Lymphomatoid Keratosis an Epidermotropic Type of Cutaneous Lymphoid Hyperplasia: Clinicopathological, Immunohistochemical, and Molecular Biological Study of 6 Cases

Home , Keratosis, Seborrheic keratosis

STUDY Lymphomatoid Keratosis An Epidermotropic Type of Cutaneous Lymphoid Hyperplasia: Clinicopathological, Immunohistochemical, and Molecular Biological Study of 6 Cases

Eiichi Arai, MD; Michio Shimizu, MD; Tetsuya Tsuchida, MD; Seiichi Izaki, MD; Fumihiro Ogawa, MD; Takanori Hirose, MD

Objective: To provide evidence that lymphomatoid kera- immunoglobulin heavy chain gene and T-cell receptor tosis should be categorized as an epidermotropic sub- (TCR)-␤ and TCRγ genes was also investigated by the type of cutaneous lymphoid hyperplasia. polymerase chain reaction method.

ϩ Design: Clinicopathological, immunohistochemical, and Results: Immunohistochemically, epidermotropic CD20 molecular biological studies of epidermotropic and der- and/or CD79aϩ cells were present. In the upper dermal mal bandlike infiltrates of lymphocytes without ne- lymphocytic infiltrates, the CD3ϩ/CD79aϩ cell ratio ranged crotic keratinocytes, Civatte bodies, or Max-Joseph spaces from 5:5 to 8:2. The CD4ϩ/CD8ϩ cell ratio was within and solar lentigo or seborrheic keratosis adjacent to the normal limits. Rearrangements of the TCRγ gene were lesion, but with epidermal hyperplastic change (clini- demonstrated in 2 cases and of the TCRβ gene in 1 case. cally scaly plaque) in cases of lymphomatoid keratosis. Conventional histopathologic study as well as immuno- Conclusions: Our results indicate that lymphomatoid histochemical examinations for CD1a, CD3, CD4, CD8, keratosis is a clinically benign keratotic lesion but his- CD20, and CD79a and S100 protein and genotypic ex- tologically malignant, simulating mycosis fungoides. aminations were performed. Immunohistochemical findings showed a reaction pattern in all cases, but genotypical examination showed Setting: University departments comprising 2 sections some clonal dermatoses. Therefore, “lymphomatoid” of dermatology and 1 section of pathology. keratosis should be classed as a pseudolymphoma, namely, a subtype of cutaneous lymphoid hyperplasia Main Outcome Measures: Ratio of T to B cells and with epidermotropism. of CD4ϩ to CD8ϩ cells, and the phenotype of epidermotropic cells were evaluated. Gene rearrangement of the Arch Dermatol. 2007;143:53-59

HE TERM LYMPHOMATOID is noteworthy that the term pseudolym- keratosis was originally pro- phoma was originally adopted to indicate posed by Kossard1 and was a lesion clinically or histologically simu- thought to be a possible lating malignant lymphoma. Therefore, the variant of benign lichen- term lymphomatoid is considered to be oidT keratosis showing lymphomatoid fea- equivalent to so-called pseudolymphoma. tures. He considered that the case re- Epidermotropism is defined as an affin- ported by Evans et al2 as a unilesional ity of tumor cells for the epidermis. Vari- mycosis fungoides (MF) should be termed ous conditions display lymphocytic infil- lymphomatoid keratosis. Clinically, the case trates with tropism for the epidermis. reported by Evans et al2 was character- Epidermotropism was not included in the glossary of the fifth edition of Histopathol- ized by an asymptomatic scaly plaque, but Author Affiliations: ogy of the Skin by Lever and Schaumburg- Departments of Pathology the histological features were those seen 4 (Drs Arai, Shimizu, Ogawa, and Lever in 1975. However, it appeared in in MF. Therefore, the most important the sixth edition in 1983.5 In this text- Hirose) and Dermatology pathological feature of lymphomatoid (Dr Tsuchida), and Department book, epidermotropism was reportedly re- keratosis is epidermotropism resembling stricted to MF as follows5(p764): of Dermatology, Saitama 3 Medical Center (Dr Izaki), that seen in MF. Namely, the term lym- Saitama Medical University, phomatoid in lymphomatoid keratosis in- Presence of mononuclear cells in the epider- Saitama, Japan. dicates histological simulation of MF. It mis without spongiosis occurring in MF. The

(REPRINTED) ARCH DERMATOL/ VOL 143, JAN 2007 WWW.ARCHDERMATOL.COM 53

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 cells lie either singly, surrounded by a clear halo, or aggre- mal collection of more than 3 lymphocytes, (2) disproportion- gated as in a Pautrier microabscess. Epidermotropism must be ate distribution of haloed lymphocytes in the epidermis, and differentiated from exocytosis. (3) linear aggregates of haloed lymphocytes at the dermoepidermal junction. However, there have been descriptions of epidermotropism in other tumors. In 1983, Burg and Braun- Falco6(p386) stated that in histiocytosis X, “An important his- IMMUNOHISTOCHEMICAL ANALYSIS tological feature is epidermotropism of the characteristic cells.” Burkert et al7 used the term pseudo-Pautrier ab- A set of 4-µm-thick tissue sections were prepared from forma- lin-fixed and paraffin-embedded blocks, deparaffinized in xy- scess for Langerhans cell microgranulomas, and Klein et 8 lene, rehydrated, and microwaved for 10 minutes at 30% al used the term epidermotropic nature to describe poro- power in citrate buffer, pH 9.0 (Dako Japan, Kyoto) for anti- carcinoma (malignant poroma). Moreover, Murphy and gen retrieval. Endogenous peroxidase activity was blocked us- Schwarting 9 used the term atypical epidermotropic infil- ing 0.3% hydrogen peroxide in methanol for 5 minutes. Im- trate for benign conditions such as lymphomatoid drug munostaining was carried out after antigen retrieval by eruption. Bayer-Garnar et al10 reported that CD68ϩ his- microwaving in 1 mM EDTA (pH 8.0) 2 times for 5 minutes tiocytes showed epidermotropism in benign lichenoid kera- each time at 900 W. Then the streptavidin-biotin-peroxidase tosis. In other words, all cells tropic for the epidermis have complex method was used for immunostaining with a Ven- so far been included in the concept of epidermotropism. tana OH system immunostainer (Ventana-Biotech, Tucson, Therefore, epidermotropism has been used mostly as Ariz). The primary antibodies against the lymphoid antigens were CD1a (O10; Immunotech, Marseille, France [undi- a descriptor for MF, which is epidermotropism in the nar- luted]), CD3 (PS-1; Novocastra, Newcastle-upon-Tyne, En- row sense. All of the cases we have examined have fallen gland [1:100 dilution]), CD4 (1F6; Novocastra [1:40 dilu- into this category, which shows complete histological simi- tion]), CD8 (C8/144B; Dakopatts, Glostrup, Denmark [1:100 larity to MF. The epidermotropism of MF is a phenom- dilution]), CD20 (L26; Dakopatts [1:100 dilution]), CD68 enon whereby lymphocytes infiltrate into the epider- (PG-M1; Dakopatts [1:200 dilution]), CD79a (JCB117; Da- mis, slippery with perinuclear halo, and do not attack the kopatts [1:100 dilution]), ␬chain (A8B5; Dakopatts [1:100 di- basement membrane or keratinocytes. This phenom- lution]), ␭ chain (C4; Immunotech [1:50 dilution]), and S100 enon occurs in specific conditions caused by long- protein (Dakopatts [1:300 dilution]). Human tonsillar tissue standing chronic inflammation in the skin-associated lym- was used as a normal control. The main features evaluated 11 during immunohistochemical testing were (1) the B to T-cell phoid tissue of the upper dermis. Kazakov et al and ϩ ϩ 12 ratio; (2) the ratio of the CD4 to CD8 cells; (3) the pheno- Massone et al have described epidermotropism in sev- type of epidermotropic cells; and (4) the proliferation of eral of the following conditions: (1) disproportionate epi- CD1a- and/or S100 protein-positive cells in the epidermis and dermotropism (presence of many lymphocytes distrib- dermis. uted irregularly), (2) basilar lymphocytes (presence of linear aggregates of small hyperconvoluted lympho- GENOTYPIC ANALYSIS cytes located at the dermoepidermal junction), (3) large epidermal lymphocytes (intraepidermal lymphocytes For genotypic studies, DNA was extracted from 10-µm-thick larger than those in the dermis), (4) Pautrier microab- paraffin sections by proteinase K (200 µg/mL) digestion. The scesses (presence of intradermal collection of more than supernatant containing DNA was used directly for polymerase 3 lymphocytes), and (5) haloed lymphocytes (presence chain reaction amplification. The polymerase chain reaction was of a perinuclear clear space), all of which may be recog- used to detect rearrangement of the immunoglobulin heavy chain nized as epidermotropism in the narrow sense. (IgH) gene using 3 VH primers (FR1c, FR2a, and FR3a) and 2 13 ␤ Based on these facts, we performed clinicopathologi- JH primers (LJH and VLJH) ; the T-cell receptor (TCR) chain ␤ ϩ ␤ ϩ cal, immunohistochemical, and molecular biological stud- gene using the following 5 primer sets: 1 (V J1), 2 (V J2), ␤ ϩ ␤ ϩ ␤ ϩ 14 ␥ ies of 6 cases of clinically benign scaly plaque and epi- 3 (D1 J1), 4 (D1 J2), and 5 (D2 J2) ; and the TCR chain gene using the following 20 mixed primer sets: mix 1 (V V , dermotropism histologically similar to that in MF. We 2 8 V3,V4,V9,J1.12.1,J1.2,J1.32.3,J1.12.1 in,J1.2 in,J1.32.3 in)andmix2(V5, investigated whether lymphomatoid keratosis should be 15 V10,V11,V12,J1.12.1,J1.2,J1.32.3,J1.12.1 in,J1.2 in,J1.32.3 in). classified as an epidermotropic subtype of cutaneous lymphoid hyperplasia. RESULTS

METHODS CLINICAL FINDINGS

CASE SELECTION The clinical data are demonstrated in Table 1. The patients ranged in age from 36 to 78 years, with a mean age A retrospective review of the files of Saitama Medical Univer- of 59 years, and the male-female ratio was 1:1. The size sity Hospital and Saitama Medical Center Hospital, Saitama, Ja- (largest diameter) of the lesions ranged from 0.6 to 1.6 pan, for the period 2000 to 2004 identified 6 cases of lympho- cm, with a mean of 0.85 cm. All cases revealed solitary matoid keratosis, which showed solitary scaly plaque clinically, scaly plaques (Figure 1). The face was the most com- and histologically, typical epidermotropism and bandlike lymphocytic infiltration in the upper dermis without necrotic ke- mon lesion site. Either actinic keratosis or seborrheic kera- ratinocytes, Civatte bodies, or Max-Joseph spaces and solar len- tosis was suspected clinically in 5 of the 6 cases. The pe- tigo or seborrheic keratosis adjacent to the lesion. In the present riod from the patient’s recognition of the lesion until study, the epidermotropism showed 3 of the following pat- visiting the hospital ranged from 3 months to several years. terns: (1) Pautrier microabscesses, which are an intraepider- Follow-up data from the diagnosis were obtained in cases

(REPRINTED) ARCH DERMATOL/ VOL 143, JAN 2007 WWW.ARCHDERMATOL.COM 54

Case No./ Lesion Largest Period Prior to Sex/Age, y Location Diameter, cm Medical Examination Clinical Diagnosis 1/M/78 Right cheek 1.6 ϫ 0.5, cm 2-3 y Actinic keratosis 2/F/52 Left eyelid 0.8 ϫ 0.3, cm Several years Actinic keratosis 3/F/61 Right cheek 1.0 ϫ 1.0, cm 3 mo Actinic keratosis 4/M/58 Right forearm 1.2 ϫ 1.0, cm NA Senile angioma 5/M/69 Right forehead 0.6 ϫ 0.5, cm Several years Seborrheic keratosis 6/F/36 Right eyelid 0.9 ϫ 0.8, cm 2 mo Seborrheic keratosis

Abbreviation: NA, not available.

A B A

B Figure 1. Clinical features of lymphomatoid keratosis. A, Solitary scaly and elevated plaques are present on the right cheek (case 1); B; close-up view of affected cheek.

1 and 6; neither showed recurrence or cutaneous dis- semination in 34 months and 13 months, respectively.

HISTOPATHOLOGICAL FINDINGS

All of the cases showed hyperkeratosis, parakeratosis, acanthosis, and bandlike lymphocytic infiltration (Figure 2). All of them showed epidermotropism; 3 cases showed Pautrier microabscesses, 3 showed disproportionate lymphocytes, and 2 showed basilar lymphocytes (Figure 3). No atypical keratinocytes, basal cells, or atypical lymphocytes were observed. Various degrees of in- Figure 2. Histopathological features of lymphomatoid keratosis. A, Scanning filtration of plasma cells, eosinophils, and mela- examination shows bandlike lymphocytic infiltration in the upper dermis. B, The middle-power view shows acanthosis with mild hyperkeratosis and nophages were noted in all of the lesions. parakeratosis in the epidermis. Epidermotropism is present (case 2) (hematoxylin-eosin, original magnification ϫ4 [A] and ϫ20 [B]). IMMUNOHISTOCHEMICAL FINDINGS

The immunohistochemical data are summarized in epidermis were increased in number and were also pre- Table 2. Dermal infiltrating cells including many CD20ϩ sent in the upper dermis. Such cells were also present in and/or CD79aϩ cells were intermingled among lym- the dermal inflammatory infiltrate. phoid follicles in 2 of the 6 cases. The dermal infiltrating lymphocyte population was composed of various pro- GENOTYPIC FINDINGS portions of T and B cells: the CD3ϩ/CD79ϩ cell ratio ranged from 5:5 to 8:2 (Table 2). In all cases epidermo- The genotypic data are given in Table 2. No rearrange- tropic CD20ϩ and/or CD79aϩ cells were present ment was observed in the IgH gene. However, using the (Figure 4). The dermal infiltrating cells comprised nor- mix 1 primer set, rearrangements of the TCRγ gene were mal CD4ϩ and CD8ϩ lymphocytes (Figure 5). Cells posi- demonstrated in 2 cases (case 1 [Figure 6] and case 6) tive for CD1a and/or S100 protein within the overlying and of the TCRβ gene in 1 case (case 6).

(REPRINTED) ARCH DERMATOL/ VOL 143, JAN 2007 WWW.ARCHDERMATOL.COM 55

Figure 3. Epidermotropism in lymphomatoid keratosis. A, Pautrier microabscesses are seen in case 2. B, Lined-up distribution at the dermoepidermal junction is evident in case 6 (hematoxylin-eosin, original magnification ϫ4 [A] and ϫ20 [B]).

Table 2. Immunohistochemical and Genotypical Findings in Lymphomatoid Keratosis

B-Cell Lymphoid CD3/CD79a TCR␤ TCR␥ Case No. Epidermotropism Follicles Ratio Rearrangement Rearrangement 1PM ϩ 6:4 − Mix 1 (ϩ) 2PM ϩ 5:5 − − 3 PM − 6:4 − − 4 DE − 8:2 − − 5DEϩ BL − 7:3 − − 6DEϩ BL − 7:3 ϩ Mix1(ϩ)

Abbreviations: BL, basilar lymphocytes; DE, disproportionate epidermotropism; PM, Pautrier microabscesses; TCR, T-cell receptor; ϩ, positive findings; −, negative findings.

A B

Figure 4. Epidermotropism of CD3- and CD20-positive cells. Epidermotropic and dermal infiltrative cells in case 4 stained for CD3 (A) and in case 4 stained for CD20 (B) (original magnification ϫ60 [A and B]).

A B

Figure 5. Immunohistochemical features of lymphomatoid keratosis (case 2). Cells positive for CD20, CD4, and CD8 are intermingled in the upper dermis. Many cells positive for CD20 (and/or CD79a) are present. CD4-positive cells (A) are predominant over CD8-positive cells (B) compared with the normal CD4/CD8 ratio (original magnification ϫ40 [A and B]).

COMMENT 93%, 3 or more lymphocytes aligned along the basal layer without overlying intraspinous lymphocytes or spongio- Lymphomatoid keratosis has been recognized as a vari- sis in 93%, and intraepidermal lymphocytes surround- ant of lichenoid keratosis,1 which clinically forms scaly ing haloes without spongiosis in 80%. Namely, all of these plaques and histologically shows epidermotropism that cases were thought to have epidermotropism in the nar- is a characteristic feature of MF. Al-Hoqail and Craw- row sense. Clinically, the age of their studied patients ford16 reported 15 cases of benign lichenoid keratosis with ranged from 28 to 83 years, with a mean age of 50 years; histological features of MF showing marked overlap- the male-female ratio was 3:2; and the lesions ranged in ping with lymphomatoid keratosis. Their cases showed size from 0.2 to 1.8 cm, with a mean of 0.6 cm. The up- intraepidermal aggregation of 3 or more lymphocytes in per trunk was the most commonly affected site in 7 of

(REPRINTED) ARCH DERMATOL/ VOL 143, JAN 2007 WWW.ARCHDERMATOL.COM 56

194 bp 190 bp

Figure 6. TCR␥ chain gene rearrangement in lymphomatoid keratosis. A, Case 1 of mix 1 shows a positive band; B, case 1 of mix 2 shows a smearlike band at a position different from the control band.

the 15 cases, followed by the face and extremities in 4 Kazakov et al11 have reported that unilesional MF can cases. These clinical features were compatible with those sometimes recur after surgical excision. However, there seen our present cases. However, 4 of these 15 cases did have been no reports of extradermal spread, and all re- not have necrotic keratinocytes and 6 did not have solar ported cases have shown a benign course.18-22 There- lentigo or seborrheic keratosis adjacent to the lesion. Ne- fore, the cases reported by Yoo et al23 as “unilesional my- crotic keratinocytes were adopted as a feature to consti- cosis fungoides mimicking Bowen’s disease” and by Bazza tute an entity of papular MF.17 The presence of solar len- et al24 as “[m]ycosis fungoides masquerading as sebor- tigo or seborrheic keratosis adjacent to the lesion showed rheic keratosis”24 might have been cases of lymphoma- that the lesion was in a regressing state from solar len- toid keratosis. Thus, the diagnosis of lymphomatoid kera- tigo or seborrheic keratosis. Therefore, it is suggested that tosis requires careful clinicopathological examination to these cases included some cases having both necrotic ke- make a distinction from unilesional MF. ratinocytes and solar lentigo or seborrheic keratosis ad- Hodak et al21 suggested the possibility of actual jacent to the lesion. These limited cases, which showed T-cell pseudolymphoma in unilesional MFs as well as the same features as our cases, are in fact thought to be minimal stage IA MF. We previously demonstrated that lymphomatoid keratosis. In the cases reported by Al- cases formerly diagnosed as cutaneous lymphoid hyper- Hoqail and Crawford,16 the clinical diagnoses included plasias (including lymphocytoma cutis, lymphadenosis 10 cases of cutaneous malignancy (basal cell carcinoma, benigna cutis, or Spiegler-Fendt–type pseudolym- squamous cell carcinoma, and actinic keratosis). In our phoma) could be reclassified into cutaneous marginal zone series, 3 cases of actinic keratosis were noted. Reported lymphoma, diffuse large B-cell lymphoma, pseudolym- cases of benign lichenoid keratosis with histological fea- phomatous folliculitis, cutaneous lymphoid hyperpla- tures of MF and lymphomatoid keratosis1,16 have not sia in the narrow sense, and solitary nonepidermotropic shown any development of MF. pseudo-T-cell lymphoma.25 Now we consider it feasible Although lymphomatoid keratosis was first recog- to add not only solitary nonepidermotropic pseudo–T- nized as unilesional MF by Evans et al,2 Kossard1 sug- cell lymphoma but also lymphomatoid keratosis to the gested that their case was lymphomatoid keratosis. There- cutaneous MF-like T-cell–type “pseudolymphoma” group. fore, lymphomatoid keratosis should be differentiated from Although lymphomatoid keratosis shows epidermot- unilesional MF clinicopathologically. Unilesional MF is ropism in the narrow sense, its immunological micro- typified by involvement of less than 5% of the body sur- environment is different from that of MF. Our findings face.18 It is usually found in the same body regions as clas- from immunohistochemical analysis showed many B cells sic MF, such as the breast, axilla, and buttock. Histopatho- in the dermal infiltrates and B-cell epidermotropism. logical findings are identical to those seen in classical Moreover, there were increased numbers of cells posi- MF.19-21 Patients with unilesional MF demonstrate an ex- tive for CD1a and/or S100 protein within the lesions in cellent response to topical chemotherapy or irradiation. the overlying epidermis. In contrast, in MF, S100 protein– In other words, unilesional MF appears as a typical clini- positive dendritic cells are increased in the dermis and cal cutaneous lesion of MF in spite of its small size. There- decreased in the epidermis.26 fore, clinical information is important to distinguish be- Bayer-Garner et al10 considered the immunopatho- tween these lesions. However, lymphomatoid keratosis logical change in benign lichenoid keratosis to be “re- clinically mimics basal cell carcinoma, actinic keratosis, gression.” Cytotoxic T cells might be a final common de- or seborrheic keratosis.1,4,16 Unilesional MF usually devel- nominator (key effector cell) of regression. This ops as erythema or plaques, but its boundary is not highly phenomenon was confirmed by Jang et al.27 In benign li- clear. Unilesional MF can also occur in childhood, as Ho- chenoid keratosis CD3ϩ, CD4ϩ T lymphocytes, natural dak et al21 and Alsaleh et al22 have reported. killer cells, macrophages, and Langerhans cells were in-

(REPRINTED) ARCH DERMATOL/ VOL 143, JAN 2007 WWW.ARCHDERMATOL.COM 57

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 3. Comparison of Histological, Phenotypical, and Genotypical Differentiation of Lymphomatoid Keratosis, Lichenoid Actinic Keratosis, Benign Lichenoid Keratosis, and Unilesional Mycosis Fungoides

Civatte Bodies and Max-Joseph Bandlike Phenotypes of TCR Gene Pathophysiological Variable Epidermotropism Spaces Infiltration Lymphocytes Rearrangement Feature Lymphomatoid keratosis ϩ − ϩ B and T Partially ϩ Reaction to stimulus Lichenoid actinic keratosis − ϩ (−) ϩ Predominantly cytotoxic T − Regression Benign lichenoid keratosis − (ϩ) ϩ (−) ϩ Predominantly cytotoxic T − Regression Unilesional mycosis fungoides ϩ − ϩ Helper T ϩ Malignant proliferation

Abbreviations: TCR, T-cell receptor; ϩ, with; −, without; ϩ (−), usually ϩ but sometimes −; − (ϩ), usually − but sometimes ϩ.

termingled in the dermis. Epidermotropism of cells posi- study cases. In lichenoid keratosis, the essential feature is tive for CD1a, CD68, CD3, and CD8 was also noted. How- regression, and no clonality is evident.28 That is, lympho- ever, no B-cell epidermotropism has been reported in matoid keratosis and lichenoid keratosis differ in their im- benign lichenoid keratosis. Whereas Smith et al28 dem- munological microenvironment. The most important fea- onstrated no rearrangement of the TCRγ gene by the poly- ture of lymphomatoid keratosis is the mobilization of B merase chain reaction method in lichenoid keratosis, 2 cells. The epidermotropism of B cells activates the epider- cases in the present study showed TCRγ clonality and 1 mis, and thereafter scaly plaques may form on the surface case revealed TCRβ clonality. of the skin. It has been reported that T-cell clonality, known There had been an attempt to classify benign lichen- as clonal dermatitis,31 is present in benign lymphomatoid oid keratosis into the following 3 groups27: lichen planus– conditions32; some lymphomatoid keratoses, which is a re- like keratosis, seborrheic keratosis–like lichenoid kerato- active process that histologically simulates MF, might pos- sis, and lupus erythematosus–like lichenoid keratosis. sess T-cell clonality. Although there may be areas be- However, Weedon29 claimed that the seborrheic keratosis– tween lymphomatoid keratosis and benign lichenoid like variant should be classified as an irritated seborrheic keratosis and between lymphomatoid keratosis and unile- keratosis. In addition, the lupus erythematosus–like vari- sional MF where the 2 entities show partial merging, we ant is simply a lesion with some basal clefting. Another suggest that lymphomatoid keratosis should be differen- recent large study of benign lichenoid keratosis, which ex- tiated from lichenoid actinic keratosis, benign lichenoid cluded lichen planus, lichenoid drug eruption, lupus ery- keratosis, and unilesional MF (Table 3). Our present find- thematosus, MF, and actinic keratosis, divided the cases ings indicate that lymphomatoid keratosis might be a re- into the following 5 groups30: classic, atrophic, early, bul- active process that histologically simulates MF and that it lous, and atypical. The pathologic features of the fifth atypi- should be considered a form of cutaneous lymphoid hy- cal group are scattered atypical lymphocytes and lichen- perplasia (pseudolymphoma) rather than benign lichenoid infiltrates. In their discussion, the authors described oid keratosis, which is characterized by a regressive pro- the 15 cases of Al-Hoqail and Crawford16 as follows: “al- cess, or unilesional MF, which is characterized by a though they noted the presence of significant lymphocytic tumorous process. epidermotropism and formation of Pautrier abscess, the lymphocytes in this study were not immunophenotyped Accepted for Publication: June 29, 2006. and there was no mention of a T-cell receptor study or ex- Correspondence: Eiichi Arai, MD, Department of Pa- clusion from cutaneous T-cell lymphoma.”30(p391) thology, Saitama Medical School, 38 Morohongo, If lymphomatoid keratosis is to be included in a group Moroyama-machi, Iruma-gun, Saitama 350-0495, Ja- of lichenoid keratotic reaction, then lichenoid actinic kera- pan ([email protected]). tosis and benign lichenoid keratosis (including lichen Author Contributions: Study concept and design: Arai. Ac- planus–like keratosis) are important differential diag- quisition of data: Arai. Analysis and interpretation of data: noses. First, lichenoid actinic keratosis can be differen- Arai, Shimizu, Tsuchida, and Izaki. Drafting of the manu- tiated by the presence of atypical cells among basal cells script: Arai, Shimizu, Tsuchida, Izaki, Ogawa, and Hi- and keratinocytes. Second, benign lichenoid keratosis can rose. Critical revision of the manuscript for important in- be ruled out by the presence of a reaction pattern includ- tellectual content: Arai. ing necrotic keratinocytes, Civatte bodies, Max-Joseph Financial Disclosure: None reported. spaces, and surrounding adjacent solar lentigo or seborrheic keratosis without epidermotropism. To date, in ma- REFERENCES jor dermatopathology textbooks, lymphomatoid keratosis has not been considered a variant of benign lichenoid 1. Kossard S. Unilesional mycosis fungoides or lymphomatoid keratosis? Arch 9,29 keratosis. Dermatol. 1997;133:1312-1313. Strictly speaking, in MF, only CD4ϩ T cells are epider- 2. Evans L, Mackey SL, Vidmar DA. An asymptomatic scaly plaque: unilesional my- motropic, whereas in lymphomatoid keratosis, epidermo- cosis fungoides (MF). Arch Dermatol. 1997;133:231-234. 3. Arai E, Shimizu M, Hirose T, et al. A case of lymphomatoid keratosis [article in tropic cells as well as infiltrating cells are composed of both Japanese with English abstract]. J Jpn Dermatohistopathol Soc. 2004;20:6-9. T and B cells. The incidence of clonality in lymphoma- 4. Lever WF, Schaumburg-Lever G. Histopathology of the Skin. 5th ed. Philadel- toid keratosis may not be high, although it did exist in our phia, Pa: Lippincott; 1975:717-722.

(REPRINTED) ARCH DERMATOL/ VOL 143, JAN 2007 WWW.ARCHDERMATOL.COM 58

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 5. Lever WF, Schaumburg-Lever G. Histopathology of the Skin. 6th ed. London, therapy, and follow-up of 10 patients with a treatment-responsive mycosis fun- England: Lippincott; 1983:762-768. goides variant. J Am Acad Dermatol. 2000;42:283-285. 6. Burg G, Braun-Falco O. Cutaneous Lymphomas. Berlin, Germany: Springer- 19. Oliver GF, Winkelmann RK. Unilesional mycosis fungoides: a distinct entity. Verlag; 1983:378-389. J Am Acad Dermatol. 1989;20:63-70. 7. Burkert KLI, Huhn K, Menezes DW, et al. Langerhans cell microgranulomas (pseudo- 20. Oliver GF, Winkelmann RK, Banks PM. Unilesional mycosis fungoides: clinical, Pautrier abscess): morphologic diversity, diagnostic implications and pathoge- microscopic and immunophenotypic features. Australas J Dermatol. 1989; netic mechanisms. J Cutan Pathol. 2002;29:511-516. 30:65-71. 8. Klein W, Chan E, Seykora JT. Tumors of the epidermal appendages. In: Elder DE, 21. Hodak E, Phenig E, Amichal B, et al. Unilesional mycosis fungoides: a study of ed. Lever’s Histopathology of the Skin. 9th ed. Philadelphia, Pa: Lippincott Wil- seven cases. Dermatology. 2000;201:300-306. liams & Wilkins; 2005:867-926. 22. Alsaleh QA, Nanda A, Baker H, Al-Sabah H, Calonje E. Unilesional (segmental) 9. Murphy GF, Schwarting R. Cutaneous lymphomas and leukemias. In: Elder DE, mycosis fungoides presenting in childhood. Pediatr Dermatol. 2004;21:558- ed. Lever’s Histopathology of the Skin. 9th ed. Philadelphia, Pa: Lippincott Wil- 560. liams & Wilkins; 2005:927-978. 23. Yoo SS, Viglione M, Moresi M, Vonderheid E. Unilesional mycosis fungoides mim- 10. Bayer-Garner IB, Ivan D, Schwartz MR, Tschen JA. The immunopathology of re- icking Bowen’s disease. J Dermatol. 2003;30:417-419. gression in benign lichenoid keratosis, keratoacanthoma and halo nevus. Clin 24. Bazza MA, Ryatt KS, Dharmagunawardena PV. Mycosis fungoides masquerad- Med Res. 2004;2:89-97. ing as seborrheic keratosis. Br J Dermatol. 2002;147:1264-1265. 11. Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. 25. Arai E, Shimizu M, Hirose T. A review of 55 cases of cutaneous lymphoid hy- J Eur Acad Dermatol Venereol. 2004;18:397-415. perplasia: reassessment of the histopathologic findings leading to reclassifica- 12. Massone C, Kodama K, Kerl H, Cerroni L. Histopathologic features of early (patch) tion of 4 lesions as cutaneous marginal zone lymphoma and 19 as pseudolym- lesions of mycosis fungoides: a morphologic study on 745 biopsy specimens phomatous folliculitis. Hum Pathol. 2005;36:505-511. from 427 patients. Am J Surg Pathol. 2005;29:550-560. 26. Igisu K, Watanabe S, Shimosato Y, et al. Mycosis fungoides and T-zone histiocytes. 13. Tange Y, Kayano H. Diagnostic polymerase chain reaction amplification for im- Jpn J Clin Oncol. 1983;13:693-702. munoglobulin heavy chain (IgH) gene rearrangement in routine paraffin sec- 27. Jang KA, Kim S-H, Choi J-H, Sung K-J, Moon K-C, Koh J-K. Lichenoid keratosis: tions [article in Japanese with English abstract]. J Saitama Med School. 1997; a clinicopathologic study of 17 patients. J Am Acad Dermatol. 2000;43:511- 24:11-16. 516. 14. Diss TC, Watts M. The polymerase chain reaction in the demonstration of mono- 28. Smith DI, Vnencak-Jones CL, Boyd AS. T-lymphocyte clonality in benign lichen- clonality in T cell lymphomas. J Clin Pathol. 1995;48:1045-1050. oid keratosis. J Cutan Pathol. 2002;29:623-624. 15. Algara P, Soria C, Martinez P, et al. Value of PCR detection of TCR-␥ gene rear- 29. Weedon D. Skin Pathology. 2nd ed. London, England: Churchill Livingston; 2002: rangement in the diagnosis of cutaneous lymphocytic infiltrates. Diagn Mol Pathol. 40-41. 1994;3:275-282. 30. Morgan MB, Stevens GL, Switlyk S. Benign lichenoid keratosis: a clinical and 16. Al-Hoqail IA, Crawford RI. Benign lichenoid keratosis with histologic features of pathological reappraisal of 1040 cases. Am J Dermatopathol. 2005;27:387- mycosis fungoides: clinicopathologic description of a clinically significant his- 392. tologic pattern. J Cutan Pathol. 2002;29:291-294. 31. Slater D. Cutaneous lymphoproliferative disorders: an assessment of recent in- 17. Kodama K, Fink-Puches R, Massone C, Kerl H, Cerroni L. Papular mycosis fun- vestigative techniques. Br J Dermatol. 1991;124:309-323. goides: a new clinical variant of early mycosis fungoides. J Am Acad Dermatol. 32. Magro CM, Crowson AN, Kovatch AJ, et al. Drug-induced reversible lymphoid 2005;52:694-698. dysclasia: a clonal lymphoid dermatitis of memory and activated T cells. Hum 18. Heald PW, Glusac EI. Unilesional cutaneous T-cell lymphoma: clinical features, Pathol. 2003;34:119-129.

(REPRINTED) ARCH DERMATOL/ VOL 143, JAN 2007 WWW.ARCHDERMATOL.COM 59