Mycosis fungoides is the most common primary cutaneous lymphoma; however, it remains a significant diagnostic challenge, in part because of the overlap with several inflammatory dermatoses. Despite advances in immunohistochemistry and molecular diagnostics, false-positive, false-negative, and indeterminate diagnoses are not uncommon. In most cases, the overall balance of morphologic, immunophenotypic, and genetic features must be considered carefully because there are few sensitive and specific clues to the diagnosis. Moreover, an appropriate clinical presentation is essential to the diagnosis and helps to favor or exclude inflammatory/reactive processes. Herein, we discuss 3 important inflammatory dermatoses that may closely simulate mycosis fungoides, and we review the use of ancillary studies in these challenging cases.
A 38-year-old man underwent circumcision for phimosis. Hematoxylin-eosin–stained sections of the circumcision specimen revealed a bandlike, lymphoid infiltrate in the papillary and superficial dermis with associated, patchy, coarse or “wiry” dermal fibrosis (Figure 1, A through D). Lymphoid cells aligned along the basilar epidermis and entered the lower epidermis, with occasional, small, intraepidermal collections that resembled Pautrier microabscesses. The lymphoid cells were predominantly small and displayed round to slightly irregular nuclear contours, mature chromatin, and pericellular haloes. The epidermis also showed focal interface changes.
Immunohistochemical studies demonstrated a mixed lymphoid population that included CD20+ B cells and predominant, CD3+ T cells in the dermal infiltrate, whereas the intraepidermal lymphocytes were exclusively CD3+ T cells (Figure 1, E through H). Both epidermal and dermal T cells included a mixed population of CD4+ and CD8+ T cells with a CD8 predominance. No loss of CD2, CD5, or CD7 was appreciated. Molecular analysis revealed a clonal T-cell receptor γ-chain gene rearrangement. Additional clinical information was obtained and revealed that the patient had no history of mycosis fungoides. A diagnosis of early lichen sclerosus et atrophicus (LSA) was rendered based on these findings. The patient did not develop mycosis fungoides in the 10 years of available follow-up information.
Mycosis fungoides (MF) is the most common primary cutaneous lymphoma, accounting for almost 50% of such cases.1–3 Adults and the elderly are most commonly affected, with a median age at presentation in the mid-50s and a male-to-female ratio of approximately 2:1. The disease slowly progresses for years, evolving from erythematous patches on sun-protected skin to plaques to tumors. Infrequently, patients may be erythrodermic. Early MF (patch phase) is clinically characterized by large, well-demarcated lesions (typically, >1 lesion >5 cm in diameter) that vary in size and shape over time (progression and regression) but that tend to enlarge and become more numerous with continued disease (Figure 2, A).2–5 The clinical course generally remains indolent, with 5-year, disease-specific survival approaching 90%.1 However, prognosis and therapeutic options depend on the type of lesion (patch, plaque, or tumor), the extent of cutaneous involvement, and the presence of extracutaneous disease and large-cell transformation.1,4,6 In addition, the expected outcome and treatment options for MF differ from inflammatory dermatoses. For these reasons, accurate and early diagnosis of MF is desirable.
The diagnosis of MF may be quite challenging, particularly in early (patch) lesions, where the histopathologic findings may overlap with a wide range of inflammatory dermatoses, and the characteristic clinical features are not well-established.4,6–11 The histopathologic features of early MF vary from person to person, over time, and even between multiple sites in a single patient.12,13 In addition, topical steroid therapy and systemic immunosuppressants may influence the findings for up to 2 to 4 weeks.4,14 These difficulties are highlighted by reported false-negative and false-positive rates as high as 40%,15 in addition to low concordance and reproducibility rates.4,8–10
Because of these diagnostic challenges in early MF, during the past decades, several authors have attempted to identify the most-reliable diagnostic criteria for distinguishing MF from benign dermatoses.4,5,7,10–14,16,17 Characteristic histopathologic features of early MF include the presence of enlarged epidermal lymphocytes with cerebriform nuclei within the epidermis and minimal associated spongiosis (epidermotropism), larger lymphocytes in the epidermis than in the dermis, lymphocytes with perinuclear clearing (halo), and a linear arrangement of basilar epidermal lymphocytes along the dermal-epidermal junction (tagging) (Figure 2, B through D).* Some of the variable features that have been proposed as the most helpful in making a diagnosis of MF on multivariate analysis include strikingly irregular nuclear contours,4 haloed lymphocytes,7 cerebriform lymphocytes as large as a basal keratinocyte nucleus (ie, 7–9 μm),17 and a linear arrangement of epidermal lymphocytes at the dermal-epidermal junction.17 However, none of these features are entirely specific for MF. In contrast, although Pautrier microabscesses are considered more specific for MF, they are only seen in 4% to 37% of early lesions.3,5,7,11,12,17 Although the pattern may vary, epidermotropism is considered a hallmark of MF and has been reported in up to 96% of patients with early MF.12 In some cases, the atypical lymphocytes in MF may be associated with spongiosis, but the degree of spongiosis is usually far less than would be expected for the number of lymphocytes in the epidermis, a feature that is sometimes called disproportionate epidermotropism.4,7,12,16 In cases with limited or absent epidermotropism, the presence of a bandlike infiltrate in a thickened papillary dermis with coarse collagen bundles may suggest the diagnosis. Awareness of the variable appearances of early MF is important for appropriate diagnosis of these challenging cases.
Despite the continued refinement of histologic criteria for diagnosing early MF, the diagnosis is best made using a combination of clinical history and histopathologic, immunophenotypic, and genetic findings. An algorithm to incorporate these aspects was proposed and subsequently validated in practice.4,13 In cases in which integration of clinical history, histopathology, and ancillary techniques fails to discern a definitive diagnosis, it may be preferable to defer the diagnosis until a subsequent biopsy is obtained.13,19,20 Despite all the challenges in diagnosing MF and its mimics, accurate classification is necessary for patient staging, prognosis, and therapy. Herein, we review selected inflammatory dermatoses that may closely simulate MF, focusing on distinguishing clinicopathologic features and the use of ancillary studies.
Lichen Sclerosus et Atrophicus
Lichen sclerosus et atrophicus is a chronic, inflammatory disorder most commonly affecting the anogenital region of middle-aged and elderly women.21 In men, LSA (also referred to as balanitis xerotica obliterans) characteristically involves the glans and foreskin, while sparing the perianal region.22 Acquired phimosis is frequent with disease progression.21–23 Clinically, lesions in both men and women present as white, atrophic macules, papules, or plaques and are often associated with pruritus, burning, or tenderness.21,22
Histopathologically, early LSA displays a bandlike, lymphoid infiltrate in the superficial dermis.24,25 Usually, there is evidence of interface dermatitis, including vacuolar alteration of basal keratinocytes, dyskeratotic keratinocytes, and blurring of the dermal-epidermal junction. Lymphocytes may migrate into the basilar epidermis with limited, associated spongiosis, resembling MF.19,25–28 In addition, the papillary dermis may display coarse or wiry collagen bundles.26 Developed lesions of LSA show hyperkeratosis, follicular plugging, and epidermal atrophy. Basement membrane thickening, papillary dermal edema, and broad, dermal collagen hyalinization are characteristic. Deep to the altered collagen, there is a diffuse, bandlike to perivascular infiltrate of lymphocytes, predominantly T cells. Typically, the intensity of the lymphocytic infiltrate lessens as the lesion becomes more developed.
There have been several reports of overlapping histopathologic features between MF and LSA.19,26–30 Citarella and colleagues26 described 9 patients with presentations clinically characteristic of LSA but with histopathology mimicking MF; 6 (67%) had lesions on the foreskin, 2 (22%) on the glans, and 1 (11%) on the labia minora. These lesions of early, less–well-developed LSA included small to medium, intraepidermal lymphocytes; a dense, bandlike, lymphoid infiltrate in the superficial dermis; and thickened bundles of collagen within the papillary dermis, similar to our case (Figure 1, A through H). Despite the morphologic overlap, several features help to favor a diagnosis of MF. Haloed lymphocytes are less common in LSA but may occur.26 In addition, the intraepidermal lymphocytes of LSA tend to be confined to the lower epidermis, whereas those in MF are more likely to show pagetoid spread.11,16,17,26 In addition, LSA tends to show a zonal pattern of subepidermal fibrosis, with focal areas of the dermis replaced by dense collagen.26 Interface changes, such as vacuolar alteration of basal keratinocytes, dyskeratotic keratinocytes, and blurring of the dermal-epidermal junction by lymphoid cells, also favor LSA,26 although they have also been reported in MF.5,11,12,14,16 At least focal, vacuolar alteration of basal keratinocytes has been reported in 21% to 70% of MF cases,5,11–14 whereas associated dyskeratotic keratinocytes are less common,11,13,16 and a lymphocytic infiltrate that obscures the dermal-epidermal junction is not usually seen.5 Conversely, significant lymphocyte atypia and Pautrier microabscesses support a diagnosis of MF.4,7,11,16,17,26,28 Finally, the clinical setting is a critical distinguishing feature. A background of patches, plaques, or tumors characteristic of MF, argues in favor of MF. In contrast, although MF may occur in genital sites, LSA should be excluded before making a diagnosis of MF in a genital location.26
Allergic Contact Dermatitis
Allergic contact dermatitis (ACD) is a T-cell–mediated, spongiotic dermatitis that arises from contact with an allergen.31 It is a delayed-type, hypersensitivity reaction (type IV) and requires that the patient be previously sensitized to the allergen. Patients typically develop lesions within 12 to 96 hours and may show a distribution that suggests an exogenous agent, although lesions may extend beyond the area of direct contact.31 Typically, ACD appears as pruritic, erythematous papules and/or plaques and may include vesicles or weeping fluid. In the chronic phase, the skin becomes lichenified and fissured. Clinical history often helps to identify the allergen. In addition, a positive patch test may help to confirm the diagnosis.31–34
Acute ACD reveals spongiosis with vesicle formation.31,35,36 There is a mild to moderate dermal inflammatory infiltrate that shows perivascular accentuation and includes lymphocytes, macrophages, Langerhans cells, and eosinophils. Lymphocytes and eosinophils may extend into the epidermis. As ACD persists, lesions develop a dense, bandlike, dermal lymphoid infiltrate; mild, papillary dermal fibrosis; and epidermal lymphocytes with only mild spongiosis. It is the later subacute to chronic ACD, with mild spongiosis, intraepidermal lymphocytes and Langerhans cells, and a bandlike, dermal lymphocytic infiltrate with associated fibrosis that most closely simulates MF (Figure 3, A through C).20,27,32–34,36–38 In these later lesions, scattered, dyskeratotic keratinocytes may be identified. Langerhans cell microabscesses (LCMs), which are evidence of a spongiotic process, are frequently present in the epidermis.20 Occasionally, LCMs can take on a vaselike shape that is oriented so they appear to empty out onto the epidermal surface.38
There are several features of subacute and chronic ACD that aid in distinguishing it from MF. Dyskeratotic cells are less common in MF.13,16,27 Prominent, papillary, dermal edema and significant spongiosis with vesicle formation, when present, argue in favor of ACD.11,12,16,27 In addition, LCM is a helpful indicator of spongiosis but does not exclude MF.27,38,39 Candiago and colleagues39 found LCM in 43.4% of spongiotic/eczematous dermatitis and in 13.3% of mycosis fungoides. The incidence of LCM in MF is not entirely unexpected because spongiosis may be present in MF; a study of early (patch) MF showed 4% of MF had marked spongiosis.12 Notably, LCMs may superficially resemble Pautrier microabscesses and are CD4+, potentially leading to a diagnostic pitfall (Figure 3, D through E). However, the cells in LCM display the characteristic reniform nucleus and linear nuclear grooves of Langerhans cells, as well as fairly abundant, pale cytoplasm. Moreover, the LCM cells are CD3− and express CD1a. In contrast, lymphocyte atypia, haloed lymphocytes, and Pautrier microabscesses support a diagnosis of MF.4,7,11,16,17,26,28
Drug reactions may closely resemble MF histopathologically, but they usually have a distinct clinical setting. Lesions are often associated with a new medication and resolve completely with discontinuation of the offending drug, although that may take several months.40–42 The clinical presentation ranges from a diffuse, maculopapular eruption to papules, plaques, and/or nodules that may be solitary or multiple.41–46 Rare cases of erythroderma have been reported (Figure 4, A and B).42,43,47 Medications that may cause drug-induced pseudolymphoma (DIP) are numerous and include antiepileptic drugs (eg, phenytoin, carbamazepine, sodium valproate), as well as other commonly prescribed medications, such as penicillin, β-blockers, angiotensin-converting enzyme inhibitors, and fluoxetine (as reviewed in Ploysangam et al43 and Albrecht et al48).
Patients with anticonvulsant-induced pseudolymphoma may develop a characteristic pseudolymphoma syndrome,40,41,43,44 which many experts include within the spectrum of hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.42,45,47,48 Uncommonly, this syndrome may occur with medications other than anticonvulsants.42 Pseudolymphoma syndrome generally develops 2 to 8 weeks after initiation of the offending drug and is characterized by a typically widespread, maculopapular eruption; facial edema; fever; lymphadenopathy; arthralgia; peripheral eosinophilia; hepatosplenomegaly; and elevated liver enzymes.41,42,47 Circulating, atypical lymphocytes may also be identified.41,47 Notably, patients may not display all features typical of the syndrome.41,46,47
Drug-induced pseudolymphoma may be remarkably similar to MF with a dense, bandlike, lymphoid infiltrate in the superficial dermis; mild lymphocyte enlargement and atypia; and intraepidermal lymphocytes (Figure 4, C through H).40,41,44 Pautrier microabscess-like structures have been reported.41,46 However, DIP is more commonly found as a single lesion, whereas unilesional MF is uncommon.40,44,48–50 In addition, MF is more likely to involve sun-protected skin and show a variety of clinical morphologies.4,48 On biopsy, the presence of spongiosis, dyskeratotic keratinocytes, extravasated erythrocytes, pigment incontinence, dermal edema, and/or numerous eosinophils are more supportive of a diagnosis of DIP.37,41,48,51 Before making the diagnosis of a cutaneous lymphoma, one should first consider the possibility of DIP. Clinical history associating the onset of the skin findings with a new medication can be very helpful. Systemic findings compatible with a hypersensitivity syndrome (pseudolymphoma syndrome) also support a diagnosis of DIP. Importantly, DIP should completely resolve following cessation of the offending medication.
Ancillary studies can support a diagnosis of MF and, conversely, can favor a reactive, inflammatory process. Nevertheless, they should be interpreted within the context of the case as a whole, including clinical and histopathologic findings. Loss of pan–T-cell markers (CD2, CD3, CD5, CD7) and a marked CD4 or CD8 predominance favor a diagnosis of MF, particularly if those findings are seen in epidermal, but not dermal, lymphocytes.3,4,15,52–54 Importantly, reactive processes may show loss of T-cell markers, most commonly CD7 and CD5.19,44,51,53,55–58 However, the loss of those markers in inflammatory conditions is often less extensive than it is in MF.4,59 In addition, many inflammatory dermatoses show a near-equal mixture of CD4+ and CD8+ T cells or only a mild predominance,19,40,44,54,55 although this generalization is far from universal.51
T-cell receptor gene rearrangement studies may also substantiate a diagnosis of MF but are neither entirely sensitive nor specific. Because of the failure of polymerase chain reaction primers to properly anneal with target sequences, alterations to DNA during processing, and other technical issues, clonal T-cell gene rearrangements may not be recognized by current assays.3,60 Conversely, nonneoplastic processes in the skin may have an associated clonal T-cell proliferation.41,51,52,57,61 For example, clonal T-cell populations have been detected in approximately 50% of LSA cases57,58 and may also be seen in a subset of DIP.41,51,61 However, finding an identical T-cell clone in more than one distinct anatomic site lends support to a diagnosis of MF.60,62
PROGNOSIS AND TREATMENT
Patients with the inflammatory mimics of MF generally do quite well when accurately recognized and treated. Although LSA may be treated with highly potent topical steroids to relieve symptoms, such as pruritus,21,22 many patients do not experience complete resolution of the lesions.21,22 Even among patients with an initial cure, relapse is common. Circumcision may be required in men with phimosis.21–23 Notably, genital LSA has been associated with squamous cell carcinoma and, consequently, these patients often require periodic follow-up.21,22 In the short term, ACD can be treated using strong to moderately strong topical steroids and/or oral steroids.31 Patients usually experience resolution 2 to 6 weeks following removal of the allergen. Typically, patients with DIP experience a complete resolution of their symptoms after cessation of the offending drug, although it may take several months.40–42,48 The mortality rate for patients with pseudolymphoma syndrome/hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms is approximately 10%.42,47,48 Oral and topic steroids and antihistamines may be required until the process subsides.41,42,45,48
Careful clinicopathologic correlation is necessary to accurately diagnose MF and its imitators (Table). Early LSA may resemble the patch or plaque stage of MF but tends to show a subepidermal zone of fibrosis and interface changes. In addition, fewer lymphocytes and fewer atypical lymphocytes are seen in the epidermis in LSA. Finally, a genital location favors LSA. ACD is an eczematous mimic of MF; however, acanthosis, dyskeratotic keratinocytes, spongiosis, papillary dermal edema, and Langerhans cell microabscesses support a diagnosis of ACD. Clinical history can also help to identify an allergen. Although DIP may be histopathologically identical to MF, a clinical history of a recent medication typically associated with DIP, a single lesion, clinical findings compatible with a hypersensitivity syndrome, and resolution of the process with discontinuation of the offending drug support a diagnosis of DIP. Finally, ancillary studies showing a loss of pan–T-cell markers and a T-cell clone substantiate a diagnosis of MF but should be interpreted within the context of the case as a whole because these characteristics may be seen in nonneoplastic conditions.
The authors have no relevant financial interest in the products or companies described in this article.
Presented as part of the Dermatopathology Greatest Hits short course at annual meeting of the United States and Canadian Academy of Pathology, March 7, 2013, Baltimore, Maryland; and at the New Frontiers in Pathology: An Update for Practicing Pathologists meeting; University of Michigan; September 26–28, 2013; Ann Arbor, Michigan.