologic differential diagnoses, an incorrect diagnosis may be selected.

The approach to the recognition and diagnosis of panniculitis will be discussed here. The clinical features and management of specific forms of panniculitis are reviewed in greater detail separately.

TERMINOLOGY — The term "panniculitis" refers to a group of inflammatory disorders in which the primary site of inflammation is in the subcutaneous fat. In contrast, inflammatory disorders that mainly involve the overlying dermis or underlying fascia and incidentally extend into the nearby subcutaneous fat are not considered types of panniculitis.

The nomenclature of the panniculitides has been inconsistent and a potential source of confusion. For example, "stasis panniculitis," "lipodermatosclerosis," "sclerosing panniculitis," "hypodermitis sclerodermiformis," and "chronic panniculitis with lipomembranous changes" are synonymous terms [1].

In other cases, one name has been given to multiple different conditions. Weber-Christian disease, which was once thought to be a distinct entity, appears to have been an overly inclusive term applied to multiple disorders, including alpha-1 antitrypsin deficiency panniculitis, pancreatic panniculitis, factitial panniculitis, lymphoma panniculitis, and others [1]. With improved ability to identify these conditions, the term "Weber-Christian disease" has largely been abandoned by dermatologists in favor of the more specific diagnoses.

SUGGESTIVE FEATURES — Suspicion for panniculitis typically first arises from the physical examination. Although the visible findings may be limited to a nonspecific area of erythema, palpation of an affected area reveals the deep-seated nodules and plaques characteristic of an inflammatory process located beneath the dermis. Depending on the type of panniculitis, additional features such as ulceration, atrophy, or sclerosis may also be detected. Associated tenderness is common but is not always present.

However, deep inflammatory nodules and plaques are not exclusive to panniculitis, and based upon the clinical scenario, disorders involving the deep dermis or fascia may need to be considered. For example, plaque morphea involving the deep dermis and eosinophilic fasciitis may be difficult to distinguish from deep morphea, which may present with true panniculitis (picture 1). (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults", section on 'Clinical manifestations' and "Eosinophilic fasciitis", section on 'Clinical features'.)

In addition, benign and malignant tumors can manifest as subcutaneous nodules. If incidental inflammation is also present, it may be difficult to distinguish these tumors clinically from panniculitides. Nodules associated with deep bruising may also be mistaken for panniculitis.

SUBTYPES — Once panniculitis is suspected, the clinical and/or histopathologic evaluation will help to confirm the presence of panniculitis and to identify the subtype of panniculitis, thereby allowing for proper patient management. Most panniculitides can be placed in one of several etiologic categories. These categories are listed below:

●Inflammatory

●Infection

●Trauma

●Deposition

●Enzymatic destruction

●Malignancy

Definitive information about the relative frequency of panniculitides is not available, but there is general agreement that erythema nodosum is the most common form of panniculitis. Stasis panniculitis is likely an underappreciated, but relatively common, phenomenon. Other panniculitides that, while not common, are seen on occasion in a general dermatology practice include traumatic panniculitis, lupus panniculitis, erythema induratum, cutaneous polyarteritis nodosa, subcutaneous granuloma annulare, subcutaneous sarcoidosis, and factitial panniculitis. Selected examples of panniculitides in each etiologic category are described below; a more extensive list is provided in a table (table 1).

Inflammatory disorders

●Erythema nodosum – Erythema nodosum occurs most often in young women and typically presents as crops of painful nodules on the shins (picture 2A-B) [2,3]. Nodules may also occur on the thighs and forearms. In contrast to many other types of panniculitis, ulceration is rare. Associated arthralgias, fever, and malaise are not uncommon.

Histopathologic examination reveals a septal panniculitis with a primarily lymphocytic or mixed inflammatory infiltrate and thickened septa. Histiocytes surrounding a banana-shaped cleft (Miescher's radial granulomas) may be present [3]. (See "Erythema nodosum".)

Erythema nodosum usually lasts a few weeks and resolves spontaneously, but may recur. No cause is found in many cases. Infections, inflammatory bowel disease, sarcoidosis, oral contraceptives, pregnancy, and multiple other factors have been associated with erythema nodosum (table 2). Streptococcal pharyngitis is the most common identifiable cause. (See "Erythema nodosum", section on 'Etiology'.)

●Lipodermatosclerosis/sclerosing panniculitis – Lipodermatosclerosis, also known as sclerosing panniculitis, is a form of panniculitis that usually occurs in the setting of venous insufficiency [4,5]. Indurated plaques with associated erythema, edema, and hyperpigmentation on one or both lower legs (often on the medial aspect) are characteristic and result from the fibrosis and atrophy of subcutaneous fat (picture 3A-B) [6]. On the legs, the sclerosis may have an appearance that is reminiscent of an inverted wine bottle or piano leg. Lipodermatosclerosis can also occur in other areas of stasis, such as the abdominal pannus or breasts.

Histopathologic findings in lipodermatosclerosis include overlying features of stasis dermatitis; findings at the level of the subcutaneous fat vary based upon the stage of the disease. Late-stage lesions demonstrate thickened, fibrotic septa, extensive fat atrophy, and an inflammatory infiltrate composed of lymphocytes, histiocytes, and foamy macrophages [6]. Lipomembranous change (eosinophilic material lining fat pseudocyst) is frequently present. (See "Clinical manifestations of lower extremity chronic venous disease", section on 'Lipodermatosclerosis (C4b)'.)

●Lupus panniculitis – Lupus panniculitis (also known as lupus profundus) is an uncommon form of panniculitis with a distinctive distribution of lesions [6]. Affected patients typically develop erythematous nodules in sites that are often spared in other panniculitides, including the upper arms, shoulders, face, scalp, and buttocks (picture 4A-C) [7,8]. There may be concurrent, overlying lesions of discoid lupus erythematosus. Systemic lupus erythematosus is present in a minority of patients. (See "Overview of cutaneous lupus erythematosus", section on 'Lupus profundus (lupus panniculitis)'.)

Histopathologic examination reveals a lobular lymphocytic panniculitis that often demonstrates lymphoid follicles. Overlying histopathologic features of discoid lupus may be present. Direct immunofluorescence of the skin is often positive with linear deposition of immunoglobulin M (IgM) and C3 at the dermal-epidermal junction but is not usually necessary for diagnosis [6]. Disfiguring lipoatrophy frequently occurs in sites of regressed lesions (picture 4A-C).

●Cutaneous polyarteritis nodosa – Cutaneous polyarteritis nodosa (also called "cutaneous arteritis") is a primary form of vasculitis involving the vessels in the septae of the subcutaneous fat. A more accurate term for this variant may be "primarily cutaneous polyarteritis nodosa," since internal organ involvement may also occur. Patients typically present with tender subcutaneous nodules that often ulcerate and associated livedo racemosa (picture 5A-B) [9]. Low-grade systemic symptoms (arthralgias, myalgias, malaise, and fatigue) and peripheral neuropathy may also be present [10,11].

Examination of pathology specimens from early lesions reveals neutrophilic vasculitis of arteries and arterioles in the subcutaneous septa (picture 6). The inflammatory infiltrate transitions to a predominantly lymphohistiocytic infiltrate over time [10]. The disease often follows a chronic course that may be characterized by periods of exacerbations and clinical remissions. Examples of disorders that have been associated with cutaneous polyarteritis nodosa include streptococcal infection, inflammatory bowel disease, and hepatitis B and C [9]. (See "Cutaneous polyarteritis nodosa".)

●Erythema induratum – Erythema induratum typically occurs in young to middle-aged women and usually presents as nodules on the posterior lower legs (picture 7A-C) [12]. Unlike erythema nodosum, ulceration is common. Although there is a well-established association with tuberculosis, erythema induratum can be idiopathic or associated with other infections or drugs. The terms "erythema induratum" and "nodular vasculitis" have been used synonymously by some authors. Others reserve the term "nodular vasculitis" for cases unassociated with tuberculosis. (See "Cutaneous manifestations of tuberculosis", section on 'Erythema induratum of Bazin'.)

Infection

●Infectious panniculitis – Infectious panniculitis usually presents as a primarily lobular panniculitis that may be caused by bacterial, mycobacterial, fungal, protozoal, or viral infections [13]. It may occur as a result of hematogenous dissemination of microorganisms, direct extension from a nearby focus of infection, or direct inoculation. The appearance of the lesions is dependent on the underlying cause and the severity of infection, ranging from indolent nodules to acute fluctuant abscesses. Immunosuppressed individuals are at increased risk for infectious panniculitis. Microbial cultures and histopathologic stains are useful for diagnosis.

Trauma

●Traumatic panniculitis – Panniculitis can occur at the site of blunt injury [14]. For example, minor trauma to the shins can result in the development of tender subcutaneous nodules [6]. Histopathologic examination reveals cystic spaces within the fat, variable fibrosis and hemorrhage, and a peripheral lymphohistiocytic inflammatory infiltrate [6].

●Cold panniculitis – Cold panniculitis may occur in any age group but occurs most often in very young children, in whom it is sometimes called "popsicle panniculitis." Patients present with erythematous nodules and plaques at the site of cold injury (picture 8A-B). The cheeks are a common site of involvement. Spontaneous resolution typically occurs within a few weeks. Histopathologic findings include a primarily lobular lymphohistiocytic infiltrate [15].

●Factitial panniculitis – Factitial panniculitis is a form of panniculitis that results from the injection of foreign substances into the subcutaneous fat [16]. Factitial panniculitis should be considered when lesions are in atypical locations or have unusual shapes. Although some cases result from the injection of medical therapies, other cases result from the inappropriate injection of substances for cosmetic purposes (eg, paraffin) or the injection of harmful substances (eg, urine, feces, foods, or chemicals) by patients with emotional disturbances or psychiatric disorders. It is common for patients who deliberately inject harmful substances to deny self-injection.

The clinical manifestations vary with the type and amount of substance injected. Patients may have inflammatory nodules or plaques, and abscesses may develop. The histopathologic findings are also variable. In some cases, the foreign material can be identified on pathologic sections [16].

Deposition

●Calciphylaxis – Calciphylaxis is an uncommon, life-threatening disorder that most commonly occurs in the setting of end-stage renal failure. Patients present with painful nodules and plaques associated with retiform (angulated) purpura and cutaneous necrosis (picture 9). Sites with abundant adipose tissue, such as the thighs and buttocks, are frequently affected. The histopathologic findings are specific, demonstrating calcium deposits within the walls of vessels in the reticular dermis and subcutaneous fat. Necrosis of fat lobules, fat calcification, and a mixed inflammatory infiltrate are also evident. Calciphylaxis is associated with a poor prognosis [6]. (See "Calciphylaxis (calcific uremic arteriolopathy)".)

●Gout – Rarely, individuals with hyperuricemia develop deposits of urate crystals in the subcutaneous fat that result in the development of erythematous, indurated subcutaneous plaques [17,18]. The lower extremities are common sites for involvement. Histopathologic examination reveals needle-like crystals and a granulomatous inflammatory infiltrate with multinucleated giant cells. (See "Clinical manifestations and diagnosis of gout".)

Enzymatic destruction

●Pancreatic panniculitis – Pancreatic panniculitis (also known as pancreatic fat necrosis and enzymatic panniculitis) is a rare, primarily lobular panniculitis that infrequently develops in individuals with pancreatic disease [19]. The most common associated disorders are acute and chronic pancreatitis [6]. The cause of the disorder is unknown, but a role for release of pancreatic enzymes has been considered. Tender, inflammatory nodules typically develop on the distal lower extremities, though other sites may also be affected (picture 10). The nodules may ulcerate and drain oily brown liquid derived from the necrosis of adipocytes. Acute arthritis often is present.

Characteristic histopathologic findings include a primarily lobular panniculitis with extensive necrosis of adipocytes and ghost adipocytes (adipocytes without nuclei) with calcium deposits. In patients with pancreatitis, panniculitis usually resolves upon the cessation of pancreatic inflammation. However, in patients with pancreatic carcinoma, the course of panniculitis tends to be more persistent [6].

●Alpha-1 antitrypsin deficiency panniculitis – Alpha-1 antitrypsin deficiency panniculitis is a rare form of panniculitis restricted to individuals with alpha-1 antitrypsin deficiency [20]. Trauma may precipitate lesions. Subcutaneous nodules may occur on the face, trunk, or extremities. Lesions preferentially occur on the lower trunk and thighs. Ulceration and release of oily material due to adipocyte necrosis are common.

Extensive fat necrosis is typically seen on biopsy. Infiltration of neutrophils between collagen bundles (splaying of neutrophils) and a mixture of areas of normal fat adjacent to necrotic fat may be present [21]. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Skin disease'.)

Malignancy

●Subcutaneous lymphoma – Certain lymphomas, primarily those associated with a cytotoxic T cell phenotype and less commonly with an NK/T cell type, may present with significant involvement of the subcutaneous fat [22]. Subcutaneous panniculitis-like T cell lymphoma is one of these disorders. Patients typically present with painless nodules or plaques on the extremities, trunk, or face and may have accompanying B symptoms (eg, weight loss, fever, and fatigue). Histopathologic examination demonstrates an infiltrate of atypical lymphocytes within the fat lobules and cytophagocytosis (macrophages phagocytizing erythrocytes and leukocytes). The phagocytizing macrophages are also known as "beanbag cells." (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

The term "cytophagic histiocytic panniculitis" has also been used to refer to subcutaneous panniculitis-like T cell lymphoma, but cytophagic histiocytic panniculitis may also occur in the absence of malignancy [6].

Infants and children — Certain panniculitides occur exclusively or primarily in infants or children [23]. The subcutaneous fat of infants has a higher ratio of saturated to unsaturated fatty acids and a higher melting point than the subcutaneous fat of older children and adults. Lowered skin temperatures can lead to crystallization in the fat and an inflammatory reaction, and it is hypothesized that the unique properties of infantile fat contribute to the development of these disorders. The subtypes of panniculitis that exhibit a predilection for infants and children are listed below:

●Subcutaneous fat necrosis of the newborn – Subcutaneous fat necrosis of the newborn is an uncommon condition that typically occurs in full-term infants during the first few weeks of life. The disorder presents as erythematous or violaceous indurated subcutaneous nodules or plaques on the cheeks, buttocks, arms, thighs, or back (picture 11). Occasionally, there is associated symptomatic hypercalcemia [24]. The nodules typically resolve spontaneously.

Histopathologic examination reveals a lobular panniculitis with an inflammatory infiltrate containing macrophages and multinucleated giant cells. In addition, cells that contain radially arranged, needle-like clefts that represent crystalline fat are present. Small calcium deposits may be detected. (See "Subcutaneous fat necrosis of the newborn".)

●Sclerema neonatorum – Sclerema neonatorum is a rare condition that occurs most often in severely ill premature neonates. There is a diffuse, rapidly progressive hardening of the skin, and the prognosis is poor. Histopathologic examination demonstrates minimal inflammation and necrosis. The characteristic finding is cells with radially arranged, needle-shaped clefts similar to those seen in subcutaneous fat necrosis of the newborn [6]. (See "Sclerema neonatorum".)

●Cold panniculitis – Cold panniculitis occurs most often in very young children. Cold panniculitis is described above. (See 'Trauma' above.)

●Poststeroid panniculitis – Poststeroid panniculitis is a rare lobular panniculitis that has occurred in infants and children following the sudden withdrawal of high-dose systemic glucocorticoids. Affected children develop erythematous nodules 1 to 10 days after glucocorticoid withdrawal [23]. The cheeks are a common site of involvement.

The histopathologic findings resemble subcutaneous fat necrosis of the newborn. A lymphohistiocytic infiltrate is present in the fat lobules and cells with needle-shaped clefts may be detected [6]. Lesions spontaneously resolve within a few weeks to a few months [23].

PATIENT EVALUATION

Patient history — Once panniculitis is suspected, certain clinical clues assist with narrowing the differential and creating a plan for additional work-up. Recollection of the categories of conditions that can present with panniculitis can be useful (table 1). Examples of questions that may assist with identifying the most likely cause of panniculitis are reviewed below:

●Inflammatory – Was there a preceding streptococcal infection or other risk factors associated with erythema nodosum? Does the patient have a history of connective tissue disease or symptoms suggestive of a connective tissue disease? Does the patient have a history of chronic lower extremity edema (lipodermatosclerosis)?

●Infection – Is the patient immunosuppressed? Is the patient acutely ill?

●Trauma – Is there a history of local trauma or exposure to cold? Are the lesions occurring in a site that received injections or radiation therapy?

●Deposition – Does the patient have renal failure (calciphylaxis) or gout?

●Enzymatic destruction – Are there symptoms suggestive of pancreatitis? Does the patient have early-onset emphysema (alpha-1 antitrypsin deficiency)?

●Malignancy – Is there a history of malignancy? Does the patient appear acutely or chronically ill?

Physical examination — Because inflammatory nodules and plaques occur in various forms of panniculitis as well as other types of disorders, diagnosing a specific form of panniculitis based only on examination of the affected area is usually difficult. The patient history and an assessment of additional clinical findings, such as ulceration, atrophy, sclerosis, and livedo racemosa, can be useful for diagnosis:

●Ulceration – Occurs in multiple forms of panniculitis but typically absent in erythema nodosum, which assists with distinguishing this disorder from erythema induratum.

●Atrophy – Lesions of lupus panniculitis typically resolve with significant atrophy.

●Sclerosis – Lipodermatosclerosis and deep morphea present with features of sclerosis.

●Livedo racemosa – Livedo racemosa commonly occurs in association with cutaneous polyarteritis nodosa (picture 5B).

In addition, the location of lesions may also provide important diagnostic clues. Examples of preferential sites of involvement for specific panniculitides are listed below:

●Erythema nodosum – Anterior lower legs

●Erythema induratum – Posterior lower legs

●Lipodermatosclerosis/stasis panniculitis – Medial lower legs

●Alpha-1 antitrypsin deficiency panniculitis – Buttocks, flanks, and thighs

●Subcutaneous sarcoidosis – Forearms

●Lupus panniculitis – Face, scalp, upper arms, breasts, upper trunk, buttocks, and thighs

Biopsy — Biopsies can provide valuable information for diagnosis and are indicated in cases in which the diagnosis is uncertain or to confirm the diagnosis in cases in which the clinical course of a panniculitis does not proceed as expected. Biopsies are most useful when findings characteristic of a specific form of panniculitis are identified. However, the histopathologic findings are often ambiguous. In many cases, clinical correlation and careful consideration of the differential diagnosis is required to arrive at a correct diagnosis.

Although biopsies are usually well tolerated, potential consequences include scarring, infection, and poor wound healing. Therefore, in situations in which the clinical evaluation yields a relatively certain diagnosis, the decision to perform a confirmatory biopsy is individualized. As an example, the benefit gained from the histologic confirmation of the diagnosis of erythema nodosum is not necessarily worth the resulting scar from deep excisional biopsy in a typical, short-lived case. Similarly, the benefit gained from histologic confirmation of lipodermatosclerosis may or may not be worth the risk of having a chronic wound on the lower leg. However, in other situations, a biopsy is critical for proper patient evaluation and management. For example, the attainment of a tissue specimen for histopathologic examination and microbial studies is essential when infectious panniculitis is suspected.

Procedure — In order to achieve the highest diagnostic yield, the biopsy specimen must include a generous sample of the subcutaneous fat. This is best accomplished by an elliptical excision performed with a scalpel. Alternatively, a large (6 to 8 mm) punch biopsy may be performed. Elliptical excisions often result in more cosmetically satisfactory scars. (See "Skin biopsy techniques", section on 'Biopsy techniques'.)

Interpretation — Subcutaneous fat has a fairly simple structure, consisting mainly of fat cells that are organized in lobules divided by fibrous septa, together with vessels and nerves. The panniculitides are often classified based on the histologic findings, particularly the location of the pathologic process (septal versus lobular) and the presence or absence of vasculitis (table 3) [1,25]. To narrow the histologic differential diagnosis, the following questions are addressed during histopathologic examination:

●Is the pathology primarily in the fat?

●Is the pathologic process predominantly in the septa, lobules, or both?

●Is vasculitis present?

●What types of cells make up the inflammatory infiltrate?

●What other features are present (eg, necrosis, organisms, crystals, calcium, foreign material)?

Although evaluation of the pathology in the context of the clinical findings often establishes the diagnosis, there are limitations to consider during the interpretation of the biopsy findings. These include the following:

●The relative lack of complexity of subcutaneous tissue means that there is a relatively small number of ways the subcutaneous fat can appear histologically. Even with an optimal sample, it may not be possible to narrow the histologic differential diagnosis to one entity.

●Inflammatory infiltrates are not absolutely confined to septa in septal panniculitis and are not limited to lobules in lobular panniculitis. The fundamental distinction between a septal and a lobular panniculitis is based on the predominant location of the infiltrate. In practice, this can be a difficult distinction to make, particularly if the sample size is small.

●The biopsy may not include a sufficient amount of subcutaneous fat. This is particularly likely with small punch biopsies but can also occur with excisions if the practitioner is not careful to include an adequate sample of subcutaneous fat.

●An inadequate biopsy or insufficient sampling of an adequate biopsy may affect the ability to detect the presence of vasculitis. For example, a biopsy that may initially appear to be erythema nodosum may be revealed to be polyarteritis nodosa when additional sections are examined.

●Histologic changes evolve as lesions mature.

Special studies — In some cases, obtaining a diagnosis may require investigation beyond the clinical evaluation and routine histopathologic examination. When infection is in the clinical differential diagnosis, tissue cultures and histologic stains for organisms are usually indicated. If malignancy is suspected, special studies to determine cell type may be required. In cases of panniculitis where the diagnosis is not straightforward, the tissue sample should be polarized to look for foreign material.

Additional tests — Depending on the diagnoses suspected based upon the clinical and histopathologic examinations, other tests may aid in identifying the cause of panniculitis. Examples include tests to evaluate patients for pancreatitis, tuberculosis, alpha-1 antitrypsin deficiency, and autoimmune disease. If evaluation reveals a diagnosis associated with other disorders, such as erythema nodosum (table 2) or subcutaneous fat necrosis of the newborn (hypercalcemia), additional testing is performed as indicated.

SUMMARY AND RECOMMENDATIONS

●The term "panniculitis" is used to refer to inflammatory disorders in which the primary site of involvement is the subcutaneous fat. Many types of panniculitis have been described, including immune-mediated, infectious, trauma-induced, malignant, and other types of panniculitides (table 1). (See 'Subtypes' above.)

●Suspicion for panniculitis typically arises upon the detection of the clinical findings of one or more deep-seated inflammatory nodules or plaques. Depending on the type of panniculitis, additional features such as ulceration, atrophy, or sclerosis may be present. (See 'Suggestive features' above.)

●Certain types of panniculitis are more likely to occur in children than adults. Examples include subcutaneous fat necrosis of the newborn and sclerema neonatorum, which typically occur in the neonatal period. Cold panniculitis and poststeroid panniculitis are also most likely to occur in children. (See 'Infants and children' above.)

●The clinical history and physical examination play an important role in identifying the cause of panniculitis. The recognition of the distribution of lesions and associated clinical findings is often useful. (See 'Patient history' above and 'Physical examination' above.)

●Biopsies are indicated when the diagnosis is uncertain, when the attainment of a tissue specimen may yield information useful for patient management, or when the clinical course does not proceed as expected. An elliptical excision is the preferred procedure for biopsy. A large punch biopsy (6 to 8 mm) may be performed as an alternative. (See 'Biopsy' above.)

●Certain features aid in the evaluation of a biopsy specimen. The status of panniculitis as lobular versus septal, the presence or absence of vasculitis, the nature of the inflammatory infiltrate, and the visualization of distinctive features assist with diagnosis (table 3). (See 'Interpretation' above.)

●The limitations of histology in diagnosis must always be considered. Careful clinical correlation with biopsy findings is essential. If there is discordance between the clinical and histologic findings, or if disease fails to respond as expected to therapy, the diagnosis should be reassessed. (See 'Interpretation' above.)