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Adult pityriasis lichenoides-like mycosis fungoides: a clinical variant of mycosis fungoides Blanca de Unamuno Bustos1, MD, Amparo P. Ferriols1, PhD, MD, Rosa B. S anchez1, MD, Ana G. Rabasco1, MD, Carmen G. Vela2, PhD, MD, Miguel A. Piris2, PhD, MD, and Vıctor Alegre de Mıquel1, PhD, MD
1 Department of Dermatology, General Hospital of Valencia, Valencia, Spain, and 2 Department of Anatomy and Pathology, s de Valdecilla, Santander, Hospital Marque Spain
Abstract Background Mycosis fungoides (MF) is the most frequent type of cutaneous T cell lymphoma. Its clinicopathological spectrum is wide, and the resulting diversity makes it difficult to establish a differential diagnosis among pityriasis lichenoides (PL), lymphomatoid papulosis (LyP), and atypical MF.
Correspondence Blanca de Unamuno Bustos, MD Servicio de Dermatologıa Consorcio Hospital General Universitario de Valencia Avenida Tres Cruces 2 46014 Valencia Spain E-mail: [email protected] Funding: None. Conflicts of interest: None.
Objectives This study describes four patients with longstanding PL-like lesions, in whom clinicopathological correlations contributed towards the establishment of definitive diagnoses of MF. Methods The clinical histories of the four patients were reviewed. Skin biopsies were processed by hematoxylin and eosin staining and immunohistochemical techniques. Disease spread was studied according to laboratory tests, complete blood counts, zary cells. biochemical parameters, lactate dehydrogenase, lymphocyte populations, and Se Thoracoabdominopelvic computed tomography was performed. Results The four patients included two women and two men, aged 35–70 years, all of whom had chronic skin lesions located mainly on the trunk and extremities. In three patients, initial clinicopathological correlations led to the diagnosis of PL; further biopsies were required to diagnose MF. In all patients, the atypical lymphocytic infiltrate showed a lichenoid or perivascular distribution with focal epidermotropism and parakeratosis. All cases proved positive for CD4 and CD3, and negative for CD20, CD8, and CD30. Polymerase chain reaction showed monoclonal-type T cells in one and polyclonal infiltrates in three patients. All patients were initially treated with topical corticosteroids and photochemotherapy. None of the treatments proved completely successful, but subsequent tests have yielded no evidence of disease progression in any patient. Conclusions In patients with clinical features of longstanding PL and histological findings consistent with MF, differential diagnosis must include PL, LyP, and papular MF. As some forms of PL evolve towards MF and PL-like forms of MF, these patients should undergo regular follow-up and repeated biopsies in order to discard diagnoses of atypical forms of MF.
Introduction Mycosis fungoides (MF) is the most frequent type of cutaneous T cell lymphoma (CTCL). Classical MF manifests in the form of lesions that typically evolve in three phases as, respectively, patches, plaques, and tumors. Histologically, the disease is characterized by the presence of an atypical lymphocytic infiltrate with hyperchromatic, irregular, and convoluted nuclei, showing focal epidermotropism and occasionally forming intraepidermal nests called Pautrier microabscesses.1 The clinicopathological spectrum of MF is wide and can range from typical lesions of MF to lesions mimicking inflammatory dermatosis, ª 2014 The International Society of Dermatology
especially in the early stages. This diversity makes the diagnosis of MF challenging, and sometimes all available data (clinical features, histopathological findings, immunophenotype, molecular biology, and follow-up) must be assessed in order to make a correct diagnosis.2 Occasionally, MF can manifest as recurrent outbreaks of erythematous papules. This clinical manifestation makes it difficult to establish a differential diagnosis between pityriasis lichenoides (PL), lymphomatoid papulosis (LyP), and MF of atypical presentation. The current study describes four patients who presented PL-like lesions of several years duration, which were subjected to multiple biopsies, in whom clinicopathological International Journal of Dermatology 2014, 53, 1331–1338
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2–14 years. All data are reported in Table 1.
of CD3 and CD4 positivity. In three of the four patients, the biopsies were reported as corresponding to MF in both centers, whereas in Patient 2 (Fig. 3) the diagnosis established in the external center corresponded to PL. Only the clinicopathological correlation (prolonged evolution of the disease and the observation in our preparations of atypical and convoluted lymphocytes, with the formation of Pautrier microabscesses) allowed us to establish a diagnosis of MF (Fig. 4). Gene rearrangement by PCR showed the presence of monoclonal-type T cells in Patient 4 and polyclonal infiltrates in Patients 1, 2 and 3. All patients were initially treated with topical corticosteroids and photochemotherapy. In Patient 3 (Fig. 5), interferon was added to the latter, and in Patient 2 total skin electron irradiation (TSEI) was performed, followed by the administration of bexarotene. None of the treatments proved completely successful, and the lesions reappeared in all patients except Patient 4 (Figs. 6 and 7), who remained free of symptoms after treatment with psoralen combined with ultraviolet A (PUVA). All patients are subject to regular follow-up (2–14 years). Clinical and laboratory test controls have yielded no evidence of disease progression in any patient.
Results
Discussion
The four patients included two women and two men, aged between 35 and 70 years, all of whom had chronic skin lesions (of 5–25 years in duration). These lesions presented clinically as reddish-brown, papular eruptions located mainly on the trunk and extremities. Some of the papules presented slight surface desquamation, and in some areas only residual hyperpigmentation was observed. In addition to papular lesions, one patient (Patient 1) showed erythematous desquamative areas in the region of the buttocks that had been present from the start of the clinical manifestations (Fig. 1b). In three of the four patients, initial clinicopathological correlations led to the diagnosis of PL; further biopsies were required to reach the final diagnosis of MF. Only one biopsy was obtained in Patient 4; this established a diagnosis of MF from the start. In all four patients the atypical lymphocytic infiltrate showed a lichenoid or perivascular distribution with focal epidermotropism and parakeratosis (Fig. 2). All cases proved positive for CD4 and CD3, and negative for CD8, CD20, and CD30. In those patients subjected to several biopsies before a diagnosis of MF was achieved, the preparations were examined again and re-diagnosed as MF on the basis of the presence of atypical and convoluted lymphocytes, epidermotropism of medium polygonal lymphocytes, the occasional formation of microabscesses, and a predominance
The present study describes four cases of MF with clinical features of long-evolving PL and histological findings consistent with MF. Three of the four patients were initially diagnosed with PL, although the repeated biopsy findings and the prolonged course of the disease suggested that these cases in fact may represent PL-like MF. In such cases, a differential diagnosis must be established with PL, LyP, and papular MF. Pityriasis lichenoides is an idiopathic inflammatory disorder most often found in children and young adults. It manifests as recurrent outbreaks of erythematous papules that can be accompanied by vesicles, pustules, ulcers, and crusts in the acute presentation, or as a reddish-brown papular eruption with surface desquamation in the chronic form of the disease. Histological findings comprise hyperkeratosis with focal parakeratosis, a superficial perivascular inflammatory infiltrate with marked exocytosis of lymphocytes in the epidermis, and, occasionally, the presence of apoptotic keratinocytes, spongiosis, and focal intraepidermal erythrocytes. A predominance of CD8 cytotoxic/suppressor T cells can be demonstrated, but CD4+ helper T cells are usually present. In many cases, polyclonal CD3 T cells may also be present, and in some instances even CD30+ small lymphocytes have been detected.3 This makes it very difficult to establish a differential diagnosis between PL and
correlations contributed towards the establishment of definitive diagnoses of MF. Materials and methods The clinical histories of four patients referred to our center with diagnoses of longstanding PL were reviewed. Patient age, sex, clinical presentation, and years of disease were documented in each case. In three of the four patients, several skin biopsies had been performed. In the remaining patient (Patient 4), only one biopsy had been obtained. Skin biopsies were processed by hematoxylin and eosin (H&E) staining and immunohistochemical techniques (CD3, CD4, CD8, CD20, and s CD30). Biopsies were also sent to an external center (Marque of Valdecilla University Hospital in Santander, Spain) in order to obtain biopsy reports from at least two pathologists. Gene rearrangement by polymerase chain reaction (PCR) was performed in all patients. Following the diagnosis of MF, a study of disease spread was made in all cases, including laboratory tests, a complete blood count, biochemical parameters, lactate zary dehydrogenase (LDH), lymphocyte populations, and Se cells. Thoracoabdominopelvic computed tomography (CT) was also performed. Patients were followed up for periods of
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(b)
(a)
Figure 1 Patient 1. Clinical examination shows: (a) a reddish-brown papular eruption located on the trunk, and (b) erythematous desquamative areas in the region of the buttocks
LyP. Controversy exists as to whether PL is an inflammatory reaction or a genuine lymphoproliferative process that is part of the cutaneous T cell lymphoproliferative spectrum. Recent studies based on Southern blot analysis and PCR analysis of T cell receptor (TCR) gene rearrangement support this hypothesis and provide further
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(a)
(b)
Figure 3 Patient 2. Clinical examination shows erythematous papular eruptions on the (a) lower extremities, and (b) trunk and upper extremities
evidence for the presence of a dominant T cell clone in skin lesions of patients with PL. Dereure et al.4 investigated T cell clonality in a series of 20 cases of PL and found that 65% of biopsy specimens revealed the presence of a T cell clone. There have been reports of patients with PL who subsequently develop MF.5–9 This raises the possibility that
(a)
(b)
(c)
Figure 2 Patient 1. Histopathology shows: (a) epidermal hyperplasia and perivascular infiltrate composed of atypical lymphocytes with focal epidermotropism, and (b) atypical and convoluted lymphocytes with epidermotropism. (Hematoxylin and eosin stain; original magnification [a] 9100, [b] 9200.) (c) CD3 staining shows atypical and convoluted lymphocytes with focal epidermotropism. (Original magnification 940) International Journal of Dermatology 2014, 53, 1331–1338
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(a)
Figure 1 Patient 1. Clinical examination shows: (a) a reddish-brown papular eruption located on the trunk, and (b) erythematous desquamative areas in the region of the buttocks
LyP. Controversy exists as to whether PL is an inflammatory reaction or a genuine lymphoproliferative process that is part of the cutaneous T cell lymphoproliferative spectrum. Recent studies based on Southern blot analysis and PCR analysis of T cell receptor (TCR) gene rearrangement support this hypothesis and provide further
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(a)
(b)
Figure 3 Patient 2. Clinical examination shows erythematous papular eruptions on the (a) lower extremities, and (b) trunk and upper extremities
evidence for the presence of a dominant T cell clone in skin lesions of patients with PL. Dereure et al.4 investigated T cell clonality in a series of 20 cases of PL and found that 65% of biopsy specimens revealed the presence of a T cell clone. There have been reports of patients with PL who subsequently develop MF.5–9 This raises the possibility that
(a)
(b)
(c)
Figure 2 Patient 1. Histopathology shows: (a) epidermal hyperplasia and perivascular infiltrate composed of atypical lymphocytes with focal epidermotropism, and (b) atypical and convoluted lymphocytes with epidermotropism. (Hematoxylin and eosin stain; original magnification [a] 9100, [b] 9200.) (c) CD3 staining shows atypical and convoluted lymphocytes with focal epidermotropism. (Original magnification 940) International Journal of Dermatology 2014, 53, 1331–1338
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these are not two separate disease conditions but, rather, disorders belonging to the same spectrum of T cell lymphoproliferative diseases.10 Pityriasis lichenoides may represent the result of a cytotoxic response to a T cell tumor clone that prevents the development of CTCL until the tumor clone acquires additional genetic alterations. This hypothesis would explain why cases of long-evolving PL finally develop MF. In addition to these forms of PL that evolve towards MF, Ko et al. 11 described three pediatric
(a)
(b) Figure 4 Patient 2. Histopathology shows: (a) lichenoid and perivascular infiltrate composed of atypical lymphocytes with focal epidermotropism, and (b) atypical and convoluted lymphocytes with formation of microabscesses. (Hematoxylin and eosin stain; original magnification [a] 9100, [b] 9200)
(a)
Figure 6 Patient 4. Clinical examination shows erythematous desquamative papular lesions in the pubic region and on the trunk
(b)
Figure 5 Patient 3. (a,b) Clinical examination shows erythematous desquamative papular lesions on the lower extremities ª 2014 The International Society of Dermatology
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(a)
(b) Figure 7 Patient 4. (a) Histopathology shows an intense lymphocytic band infiltrate composed of atypical lymphocytes with focal epidermotropism. (Hematoxylin and eosin stain; original magnification 940.) (b) CD3 staining shows atypical and convoluted lymphocytes with focal epidermotropism. (Original magnification 940)
patients with forms of MF that clinically simulated PL, and Wang et al. 12 subsequently reported an adult patient with PL-like MF, who represents the only non-pediatric case described to date. By contrast, papular MF has recently been described by Kodama et al.13 This is an infrequent variant, few cases of which have been published (Table 2).14–16 Clinical presentation is characterized by a chronic and symmetrically distributed papular eruption on the trunk, upper extremities, and roots of the lower extremities. Lymphomatoid papulosis is a low-grade CTCL considered to be part of a broader group of primary cutaneous CD30+ lymphoproliferative diseases. As with PL, LyP consists of a spectrum of lesions that may be clinically indistinguishable from PL in a given case. Four types of
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LyP are distinguished (A, B, C, and D) according to the type and distribution of the lymphocytic infiltrate.17–19 It is particularly important to establish a differential diagnosis with type B (or MF-like), which is characterized by atypical lymphocytes with hyperchromatic cerebriform nuclei, because the histological features may be identical. Recently, some authors have suggested that papular MF may be an atypical variant of LyP and that papular MF and type B LyP may even be the same disorder. Evidence in support of this idea is that type B LyP does not usually ulcerate, can persist for long periods before remitting, and the lymphocytic infiltrate is often not positive for CD30.20 Some authors support the hypothesis that LyP and PL are biologically related disorders, perhaps sharing a common etiology such as a virus or other infectious agent. Vonderheid et al.21 reported a patient diagnosed with LyP type B followed by PL after 11 years and suggested that these are pathogenically related conditions. Cases of PL with histological features that overlap with those of LyP have been described, and it is particularly difficult to differentiate LyP type B from PL as lymphocytes in PL can express CD30, and CD30+ cells in LyP may be absent or present in small numbers. Histological distinction is challenging and is based on the presence of atypical lymphocytes infiltrating the epidermis without associated injury to keratinocytes.22,23 In addition, it has been suggested that in MF there is a loss of expression of the T cell-associated antigen CD7,24 which may represent a valuable tool in the distinction between inflammation and neoplasia.25 However, this finding has not been confirmed, as in other studies early MF showed normal CD7+ populations,26 and inflammatory dermatosis can also show a partial loss of CD7.27 Only one of our four cases showed the presence of monoclonal-type T cells in molecular studies, but this does not exclude the diagnosis of MF as rearrangement of the TCR gene is present in only approximately 50–60% of early lesions analyzed by standard techniques.28 Thus, some cases clinically manifest as long-evolving papular lesions with histological findings consistent with MF. These variants are presently difficult to classify and are clinically and pathologically compatible with the spectrum of lymphoproliferative disorders, which includes PL, LyP, and variants of papular and PL-like MF. Moreover, as there are forms of PL that subsequently evolve towards MF, and also PL-like forms of MF, it may be advisable for patients with long-evolving PL to undergo regular follow-up, with repeated skin biopsies in some cases, in order to discard diagnoses of atypical forms of MF.
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Table 2 Clinical features of reported cases of papular mycosis fungoides (MF) Authors/year
Age, years/sex
Clinical presentation
Other lesions
Duration
Treatment
Follow-up
Kodama et al. (2005)13 Kodama et al. (2005)13
57/male
No
Not mentioned
PUVA
18 months
No
2 years
57/female
No
Few months
PUVA Extracorporeal photopheresis PUVA
51 months
Kodama et al. (2005)13
Kodama et al. (2005)13
41/male
Yes
Not mentioned
PUVA
Kodama et al. (2005)13
59/male
No
30 years
PUVA
11 years Several recurrences 24 months
Kodama et al. (2005)13
61/male
No
Not mentioned
PUVA
74 months
Uddin et al. (2007)14
31/female
No
2 years
UVB
10 months
MartorellCalatayud et al. (2010)15
50/female
Erythematous papules on the trunk Papular eruption on the trunk and upper extremities Few erythematous papules on the trunk and upper and lower extremities Scattered erythematous papules on both legs Typical MF patches Disseminated erythematous papules on the trunk and extremities Several erythematous papular lesions on the back, flanks and shoulders Reddish-brown papules on the trunk and upper extremities Reddish-brown papules on the trunk
No
2 years
15 months
MartorellCalatayud et al. (2010)15 Liu et al. (2011)16
55/female
Itchy papular eruption on the trunk, buttocks and feet Reddish-brown papules on the left chest, axilla and popliteal fossa
No
18 months
Topical corticosteroids (0.1% clobetasol dipropionate) PUVA
No
Not mentioned
UVB Topical corticosteroids
Not mentioned
58/female
27/male
10 years Several recurrences
20 months
PUVA, psoralen combined with ultraviolet A light; UVB, ultraviolet B light.
References 1 Cerroni L, Gatter K, Ker H. Mycosis fungoides. In: Cerroni L, Gatter K, Ker H, eds. Skin Lymphoma: The Illustrated Guide, 3rd edn. Oxford: Blackwell Publishing, 2009: 11–56. 2 Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol 2004; 18: 397–415. 3 Kempf W, Kazakov DV, Palmedo G, et al. Pityriasis lichenoides et varioliformis acuta with numerous CD30+ cells: a variant mimicking lymphomatoid papulosis and other cutaneous lymphomas. A clinicopathologic, immunohistochemical, and molecular biological study of 13 cases. Am J Surg Pathol 2012; 36: 1021–1029. 4 Dereure O, Levi E, Kadin ME. T cell clonality in pityriasis lichenoides et varioliformis acuta. Arch Dermatol 2000; 136: 1483–1486. 5 Tomasini D, Zampatti C, Palmedo G, et al. Cytotoxic mycosis fungoides evolving from pityriasis lichenoides ª 2014 The International Society of Dermatology
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chronica in a 17-year-old girl. Dermatology 2002; 205: 176–179. Fortson JS, Schroeter AL, Esterly NB. Cutaneous T cell lymphoma (parapsoriasis en plaque): an association with pityriasis lichenoides et varioliformis acuta in young children. Arch Dermatol 1990; 126: 149–153. Niemczy UM, Zollner TM, Wolter M, et al. The transformation of pityriasis lichenoides chronica into parakeratosis variegate in an 11-year-old girl. Br J Dermatol 1997; 137: 983–987. Thomson KF, Whittaker SJ, Russel-Jones R, et al. Childhood cutaneous T cell lymphoma in association with pityriasis lichenoides chronica. Br J Dermatol 1999; 141: 1146–1148. Boccara O, Blanche S, de Prost Y, et al. Cutaneous hematologic disorders in children. Pediatr Blood Cancer 2012; 58: 226–232. Rivera R, Ortiz P, Rodriguez-Peralto JL, et al. Febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta with atypical cells. Int J Dermatol 2003; 42: 26–28. International Journal of Dermatology 2014, 53, 1331–1338
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11 Ko JW, Seong JY, Suh KS, et al. Pityriasis lichenoideslike mycosis fungoides in children. Br J Dermatol 2000; 142: 347–352. 12 Wang SH, Hsiao CH, Hsiao PF, et al. Adult pityriasis lichenoides-like mycosis fungoides with high density of CD8-positive T-lymphocytic infiltration. J Eur Acad Dermatol Venereol 2007; 21: 401–402. 13 Kodama K, Fink-Puches R, Massone C, et al. Papular mycosis fungoides: a new clinical variant of early mycosis fungoides. J Am Acad Dermatol 2005; 52: 694–698. 14 Uddin A, Bennett N, Nayeem K, et al. A case of papular mycosis fungoides: new clinical variant of early mycosis fungoides. J Eur Acad Dermatol Venereol 2007; 21: 685– 687. 15 Martorell-Calatayud A, Botella-Estrada R, SanmartínJimenez O, et al. Papular mycosis fungoides: two new cases of a recently described clinicopathological variant of early mycosis fungoides. J Cutan Pathol 2010; 37: 330–335. 16 Liu ZH, Wang YL, Chen SY, et al. Papular mycosis fungoides: a new clinical variant of early and benign mycosis fungoides? J Clin Oncol 2011; 29: 381–383. 17 El Shabrawi-Caelen L, Kerl H, Cerroni L. Lymphomatoid papulosis: reappraisal of clinicopathologic presentation and classification into subtypes A, B, and C. Arch Dermatol 2004; 140: 441–447. 18 Calzado-Villarreal L, Polo-Rodríguez I, Ortiz-Romero PL. Primary cutaneous CD30+ lymphoproliferative disorders. Actas Dermosifiliogr 2010; 101: 119–128. 19 Saggini A, Gulia A, Argenyi Z, et al. A variant of lymphomatoid papulosis simulating primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell lymphoma. Description of nine cases. Am J Surg Pathol 2010; 34: 1168–1175.
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20 Vonderheid EC, Kadin ME. Papular mycosis fungoides: a variant of mycosis fungoides or lymphomatoid papulosis? J Am Acad Dermatol 2006; 55: 177–180. 21 Vonderheid EC, Kadin ME, Gocke CD. Lymphomatoid papulosis followed by pityriasis lichenoides: a common pathogenesis? Am J Dermatopathol 2011; 33: 835–840. 22 Magro C, Crowson AN, Kovatich A, et al. Pityriasis lichenoides: a clonal T cell lymphoproliferative disorder. Hum Pathol 2002; 33: 788–795. 23 Nair PS. A clinical and histopathological study of pityriasis lichenoides. Indian J Dermatol Venereol Leprol 2007; 73: 100–102. 24 Wood GS, Abel EA, Hoppe RT, et al. Leu-8 and Leu-9 antigen phenotypes: immunological criteria for the distinction of mycosis fungoides from cutaneous inflammation. J Am Acad Dermatol 1986; 14: 1006– 1013. 25 Cotta AC, Cintra ML, de Souza EM, et al. Diagnosis of mycosis fungoides: a comparative immunohistochemical study of T cell markers using a novel anti-CD7 antibody. Appl Immunohistochem Mol Morphol 2006; 14: 291–295. 26 Willemze R, de Graaff-Reitsma CB, Cnossen J, et al. Characterization of T cell subpopulations in skin and peripheral blood of patients with cutaneous T cell lymphomas and benign inflammatory dermatoses. J Invest Dermatol 1983; 80: 60–66. 27 Payne CM, Spier CM, Gragan TM, et al. Nuclear contour irregularities correlate with Leu-9, Leu-8 cells in benign lymphoid infiltrates of the skin. Am J Dermatopathol 1998; 10: 377–398. 28 Massone C, Kodama K, Kerl H, et al. Histopathologic features of early (patch) lesions of mycosis fungoides. A morphologic study on 745 biopsy specimens from 427 patients. Am J Surg Pathol 2005; 29: 550–560.
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Adult pityriasis lichenoides-like mycosis fungoides: a clinical variant of mycosis fungoides Blanca de Unamuno Bustos1, MD, Amparo P. Ferriols1, PhD, MD, Rosa B. S anchez1, MD, Ana G. Rabasco1, MD, Carmen G. Vela2, PhD, MD, Miguel A. Piris2, PhD, MD, and Vıctor Alegre de Mıquel1, PhD, MD
1 Department of Dermatology, General Hospital of Valencia, Valencia, Spain, and 2 Department of Anatomy and Pathology, s de Valdecilla, Santander, Hospital Marque Spain
Abstract Background Mycosis fungoides (MF) is the most frequent type of cutaneous T cell lymphoma. Its clinicopathological spectrum is wide, and the resulting diversity makes it difficult to establish a differential diagnosis among pityriasis lichenoides (PL), lymphomatoid papulosis (LyP), and atypical MF.
Correspondence Blanca de Unamuno Bustos, MD Servicio de Dermatologıa Consorcio Hospital General Universitario de Valencia Avenida Tres Cruces 2 46014 Valencia Spain E-mail: [email protected] Funding: None. Conflicts of interest: None.
Objectives This study describes four patients with longstanding PL-like lesions, in whom clinicopathological correlations contributed towards the establishment of definitive diagnoses of MF. Methods The clinical histories of the four patients were reviewed. Skin biopsies were processed by hematoxylin and eosin staining and immunohistochemical techniques. Disease spread was studied according to laboratory tests, complete blood counts, zary cells. biochemical parameters, lactate dehydrogenase, lymphocyte populations, and Se Thoracoabdominopelvic computed tomography was performed. Results The four patients included two women and two men, aged 35–70 years, all of whom had chronic skin lesions located mainly on the trunk and extremities. In three patients, initial clinicopathological correlations led to the diagnosis of PL; further biopsies were required to diagnose MF. In all patients, the atypical lymphocytic infiltrate showed a lichenoid or perivascular distribution with focal epidermotropism and parakeratosis. All cases proved positive for CD4 and CD3, and negative for CD20, CD8, and CD30. Polymerase chain reaction showed monoclonal-type T cells in one and polyclonal infiltrates in three patients. All patients were initially treated with topical corticosteroids and photochemotherapy. None of the treatments proved completely successful, but subsequent tests have yielded no evidence of disease progression in any patient. Conclusions In patients with clinical features of longstanding PL and histological findings consistent with MF, differential diagnosis must include PL, LyP, and papular MF. As some forms of PL evolve towards MF and PL-like forms of MF, these patients should undergo regular follow-up and repeated biopsies in order to discard diagnoses of atypical forms of MF.
Introduction Mycosis fungoides (MF) is the most frequent type of cutaneous T cell lymphoma (CTCL). Classical MF manifests in the form of lesions that typically evolve in three phases as, respectively, patches, plaques, and tumors. Histologically, the disease is characterized by the presence of an atypical lymphocytic infiltrate with hyperchromatic, irregular, and convoluted nuclei, showing focal epidermotropism and occasionally forming intraepidermal nests called Pautrier microabscesses.1 The clinicopathological spectrum of MF is wide and can range from typical lesions of MF to lesions mimicking inflammatory dermatosis, ª 2014 The International Society of Dermatology
especially in the early stages. This diversity makes the diagnosis of MF challenging, and sometimes all available data (clinical features, histopathological findings, immunophenotype, molecular biology, and follow-up) must be assessed in order to make a correct diagnosis.2 Occasionally, MF can manifest as recurrent outbreaks of erythematous papules. This clinical manifestation makes it difficult to establish a differential diagnosis between pityriasis lichenoides (PL), lymphomatoid papulosis (LyP), and MF of atypical presentation. The current study describes four patients who presented PL-like lesions of several years duration, which were subjected to multiple biopsies, in whom clinicopathological International Journal of Dermatology 2014, 53, 1331–1338
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2–14 years. All data are reported in Table 1.
of CD3 and CD4 positivity. In three of the four patients, the biopsies were reported as corresponding to MF in both centers, whereas in Patient 2 (Fig. 3) the diagnosis established in the external center corresponded to PL. Only the clinicopathological correlation (prolonged evolution of the disease and the observation in our preparations of atypical and convoluted lymphocytes, with the formation of Pautrier microabscesses) allowed us to establish a diagnosis of MF (Fig. 4). Gene rearrangement by PCR showed the presence of monoclonal-type T cells in Patient 4 and polyclonal infiltrates in Patients 1, 2 and 3. All patients were initially treated with topical corticosteroids and photochemotherapy. In Patient 3 (Fig. 5), interferon was added to the latter, and in Patient 2 total skin electron irradiation (TSEI) was performed, followed by the administration of bexarotene. None of the treatments proved completely successful, and the lesions reappeared in all patients except Patient 4 (Figs. 6 and 7), who remained free of symptoms after treatment with psoralen combined with ultraviolet A (PUVA). All patients are subject to regular follow-up (2–14 years). Clinical and laboratory test controls have yielded no evidence of disease progression in any patient.
Results
Discussion
The four patients included two women and two men, aged between 35 and 70 years, all of whom had chronic skin lesions (of 5–25 years in duration). These lesions presented clinically as reddish-brown, papular eruptions located mainly on the trunk and extremities. Some of the papules presented slight surface desquamation, and in some areas only residual hyperpigmentation was observed. In addition to papular lesions, one patient (Patient 1) showed erythematous desquamative areas in the region of the buttocks that had been present from the start of the clinical manifestations (Fig. 1b). In three of the four patients, initial clinicopathological correlations led to the diagnosis of PL; further biopsies were required to reach the final diagnosis of MF. Only one biopsy was obtained in Patient 4; this established a diagnosis of MF from the start. In all four patients the atypical lymphocytic infiltrate showed a lichenoid or perivascular distribution with focal epidermotropism and parakeratosis (Fig. 2). All cases proved positive for CD4 and CD3, and negative for CD8, CD20, and CD30. In those patients subjected to several biopsies before a diagnosis of MF was achieved, the preparations were examined again and re-diagnosed as MF on the basis of the presence of atypical and convoluted lymphocytes, epidermotropism of medium polygonal lymphocytes, the occasional formation of microabscesses, and a predominance
The present study describes four cases of MF with clinical features of long-evolving PL and histological findings consistent with MF. Three of the four patients were initially diagnosed with PL, although the repeated biopsy findings and the prolonged course of the disease suggested that these cases in fact may represent PL-like MF. In such cases, a differential diagnosis must be established with PL, LyP, and papular MF. Pityriasis lichenoides is an idiopathic inflammatory disorder most often found in children and young adults. It manifests as recurrent outbreaks of erythematous papules that can be accompanied by vesicles, pustules, ulcers, and crusts in the acute presentation, or as a reddish-brown papular eruption with surface desquamation in the chronic form of the disease. Histological findings comprise hyperkeratosis with focal parakeratosis, a superficial perivascular inflammatory infiltrate with marked exocytosis of lymphocytes in the epidermis, and, occasionally, the presence of apoptotic keratinocytes, spongiosis, and focal intraepidermal erythrocytes. A predominance of CD8 cytotoxic/suppressor T cells can be demonstrated, but CD4+ helper T cells are usually present. In many cases, polyclonal CD3 T cells may also be present, and in some instances even CD30+ small lymphocytes have been detected.3 This makes it very difficult to establish a differential diagnosis between PL and
correlations contributed towards the establishment of definitive diagnoses of MF. Materials and methods The clinical histories of four patients referred to our center with diagnoses of longstanding PL were reviewed. Patient age, sex, clinical presentation, and years of disease were documented in each case. In three of the four patients, several skin biopsies had been performed. In the remaining patient (Patient 4), only one biopsy had been obtained. Skin biopsies were processed by hematoxylin and eosin (H&E) staining and immunohistochemical techniques (CD3, CD4, CD8, CD20, and s CD30). Biopsies were also sent to an external center (Marque of Valdecilla University Hospital in Santander, Spain) in order to obtain biopsy reports from at least two pathologists. Gene rearrangement by polymerase chain reaction (PCR) was performed in all patients. Following the diagnosis of MF, a study of disease spread was made in all cases, including laboratory tests, a complete blood count, biochemical parameters, lactate zary dehydrogenase (LDH), lymphocyte populations, and Se cells. Thoracoabdominopelvic computed tomography (CT) was also performed. Patients were followed up for periods of
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(b)
(a)
Figure 1 Patient 1. Clinical examination shows: (a) a reddish-brown papular eruption located on the trunk, and (b) erythematous desquamative areas in the region of the buttocks
LyP. Controversy exists as to whether PL is an inflammatory reaction or a genuine lymphoproliferative process that is part of the cutaneous T cell lymphoproliferative spectrum. Recent studies based on Southern blot analysis and PCR analysis of T cell receptor (TCR) gene rearrangement support this hypothesis and provide further
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(a)
(b)
Figure 3 Patient 2. Clinical examination shows erythematous papular eruptions on the (a) lower extremities, and (b) trunk and upper extremities
evidence for the presence of a dominant T cell clone in skin lesions of patients with PL. Dereure et al.4 investigated T cell clonality in a series of 20 cases of PL and found that 65% of biopsy specimens revealed the presence of a T cell clone. There have been reports of patients with PL who subsequently develop MF.5–9 This raises the possibility that
(a)
(b)
(c)
Figure 2 Patient 1. Histopathology shows: (a) epidermal hyperplasia and perivascular infiltrate composed of atypical lymphocytes with focal epidermotropism, and (b) atypical and convoluted lymphocytes with epidermotropism. (Hematoxylin and eosin stain; original magnification [a] 9100, [b] 9200.) (c) CD3 staining shows atypical and convoluted lymphocytes with focal epidermotropism. (Original magnification 940) International Journal of Dermatology 2014, 53, 1331–1338
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(a)
Figure 1 Patient 1. Clinical examination shows: (a) a reddish-brown papular eruption located on the trunk, and (b) erythematous desquamative areas in the region of the buttocks
LyP. Controversy exists as to whether PL is an inflammatory reaction or a genuine lymphoproliferative process that is part of the cutaneous T cell lymphoproliferative spectrum. Recent studies based on Southern blot analysis and PCR analysis of T cell receptor (TCR) gene rearrangement support this hypothesis and provide further
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(a)
(b)
Figure 3 Patient 2. Clinical examination shows erythematous papular eruptions on the (a) lower extremities, and (b) trunk and upper extremities
evidence for the presence of a dominant T cell clone in skin lesions of patients with PL. Dereure et al.4 investigated T cell clonality in a series of 20 cases of PL and found that 65% of biopsy specimens revealed the presence of a T cell clone. There have been reports of patients with PL who subsequently develop MF.5–9 This raises the possibility that
(a)
(b)
(c)
Figure 2 Patient 1. Histopathology shows: (a) epidermal hyperplasia and perivascular infiltrate composed of atypical lymphocytes with focal epidermotropism, and (b) atypical and convoluted lymphocytes with epidermotropism. (Hematoxylin and eosin stain; original magnification [a] 9100, [b] 9200.) (c) CD3 staining shows atypical and convoluted lymphocytes with focal epidermotropism. (Original magnification 940) International Journal of Dermatology 2014, 53, 1331–1338
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these are not two separate disease conditions but, rather, disorders belonging to the same spectrum of T cell lymphoproliferative diseases.10 Pityriasis lichenoides may represent the result of a cytotoxic response to a T cell tumor clone that prevents the development of CTCL until the tumor clone acquires additional genetic alterations. This hypothesis would explain why cases of long-evolving PL finally develop MF. In addition to these forms of PL that evolve towards MF, Ko et al. 11 described three pediatric
(a)
(b) Figure 4 Patient 2. Histopathology shows: (a) lichenoid and perivascular infiltrate composed of atypical lymphocytes with focal epidermotropism, and (b) atypical and convoluted lymphocytes with formation of microabscesses. (Hematoxylin and eosin stain; original magnification [a] 9100, [b] 9200)
(a)
Figure 6 Patient 4. Clinical examination shows erythematous desquamative papular lesions in the pubic region and on the trunk
(b)
Figure 5 Patient 3. (a,b) Clinical examination shows erythematous desquamative papular lesions on the lower extremities ª 2014 The International Society of Dermatology
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(b) Figure 7 Patient 4. (a) Histopathology shows an intense lymphocytic band infiltrate composed of atypical lymphocytes with focal epidermotropism. (Hematoxylin and eosin stain; original magnification 940.) (b) CD3 staining shows atypical and convoluted lymphocytes with focal epidermotropism. (Original magnification 940)
patients with forms of MF that clinically simulated PL, and Wang et al. 12 subsequently reported an adult patient with PL-like MF, who represents the only non-pediatric case described to date. By contrast, papular MF has recently been described by Kodama et al.13 This is an infrequent variant, few cases of which have been published (Table 2).14–16 Clinical presentation is characterized by a chronic and symmetrically distributed papular eruption on the trunk, upper extremities, and roots of the lower extremities. Lymphomatoid papulosis is a low-grade CTCL considered to be part of a broader group of primary cutaneous CD30+ lymphoproliferative diseases. As with PL, LyP consists of a spectrum of lesions that may be clinically indistinguishable from PL in a given case. Four types of
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LyP are distinguished (A, B, C, and D) according to the type and distribution of the lymphocytic infiltrate.17–19 It is particularly important to establish a differential diagnosis with type B (or MF-like), which is characterized by atypical lymphocytes with hyperchromatic cerebriform nuclei, because the histological features may be identical. Recently, some authors have suggested that papular MF may be an atypical variant of LyP and that papular MF and type B LyP may even be the same disorder. Evidence in support of this idea is that type B LyP does not usually ulcerate, can persist for long periods before remitting, and the lymphocytic infiltrate is often not positive for CD30.20 Some authors support the hypothesis that LyP and PL are biologically related disorders, perhaps sharing a common etiology such as a virus or other infectious agent. Vonderheid et al.21 reported a patient diagnosed with LyP type B followed by PL after 11 years and suggested that these are pathogenically related conditions. Cases of PL with histological features that overlap with those of LyP have been described, and it is particularly difficult to differentiate LyP type B from PL as lymphocytes in PL can express CD30, and CD30+ cells in LyP may be absent or present in small numbers. Histological distinction is challenging and is based on the presence of atypical lymphocytes infiltrating the epidermis without associated injury to keratinocytes.22,23 In addition, it has been suggested that in MF there is a loss of expression of the T cell-associated antigen CD7,24 which may represent a valuable tool in the distinction between inflammation and neoplasia.25 However, this finding has not been confirmed, as in other studies early MF showed normal CD7+ populations,26 and inflammatory dermatosis can also show a partial loss of CD7.27 Only one of our four cases showed the presence of monoclonal-type T cells in molecular studies, but this does not exclude the diagnosis of MF as rearrangement of the TCR gene is present in only approximately 50–60% of early lesions analyzed by standard techniques.28 Thus, some cases clinically manifest as long-evolving papular lesions with histological findings consistent with MF. These variants are presently difficult to classify and are clinically and pathologically compatible with the spectrum of lymphoproliferative disorders, which includes PL, LyP, and variants of papular and PL-like MF. Moreover, as there are forms of PL that subsequently evolve towards MF, and also PL-like forms of MF, it may be advisable for patients with long-evolving PL to undergo regular follow-up, with repeated skin biopsies in some cases, in order to discard diagnoses of atypical forms of MF.
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Table 2 Clinical features of reported cases of papular mycosis fungoides (MF) Authors/year
Age, years/sex
Clinical presentation
Other lesions
Duration
Treatment
Follow-up
Kodama et al. (2005)13 Kodama et al. (2005)13
57/male
No
Not mentioned
PUVA
18 months
No
2 years
57/female
No
Few months
PUVA Extracorporeal photopheresis PUVA
51 months
Kodama et al. (2005)13
Kodama et al. (2005)13
41/male
Yes
Not mentioned
PUVA
Kodama et al. (2005)13
59/male
No
30 years
PUVA
11 years Several recurrences 24 months
Kodama et al. (2005)13
61/male
No
Not mentioned
PUVA
74 months
Uddin et al. (2007)14
31/female
No
2 years
UVB
10 months
MartorellCalatayud et al. (2010)15
50/female
Erythematous papules on the trunk Papular eruption on the trunk and upper extremities Few erythematous papules on the trunk and upper and lower extremities Scattered erythematous papules on both legs Typical MF patches Disseminated erythematous papules on the trunk and extremities Several erythematous papular lesions on the back, flanks and shoulders Reddish-brown papules on the trunk and upper extremities Reddish-brown papules on the trunk
No
2 years
15 months
MartorellCalatayud et al. (2010)15 Liu et al. (2011)16
55/female
Itchy papular eruption on the trunk, buttocks and feet Reddish-brown papules on the left chest, axilla and popliteal fossa
No
18 months
Topical corticosteroids (0.1% clobetasol dipropionate) PUVA
No
Not mentioned
UVB Topical corticosteroids
Not mentioned
58/female
27/male
10 years Several recurrences
20 months
PUVA, psoralen combined with ultraviolet A light; UVB, ultraviolet B light.
References 1 Cerroni L, Gatter K, Ker H. Mycosis fungoides. In: Cerroni L, Gatter K, Ker H, eds. Skin Lymphoma: The Illustrated Guide, 3rd edn. Oxford: Blackwell Publishing, 2009: 11–56. 2 Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol 2004; 18: 397–415. 3 Kempf W, Kazakov DV, Palmedo G, et al. Pityriasis lichenoides et varioliformis acuta with numerous CD30+ cells: a variant mimicking lymphomatoid papulosis and other cutaneous lymphomas. A clinicopathologic, immunohistochemical, and molecular biological study of 13 cases. Am J Surg Pathol 2012; 36: 1021–1029. 4 Dereure O, Levi E, Kadin ME. T cell clonality in pityriasis lichenoides et varioliformis acuta. Arch Dermatol 2000; 136: 1483–1486. 5 Tomasini D, Zampatti C, Palmedo G, et al. Cytotoxic mycosis fungoides evolving from pityriasis lichenoides ª 2014 The International Society of Dermatology
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chronica in a 17-year-old girl. Dermatology 2002; 205: 176–179. Fortson JS, Schroeter AL, Esterly NB. Cutaneous T cell lymphoma (parapsoriasis en plaque): an association with pityriasis lichenoides et varioliformis acuta in young children. Arch Dermatol 1990; 126: 149–153. Niemczy UM, Zollner TM, Wolter M, et al. The transformation of pityriasis lichenoides chronica into parakeratosis variegate in an 11-year-old girl. Br J Dermatol 1997; 137: 983–987. Thomson KF, Whittaker SJ, Russel-Jones R, et al. Childhood cutaneous T cell lymphoma in association with pityriasis lichenoides chronica. Br J Dermatol 1999; 141: 1146–1148. Boccara O, Blanche S, de Prost Y, et al. Cutaneous hematologic disorders in children. Pediatr Blood Cancer 2012; 58: 226–232. Rivera R, Ortiz P, Rodriguez-Peralto JL, et al. Febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta with atypical cells. Int J Dermatol 2003; 42: 26–28. International Journal of Dermatology 2014, 53, 1331–1338
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11 Ko JW, Seong JY, Suh KS, et al. Pityriasis lichenoideslike mycosis fungoides in children. Br J Dermatol 2000; 142: 347–352. 12 Wang SH, Hsiao CH, Hsiao PF, et al. Adult pityriasis lichenoides-like mycosis fungoides with high density of CD8-positive T-lymphocytic infiltration. J Eur Acad Dermatol Venereol 2007; 21: 401–402. 13 Kodama K, Fink-Puches R, Massone C, et al. Papular mycosis fungoides: a new clinical variant of early mycosis fungoides. J Am Acad Dermatol 2005; 52: 694–698. 14 Uddin A, Bennett N, Nayeem K, et al. A case of papular mycosis fungoides: new clinical variant of early mycosis fungoides. J Eur Acad Dermatol Venereol 2007; 21: 685– 687. 15 Martorell-Calatayud A, Botella-Estrada R, SanmartínJimenez O, et al. Papular mycosis fungoides: two new cases of a recently described clinicopathological variant of early mycosis fungoides. J Cutan Pathol 2010; 37: 330–335. 16 Liu ZH, Wang YL, Chen SY, et al. Papular mycosis fungoides: a new clinical variant of early and benign mycosis fungoides? J Clin Oncol 2011; 29: 381–383. 17 El Shabrawi-Caelen L, Kerl H, Cerroni L. Lymphomatoid papulosis: reappraisal of clinicopathologic presentation and classification into subtypes A, B, and C. Arch Dermatol 2004; 140: 441–447. 18 Calzado-Villarreal L, Polo-Rodríguez I, Ortiz-Romero PL. Primary cutaneous CD30+ lymphoproliferative disorders. Actas Dermosifiliogr 2010; 101: 119–128. 19 Saggini A, Gulia A, Argenyi Z, et al. A variant of lymphomatoid papulosis simulating primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell lymphoma. Description of nine cases. Am J Surg Pathol 2010; 34: 1168–1175.
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20 Vonderheid EC, Kadin ME. Papular mycosis fungoides: a variant of mycosis fungoides or lymphomatoid papulosis? J Am Acad Dermatol 2006; 55: 177–180. 21 Vonderheid EC, Kadin ME, Gocke CD. Lymphomatoid papulosis followed by pityriasis lichenoides: a common pathogenesis? Am J Dermatopathol 2011; 33: 835–840. 22 Magro C, Crowson AN, Kovatich A, et al. Pityriasis lichenoides: a clonal T cell lymphoproliferative disorder. Hum Pathol 2002; 33: 788–795. 23 Nair PS. A clinical and histopathological study of pityriasis lichenoides. Indian J Dermatol Venereol Leprol 2007; 73: 100–102. 24 Wood GS, Abel EA, Hoppe RT, et al. Leu-8 and Leu-9 antigen phenotypes: immunological criteria for the distinction of mycosis fungoides from cutaneous inflammation. J Am Acad Dermatol 1986; 14: 1006– 1013. 25 Cotta AC, Cintra ML, de Souza EM, et al. Diagnosis of mycosis fungoides: a comparative immunohistochemical study of T cell markers using a novel anti-CD7 antibody. Appl Immunohistochem Mol Morphol 2006; 14: 291–295. 26 Willemze R, de Graaff-Reitsma CB, Cnossen J, et al. Characterization of T cell subpopulations in skin and peripheral blood of patients with cutaneous T cell lymphomas and benign inflammatory dermatoses. J Invest Dermatol 1983; 80: 60–66. 27 Payne CM, Spier CM, Gragan TM, et al. Nuclear contour irregularities correlate with Leu-9, Leu-8 cells in benign lymphoid infiltrates of the skin. Am J Dermatopathol 1998; 10: 377–398. 28 Massone C, Kodama K, Kerl H, et al. Histopathologic features of early (patch) lesions of mycosis fungoides. A morphologic study on 745 biopsy specimens from 427 patients. Am J Surg Pathol 2005; 29: 550–560.
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