J Cutan Pathol 2007: 34: 519–525doi: 10.1111/j.1600-0560.2006.00662.xBlackwell Munksgaard. Printed in Singapore

Copyright # Blackwell Munksgaard 2006

Journal of

Cutaneous Pathology

Perspectives in Dermatopathology

Histologic mimickers of mycosisfungoides: a reviewAbstract: Mycosis fungoides (MF) is a rare type of non-Hodgkin’slymphoma affecting the skin. Because MF develops slowly over severalyears and may have a variety of clinical presentations, including itchypatches, plaques or tumors that may be confused with common benignconditions such as eczema and psoriasis, the disease presentsa diagnostic challenge. The average time to diagnosis varies but isfrequently as long as 3 to 6 years. Skin biopsies frequently reveal non-specific features of several dermatoses; thus, histologic evaluation of thedisease is also challenging. Importantly, various significant and/orbenign conditions may mimic MF histologically and result ina misdiagnosis of MF. Here we review the reported histologicmimickers of MF and discuss both similar and differentiating featuresof each, in order to aid in more accurate interpretation ofdiagnostically challenging skin biopsies. Clinicopathologic correlationis ultimately essential to make accurate diagnosis of MF and itshistologic mimickers.

Reddy K, Bhawan J. Histologic mimickers of mycosis fungoides:a review.J Cutan Pathol 2007; 34: 519–525. # Blackwell Munksgaard 2006.

Kavitha Reddy and Jag Bhawan

Dermatopathology Section, Department ofDermatology, Boston University School ofMedicine, Boston, MA, USA

Jag Bhawan, MD, Dermatopathology Section,Dermatology Department,Boston University School of Medicine,609 Albany St, J-309 Boston, MA 02118, USATel: 11 617 638 5570Fax: 11 617 638 5575e-mail: jbhawan@bu.edu

Accepted for publication August 13, 2006

Mycosis fungoides (MF) represents malignant trans-formation of CD41 T cells in the skin. Themalignancy begins in the skin but may progressover time to involve the entire lymphoreticularsystem, including lymph nodes and internal organs.Differentiation of true MF from dermatologicconditions mimicking MF is important to ensureproper management of the patient’s symptoms andtreatment, and to provide accurate prognosticinformation.Because MF often presents as randomly distri-

buted patches, plaques, and later tumors, it is oftendifficult to distinguish clinically from a myriad ofcommon and benign conditions including eczema,psoriasis and several others. Therefore, skin biopsyhas traditionally been a cornerstone of diagnosis.Skin biopsies showing features of MF must be care-fully interpreted to consider the possibility of cuta-neous T-cell pseudolymphoma, which may mimicMF histologically. A reported false-positive diagnosisrate of 44% and false-negative rate of 40% highlightthe difficulty of correct diagnosis of MF andunderscore the importance of careful review of the

histologic features of MF and its many simulators.1

Here we review the histologic mimickers of MF, inorder to be aware of these entities so that a wrongdiagnosis of MF is not rendered.

Drug-induced reversible lymphoid dyscrasia/drug-induced pseudolymphoma syndrome

A pseudolymphoma syndrome characterized bygeneralized lymphadenopathy, hepatosplenomegaly,fever, arthralgia, eosinophilia and an erythematouseruption has been described in association withcertain drugs, especially antiepileptic drugs. Re-ported cases have shown a band-like infiltrate withcerebriform nuclei in the dermis and possiblePautrier-like microabscesses in the epidermis, oftenmaking drug-induced pseudolymphoma histologi-cally indistinguishable from MF.2 The diagnosis hasbeen established by the clearing of the skin lesionsupon discontinuation of the offending drug.3 Impli-cated drugs include phenytoin, carbamazepine,sodium valproate, gemcitabine, gold and the cloni-dine patch.3 Gleevec, a protein tyrosine kinase

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inhibitor, has been reported to have induceda perivascular infiltrate of large hyperchromaticlymphocytes with focal epidermotropism resemblingMF in one patient. The 1:1 CD4:CD8 ratio of theinfiltrate, however, was consistent with a reactiveprocess and allowed for a diagnosis of drug-inducedpseudolymphoma.4

Persistent nodular arthropod bite reactions

Persistent arthropod bite reactions have often beenclassified as pseudolymphomas because of the densedermal inflammatory infiltrate with numerouslymphocytes. One case demonstrating a broad anddeep dermal atypical cellular infiltrate, withoutepidermal changes, was initially diagnosed asa non-epidermotropic T-cell lymphoma.5 A lack ofabnormalities on chest radiography, computedtomography of the abdomen and pelvis, and bloodstudies led to reconsideration of the diagnosis. Asecond interpretation was then obtained whichmade note of plasma cells and eosinophils in theinfiltrate, patchy staining with the B-cell markerCD20 and the clinical history of a wasp sting in thelocation of the biopsy area 3 months prior, leading toa revised diagnosis of persistent nodular arthropodbite reaction. In considering such cases, overlyingspongiosis of the epidermis, when present, alsosupports a diagnosis of arthropod bite rather thanMF. In addition, the formation of lymphoid folliclesin a persistent bite reaction, with germinal centerformation and lack of clonality, have aided in thediagnosis in cases mimicking MF.6

Secondary syphilis

Secondary syphilis is known as the �great imitator’clinically and may also fill this role histologically, asa variety of histologic patterns have been reported.The rare nodular form of secondary syphilis hasbeen reported to have mimicked MF both clinicallyand histologically. In one reported case, findings ofa dense infiltrate containing lymphocytes withcerebriform nuclei, single-cell epidermotropismand folliculotropism with follicular mucinosis led toan initial interpretation of atypical lymphoidinfiltrate, possibly representing MF.7 Further biopsyspecimens revealed numerous plasma cells andshowed the infiltrate to have nearly equal propor-tions of B and T cells and be polyclonal in nature.This led to a suspicion of syphilis rather than MF,and a positive rapid plasma reagin test confirmedthe diagnosis of secondary syphilis. As is exemplifiedby this case, the presence of numerous plasma cellsshould prompt consideration of secondary syphilis.When present, characteristic histologic features ofsecondary syphilis such as endarteritis, perivascular

plasma cell infiltrate, inflammatory infiltrate obscur-ing the dermoepidermal junction and epidermalhyperplasia also raise the possibility of secondarysyphilis. As is always prudent with this disease ofmany disguises, secondary syphilis should be con-sidered in the differential diagnosis of lesionsshowing histologic features of MF.

Lymphomatoid dermatitis

Lymphomatoid allergic contact dermatitis witha dense, band-like lymphocytic infiltrate has beenreported to mimic the similar dense and band-likeinfiltrate often seen in MF. In two reported cases, thedense infiltrate was initially diagnosed as consistentwith MF.8,9 In each case, the correct diagnosis ofallergic contact dermatitis was eventually establishedafter positive patch reactions to allergens known tobe in contact with the biopsy site were found: thefirst was a biopsy of hand dermatitis, with an allergyto the striker part of a matchbox, and the secondwas a biopsy of a left posterior thigh dermatitis, withan allergy to a rubber eraser the patient carried inhis back pocket. Ackerman et al. also warned thatallergic contact dermatitis could closely mimic MF,reporting several cases of spongiotic dermatitis, mostoften allergic contact dermatitis, with foci of atypicalmononuclear cells that he cautioned could be easilymisdiagnosed as Pautrier microabscesses.10

Histologically, MF does not often demonstrate theepidermal changes of spongiosis, apoptosis oracanthosis that are commonly seen in dermatitis.Therefore, the presence of significant spongiosisfavors a diagnosis of dermatitis in cases mimickingMF. However, vesicular variants of MF do occur,and in cases with intraepidermal or subcornealvesiculation, MF cannot be ruled out.11 Significantupper dermal edema should suggest an inflammatorydermatosis over a diagnosis of MF. Intraepidermalinflammatory cells may be differentiated from mycosiscells more easily if they are present in flask-shapedcollections, with the mouth of the flask open at thestratum corneum.11 The presence of Langerhanscell collections also favors a reactive process. Thesemay be identified as collections of large cells withabundant cytoplasm, pale indented nuclei andpositive CD1a staining. Dermatitis often lacks theclassic epidermal lymphocytic atypia seen in MF.12

Also, there is retention of pan-T-cell markers andusually no abnormal T-cell receptor (TCR) rear-rangement. A positive patch test may aid in con-firmation of contact dermatitis in equivocal cases.13

Nodular scabies

The nodular variant of scabies often displays a dense,chronic inflammatory lymphocytic infiltrate with

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eosinophils that has been mistaken for the denselymphocytic infiltrate seen in MF.14 In one reportedcase, a predominantly T-cell infiltrate with epider-motropism and Pautrier-like microabscesses wasinitially felt to represent a T-cell lymphoma.15 How-ever, a colleague noticed a mite in the epidermis ofone section, confirming the diagnosis of scabies. Incases where mites are not found, clearing afterscabetic therapy will establish the diagnosis; how-ever, it should be noted that nodules may persist formonths after therapy.16

Chronic actinic dermatitis (actinic reticuloid)

Chronic actinic dermatitis, a photoallergic derma-tosis seen in older men, may mimic MF bothclinically and histologically. Cases of chronic actinicdermatitis have been reported which show very littlespongiosis, Pautrier-like microabscesses and possibleatypical hyperchromatic cells with cerebriformnuclei, thus resembling lymphoma.17,18 Ultimately,acanthosis, papillary dermal changes similar tolichen simplex chronicus (thickened papillary dermiswith vertically oriented coarse collagen bundlesparallel to the rete ridges), stellate multinucleatedfibroblasts and thickened and increased blood vesselsaid in differentiation from CD81 variants of MFand aid in making the correct diagnosis of actinicreticuloid. The lymphocytes are most oftenCD81,19 allowing for distinction from MF, whichis generally CD41. The diagnosis may be con-firmed by phototesting showing positive photosen-sitivity to ultraviolet (UV) A and UVB light.

Fungal infections

We have observed several cases of tinea andcandidiasis with band-like infiltrates of lymphocytes,including atypical forms, and lymphocytic exocytosissuggestive of MF (Fig. 1A, B). However, PeriodicAcid-Schiff (PAS) examination showed the presenceof Candida or dermatophyte infection (Fig. 1C). Thisunderscores the importance of performing PASexamination in all skin biopsies with inflammatoryinfiltrates.20 It is also interesting to point out thatsome MF cases have been shown to have a concom-itant fungal infection.21

Lichen sclerosus et atrophicus

A recent study described nine cases of lichen sclerosuspresenting with histologic features of MF.22 MF wassuggested because of dense band-like infiltrates withexocytosis of lymphocytes into the lower epidermis,hyperkeratosis and superficial dermal fibrosis. Amonoclonal TCR gamma gene rearrangement was

detected in one of the nine cases. We have observeda similar case (Fig. 2A–D), which showed a narrowband of papillary dermal homogenization, band-likelymphocytic infiltrate, basal lymphocytes and lym-phocytic exocytosis suggestive of MF. However, theclinical findings and negative polymerase chainreaction studies were consistent with lichen sclerosuset atrophicus (LSA). Lichen sclerosus is most oftenfound in the vulvar or perianal area of females aswhite plaques, and thus the clinical description maystrongly suggest LSA over MF.

Fig. 1. A case of Candida infection mimicking cutaneous T-cell

lymphoma (A–C). A) A moderately dense band-like lymphocytic

infiltrate with lymphocytic exocytosis (hematoxylin and eosin 310).

B) Collections of lymphocytes in the epidermis as well as some

lymphocytes with atypical cerebriform nuclei. Pseudohyphae are

visible in the stratum corneum (hematoxylin and eosin 320).

C) Budding yeast and pseudohyphae in the stratum corneum

(PAS 320).

Histologic mimickers of mycosis fungoides

521

Lichen striatus

Lichen striatus frequently exhibits several non-specifichistopathologic features and general lichenoidchanges, which make diagnosis of this chameleon-likedisease challenging. One study of 41 cases showed10 cases which simulated other disease closely, ofwhich 3 of these 10 simulated MF.23 In these cases,pagetoid spread of large hyperchromatic lympho-cytes and the presence of a band-like lymphocyticinfiltrate simulated MF. The finding of features oflichen striatus such as collections of histiocyteswithin the epidermis and also the observation thatthe epidermotropic cells were CD81 provided cluesto the correct diagnosis of lichen striatus. We haveobserved a case where the diagnosis was mistakenfor MF, including a band-like superficial infiltratewith epidermotropism and haloed lymphocytes inthe basal layer (Fig. 3A–C). Clinicopathologic cor-relation was however not good for MF, anda diagnosis of lichen striatus was considered. TCRgene rearrangement was negative, and the patient iswell after 3 years of follow up, without any signs ofdisease. Epidermal changes such as spongiosis,edema and focal parakeratosis usually permitdifferentiation from MF.24

Lichenoid keratosis (solitary lichen planus orlichen-planus-like keratosis)

A recent retrospective study called attention to anMF-like histologic pattern of benign lichenoidkeratoses, showing most frequently Pautrier micro-abscesses and alignment of lymphocytes along thebasal layer (.90%).25 Epidermotropism was alsofrequently found (80%). Other features includedcerebriform nuclei in lymphocytes, epidermal atro-phy, larger lymphocytes in the epidermis than thosein the dermis and papillary dermal fibrosis. Thepresence of at least one of the following features oflichenoid keratosis aided in a diagnosis of lichenoidkeratosis in 87% of the cases studied: wedge-shapedhypergranulosis, necrotic keratinocytes, eosinophils,adjacent solar lentigo or seborrheic keratosis, pointedcontour of the rete ridges and plasma cells.

Pigmented purpuric dermatitis

Twenty-nine of 56 patients with pigmented purpuricdermatitis (PPD) showed histologic patterns typicalof MF, including epidermotropism, papillary dermalfibrosis, lymphocytic atypia and epidermal hyper-plasia.26 We have seen similar cases with prominentpapillary dermal lymphocytic infiltrate, lymphocyticexocytosis and papillary dermal fibrosis, givingthe appearance of MF (Fig. 4A–D). However,

Fig. 2. Lichen sclerosus et atrophicus mimicking cutaneous T-cell

lymphoma (A–D). A) A moderately dense, band-like lichenoid

lymphocytic infiltrate (hematoxylin and eosin 320). B) Band-like

lymphocytic infiltrate with marked lymphocytic exocytosis (hema-

toxylin and eosin 320). C) High-power magnification of (A) shows

an area of papillary dermal homogenization and basal layer

lymphocytes (hematoxylin and eosin 340). D) A narrow band of

papillary dermal homogenization above the infiltrate, basal layer

lymphocytes and epidermotropism (hematoxylin and eosin 340).

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Fig. 3. Lichen striatus mimicking cutaneous T-cell lymphoma

(A–C). A) A perivascular and lichenoid lymphocytic infiltrate of

moderate density (hematoxylin and eosin 310). B) Band-like

lymphocytic infiltrate, papillary dermal fibrosis and epidermotrop-

ism (hematoxylin and eosin 320). C) Band-like lymphocytic

infiltrate, papillary dermal fibrosis, lymphocytic exocytosis resem-

bling Pautrier abscess and dermal lymphoid cell infiltrate

(hematoxylin and eosin 340).

Fig. 4. Pigmented purpuric dermatitis mimicking cutaneous T-cell

lymphoma (A–D). A) Moderately dense, band-like lichenoid

lymphocytic infiltrate (hematoxylin and eosin 310). B) Papillary

dermal fibrosis and marked lymphocytic exocytosis (hematoxylin

and eosin 320). C) Extensive lymphocytic exocytosis along with

haloed lymphocytes (hematoxylin and eosin 340). D) Numerous

extravasated erythrocytes and lymphohistiocytic infiltrate and basal

lymphocytes (hematoxylin and eosin 320).

Histologic mimickers of mycosis fungoides

523

extravasation of red blood cells, along with clinicalfindings and negative T-cell gene rearrangement wasmore consistent with pigmented purpura.

Melanophages and extravasated erythrocytes maybe present in both PPD and MF. When differentia-ting between the two conditions, the presence ofintraepidermal lymphocytes larger than dermallymphocytes, atypical lymphocytes in the dermisand papillary dermal fibrosis support a diagnosis ofMF over PPD.26,27 While cases of PPD haveclinically resembled MF and vice versa, it is unlikelythat clear, undisputed cases of PPD have thepotential to progress to MF as has been suggestedby some.1

Connective tissue disease/lupus

A case of chronic cutaneous lupus erythematosusdisplaying epidermotropism and atypical lympho-cytic infiltrate initially diagnosed as MF wasreported.28 Repeated biopsies, however, showedfeatures of lupus erythematosus. A positive antinu-clear antibody test and good response to hydroxy-chloroquine led to a diagnosis of chronic cutaneouslupus erythematosus mimicking MF. In equivocalcases, a positive lupus band test in lesional skin willestablish the diagnosis of lupus erythematosus.Another study of patients with atypical lymphoidinfiltrates arising in the setting of diagnosed con-nective tissue disease reported a pattern of infiltrateswhich mimicked MF because of a dense, atypical,epidermotropic or folliculotropic T-cell-rich lym-phocytic infiltrate, including cells with cerebriformnuclei.29 Clinically, the lesions resembled subcuta-neous lupus erythematosus (SCLE) and discordlupus erythematosus (DLE). In all cases, concomi-tant lymphomatoid vasculitis, a polymorphous infil-trate with numerous histiocytes, pan-T-cell markerpreservation and polyclonal TCR gene rearrange-ments allowed for the correct diagnosis of connec-tive tissue disease without the development of MF.

Inflamed vitiligo

A case of vitiligo demonstrating a moderately denseperivascular and interstitial lymphocytic infiltratewith exocytosis into the epidermis and follicularepithelium was reported.30 This pattern initiallysuggested hypopigmented MF. However, there wasretention of pan-T-cell markers, and TCR genomeanalysis did not reveal a clonal rearrangement.Therefore, a diagnosis of MF was ruled out.Immunostaining revealed decreased numbers ofmelanocytes, suggesting possible vitiligo. Six monthslater, the lesion depigmented, confirming thediagnosis of vitiligo.

Regressed malignant melanoma

In some instances, malignant melanomas may posea diagnostic challenge and can vary from benignnevoid appearance to amelanotic spindle cell lesionsresembling mesenchymal tumors. Recently, a case ofpartially regressed malignant melanoma with a denselymphocytic response and striking epidermotropismclosely resembling MF was reported. The pre-dominant CD8 positivity of the infiltrate andHMB45 and S100 positivity of the melanoma cellsled to the correct diagnosis of regressing malignantmelanoma, but the authors caution that regressedmalignant melanoma may present a diagnosticpitfall if one is not careful.31

Conclusion

Differentiation of MF from its histologic mimickersremains one of the greatest diagnostic challenges indermatopathology. Accurate diagnosis of MF in skinbiopsy correlates significantly with the experience,skill and training of the dermatopathologist, andconsultation with a trained dermatopathologist ishighly recommended when the diagnosis is inquestion.11 Diagnosis must be based on a constella-tion of clinical and histologic criteria and nevera single finding in order to accurately confirm thediagnosis when features of MF are present.32,33 Thisis exemplified by the results of TCR gene rearrange-ment studies in MF and benign inflammatorydermatoses which may mimic MF. Early patch-stage MF frequently lacks a detectable clonalrearrangement,34 and benign inflammatory derma-toses occasionally have a clonal rearrangement.34,35

This emphasizes the need for clinicopathologiccorrelation when interpreting the results of clonalitystudies. While several authors have suggestedevolving histologic criteria for the diagnosis ofcutaneous T-cell lymphoma over the past severalyears,36–39 ultimately, clinicopathologic correlation isessential when differentiating MF from its histologicmimickers.

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