EXTRAORDINARY CASE REPORT
Vesicular Mycosis Fungoides Shabnam Momtahen, MD,* Gerard J. Nuovo, MD,† and Cynthia M. Magro, MD*
Abstract: Mycosis fungoides (MF), the most common form of cutaneous lymphoma is derived from postthymic T cells that migrate to the skin likely under the influence of chronic antigen stimulation. Less common histomorphologic variants are diagnostically challenging because of their resemblance to reactive conditions. Three men aged 46, 73, and 74 years and one 83-year-old woman were encountered in the files of one of the authors and represented the patients. The patients had a longstanding eruption for several years. In 2 cases, the clinical course was aggressive with extracutaneous lymph node and/or peripheral blood dissemination. One patient had vesicles noted clinically. In all cases, vesiculation was a prominent feature histologically, which lead to an erroneous categorization initially as a reactive process. Basilar colonization by cerebriform lymphocytes along with the mucinous quality of the vesicle was diagnostic clue histologically, whereas the phenotypic and molecular profile was typical for MF. Strong expression of interleukin 5 and interleukin 10 in atypical lymphocytes in comparison with interferon gamma suggested a T-helper type 2–dominant cytokine microenvironment. In reviewing the literature of the 6 previously reported cases, 3 patients died of the disease; all these patients had vesicular lesions both clinically and histologically. We concluded that vesicular MF is a distinct histological and in some instances clinical variant of MF. The correlation of the vesicular eczematous quality of the eruption and a more aggressive clinical course may reflect the skewing toward a T-helper type 2–dominant cytokine milieu typical of advanced disease. Key Words: mycosis fungoides, vesicular mycosis fungoides, cutaneous lymphoma (Am J Dermatopathol 2015;37:724–729)
INTRODUCTION Mycosis fungoides (MF), the most common form of cutaneous lymphoma is derived from postthymic T cells that migrate to the skin likely under the influence of chronic antigen stimulation. There is considerable heterogeneity in regards to the clinical and histological subtypes of MF including follicular, granulomatous, syringotropic, and unilesional variants of MF. From the *Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York, NY; and †Ohio State University Comprehensive Cancer Center Core Lab, Powell, OH. The authors declare no conflicts of interest. Reprints: Cynthia M. Magro, MD, Professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, Room F309-B, New York, NY 10065 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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When one considers the prototypic morphology encountered in MF, it is in the context of passive infiltration of the epidermis by atypical hyperchromatic cerebriform lymphocytes. The designation of “passive” is used to emphasize the lack of spongiosis and/or keratinocyte necrosis that one might observe in inflammatory dermatoses such as eczema and the interface dermatitis of type 4 hypersensitivity. It is not entirely a passive phenomenon as there is an epidermal response, which is usually hyperplasia but may be attenuation in poikilodermatous variants. Histomorphologic patterns of MF that emphasize those seen in reactive conditions pose the greatest problems for dermatopathologists, perhaps best exemplified by lichenoid MF. However, a distinct pattern accompanied by vesiculation defines an additional uncommon morphologic expression of MF and likely reflects a unique cytokine milieu attributable to the nature of the infiltrating neoplastic T cells. It falls under the designation of vesicular MF. The purpose of this article was to present 4 cases of vesicular MF and review all cases of vesicular MF reported to date.
MATERIALS AND METHODS Four cases of vesicular MF comprising 3 men and 1 woman, ranging in age from 46 to 83 years, were encountered in the files of one of the authors. The paraffin-embedded samples were examined by routine hematoxylin and eosin for all 4 cases followed by phenotypic studies to assess the expression of CD3, CD4, CD5, CD7, and CD8. In 2 cases (case 1 and 2), the expression of interferon g (IFN-g), interleukin 5 (IL-5), and IL-10 was also evaluated by immunohistochemical analysis. Our immunohistochemical protocol has been previously described and used the Leica BOND-MAX (Leica Biosystems, Buffalo Grove, IL).1 Serial sections were tested after optimizing each antibody with formalin-fixed paraffin-embedded tonsils. Each antibody (obtained from Abcam) was optimized with antigen retrieval for 30 minutes. Alcian blue special staining were performed on 3 cases for better visualization of mucin deposits.
RESULTS Case 1 An 83-year-old woman presented with a 3-year history of erythematous and vesicular skin eruptions on her lower extremities with no other accompanying clinical signs or symptoms. On examination, she had erythematous, vesicular and scaly eruptions with oozing over the lower extremities. The initial biopsies were interpreted as a reactive eczematous process. Laboratory analysis including hemoglobin, white blood cell, platelet, and comprehensive metabolic profile were within normal limits. The human T-cell lymphotropic virus Am J Dermatopathol Volume 37, Number 9, September 2015
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(HTLV) 1 and 2 antibodies were not detected. The skin eruptions were treated with a variety of topical medications with only a transient improvement. Subsequent repeat biopsies and review of the earlier biopsies were held to be diagnostic of vesicular MF. A peripheral blood flow cytometry revealed 34% lymphoid cells including a minor B-cell population with expression of the pan-B-cell markers, and coexpression of CD5 and CD23, as well as a T-cell population with pan-T-cell antigen expression in a nonaberrant fashion. UV phototherapy was started 3 times per week with complete response within 5 months. Follow-up examination after 1 year showed that the patient was still in remission and phototherapy continued every other week.
Case 2
Vesicular Mycosis Fungoides
A narrowband UV-B phototherapy was initiated and the patient showed a significant improvement within the next 3 years. However, after 3 years, he was found to have a cervical lymphadenopathy. A biopsy of the lymph node showed CD30+ large T-cell lymphoma. Chemotherapy was initiated while the UV-B phototherapy was withheld. After few weeks, he developed new rashes on the arms, trunk, and legs. A second skin biopsy showed recurrent plaque stage MF. The patient continued to receive UV-B and topical corticosteroids. A third skin biopsy demonstrated significant spongiosis, frank vesiculation, and exocytosis of atypical lymphocytes into the epidermis, highly characteristic for vesicular MF. Given the fact that the patient was refractory to standard therapy, he was enrolled in a clinical trial for chemotherapy.
A 46-year-old man presented with a pruritic rash over his body along with waxing and waning lymphadenopathy in the inguinal and cervical regions for many years. His biopsies had always been interpreted as an eczematous dermatitis likely reflective of an atopic diathesis. He was treated with various topical treatments with no improvement. On examination, he had diffuse, dry, and scaling skin, erythematous plaques on his feet and a significant posterior cervical, axillary, and inguinal lymphadenopathy. Laboratory analysis revealed normal values for hemoglobin, white blood cell, platelet, and comprehensive metabolic profile. The HTLV 1 and 2 antibodies were not detected. The peripheral blood flow cytometry revealed 74% circulating Sezary cells. The cells expressed CD4 (90%) and showed a loss of CD7. There was a minor T-cell population representing 14% of the lymphocytes, which appeared to be double negative for CD4 and CD8 and demonstrated a loss of CD7. The initial biopsy was consistent with plaque stage MF. Biopsies of the bone marrow and right inguinal lymph node were unremarkable. He was treated with various chemotherapy regiments along with UV phototherapy with no improvement after 6 months. Physical examination showed new forming papules and plaques on his face, upper body, and arms, affecting more than 75% of his body surface area. A repeat biopsy of the right dorsal wrist was highly characteristic for vesicular MF and a new chemotherapy regimen was initiated.
Pathological Findings
Case 3
Immunophenotypic Studies
A 74-year-old man presented with poikilodermatous patches with scales localized to the left forearm for few years. Additional smaller plaques had arisen in this vicinity over the years. The patient was otherwise asymptomatic. Earlier biopsies had been interpreted as an eczematous dermatitis. After a diagnosis of vesicular MF was established, the patient was treated conservatively with narrowband UV phototherapy.
Cytokine expression analysis was performed on case 1 and case 2. The IFN-g showed no expression in atypical lymphocytes and a weak expression in the superficial squamous cells (Fig. 3). The IL-5 and IL-10 were strongly expressed in atypical lymphocytes with a high IL-5 or IL10-to-IFN-g ratio.
Case 4 A 73-year-old man presented with a history of erythematous and scaly rash on the trunk and extremities for 4 to 5 years. He was initially treated with a course of topical steroids with temporary improvement. A skin biopsy of the lower extremity was characteristic for plaque stage MF. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
In all cases, the biopsies appeared similar. The skin biopsy showed a superficial interstitial and perivascular lymphocytic infiltrate that focally assumed a band-like disposition (Fig. 1). In addition, there was infiltration of the epidermis by lymphocytes in a relatively passive pattern. There were multiple intraepidermal vesicles remarkable for an accumulation of atypical lymphocytes, Langerhans cells, and abundant intraepidermal mucin essentially equivalent to follicular mucinosis but involving the interfollicular epidermis. There was some accentuation of lymphocytic infiltration around the straight eccrine duct. From a cytomorphologic perspective, the lymphocytes were small to intermediate in size with hyperchromatic nuclei and significant nuclear contour irregularity whereby the atypia appeared to be greater in the epidermis compared with the dermal compartment. A large cell component was identified in 1 case. Alcian blue special stain revealed striking intraepidermal and follicular mucin deposits in 2 cases.
Phenotypic Studies The lymphocytes that defined these lesions were cerebriform and phenotypically exhibited a very high CD4to-CD8 ratio in excess of 10:1 along with a marked reduction of CD7 (Fig. 2). In 1 case, 30% of the infiltrate was positive for CD30. There was preservation of the other pan-T-cell markers namely CD2, CD3, and CD5.
DISCUSSION We have presented 4 cases of MF associated with prominent vesiculation histologically. In 1 case, there was both clinical and histological evidence of a vesicular process, whereas in the other 3 cases the designation of vesicular referred to the histological findings of vesiculation as opposed www.amjdermatopathology.com |
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Momtahen et al
Am J Dermatopathol Volume 37, Number 9, September 2015
FIGURE 1. Hematoxylin and eosin on case 1. A, Superficial interstitial and perivascular lymphocytic infiltrate in a band-like disposition. B, The intraepidermal vesicles are remarkable for an accumulation of atypical hyperchromatic lymphocytes with significant nuclear contour irregularity. C, Alician blue stain shows intraepidermal mucin deposit.
to vesiculation clinically. In 3 cases, earlier biopsies were interpreted as a reactive eczematous dermatitis. Retrospective review of those biopsies showed classic changes of vesicular MF, emphasizing the great diagnostic difficulty posed by such cases. The clinical course and diagnostic criteria of vesicular MF will be reviewed. Our patient cohort was represented by 3 men and 1 woman with an age range of 46–83 years and an average age of 69 years. All 4 patients had a longstanding eruption for at least 3 years. In 2 cases, the clinical course was aggressive with extracutaneous lymph node and/or peripheral blood dissemination. The other 2 patients had limited disease response to UV phototherapy. Although most patients had biopsies interpreted as a reactive process, even in the earlier biopsies the changes were diagnostic of vesicular MF. Although the diagnosis was obscured by vesiculation, there were important clues pointing to the correct diagnosis. In all cases, a very atypical cerebriform epitheliotropic lymphocytic infiltrate was present. The background architectural disposition of basilar colonization of the epidermis by atypical lymphocytes was noted in every case. When one considers a conventional eczematous dermatitis, this pattern of passive interface dermatitis is not a feature. An additional clue, although not identified in every case, was the mucinous quality of the vesicles essentially recapitulating follicular mucinosis. Although epidermal mucinosis has been previously described in patch-plague stage MF, mucinosis in
the context of vesiculation has not been described.2 In 2004, Böer et al3 reviewed 54 skin biopsies that were initially diagnosed as “follicular mucinosis” along with a comprehensive review of the literature concerning the terms “follicular mucinosis” and “alopecia mucinosa.” The authors proposed a concept to use the terminology “MF with epithelial mucinosis” rather than “follicular mucinosis” or “alopecia mucinosa.” They did not specifically allude to the presence of intraepidermal mucin but rather only emphasized the localization of mucin to the follicular apparatus. The phenotypic profile was typical for MF; however, without an appropriate index of suspicion, such studies would not be routinely conducted on a process that has the histological semblance of a reactive eczematous process. Hence, the recognition of the salient features by routine hematoxylin and eosin assessment are of cardinal importance. The abnormal lymphoid populace was of the CD4 subset exhibiting striking reductions in the expression of CD7 typical for plaque stage MF. At variance with classic MF was the very extensive vesiculation, whereby there were frank intraepidermal Langerhans cell–rich microvesicles that recapitulated those encountered in a reactive eczematoid process. We showed that in 2 cases in our study, the IL-10 and IL-5 were strongly positive, whereas the IFN-g revealed no expression in the atypical lymphocytes. This is highly suggestive of a T-helper type 2 (Th2)–dominant cytokine microenvironment.
FIGURE 2. Immunohistochemical phenotypic studies on case 1: (A) CD4; (B) CD8; (C) CD7. The lymphocytes exhibit a very high CD4 to CD8 ratio in excess of 10:1 along with a marked reduction of CD7.
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Vesicular Mycosis Fungoides
FIGURE 3. Immunophenotypic studies on case 2: (A) IL-5; (B) IFN-g. The atypical CD3-positive lymphocytes exhibit a very high IL-5-to-IFN-g ratio.
With regards to vesicular bullous MF, we are limiting the diagnosis to cases showing intraepidermal vesiculation histologically with or without a clinical correlate of vesiculobullous lesions. In addition, we consider pustular MF to be distinct from vesicular MF. In reviewing the literature, there are only few earlier reports falling under the designation of vesicular MF. In most cases, there was extensive disease noted clinically with a clinical course that was very aggressive, and all the patients showed frank erosive oozing vesicles. However, in our study, only 1 patient had vesicular lesions clinically. The question arises regarding the pathogenesis of vesicular MF including the basis for the apparently more aggressive clinical course associated with vesicular MF. It is very possible that true vesicular MF arises in the background of an atopic diathesis; however, that particular theoretical construction would not explain its more aggressive clinical behavior at least in the few cases reported. It has been suggested that the bullous variant of MF has a worse prognosis; however, the bullous variants of MF really represent accumulations of malignant lymphocytes within the epidermis resulting in the separation of the epidermis from the dermis and hence is really not synonymous with vesicular MF. Whether vesicular MF exists as an initial process and/or develops in a background of a preceding eczematoid eruption is not known because of the infrequency with which this variant of MF has been reported. There are 6 earlier cases of vesicular MF reported in the literature. Lund et al described the first case in 1990. The patient was a 66-year-old man who had a history of dermatitis for 12 years before presenting with a necrotic finger and a vesicular eruption. The digit was amputated and the histology showed inflammation and necrosis. During the next month, the grafted base of the finger became necrotic again and the subsequent biopsy showed microabscesses and an extensive infiltrate of numerous large lymphocytes. A diagnosis of tumor stage MF was made. Retrospective review of the amputated specimen revealed lymphoma within the necrotic tissue. The patient received electron beam therapy with a very good response. However, after 2–3 years, he developed large, erythematous, and scaly patches on his legs along with vesiculopustular erosive dermatitis on both hands. All biopsy showed intraepidermal vesicles with spongiosis, epidermotropism, and a lichenoid infiltrate of atypical lymphocytes consistent with vesicular MF. Electron beam Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
therapy was restarted and the patient remained asymptomatic for 14 months.4 In a review of 222 skin biopsies of patients with MF by Shapiro and Pinto in 1994, there was 1 case of “subepidermal vesicular MF.” The patient was a man with MF who developed a blister on his leg within a chronic large, ovoid, and eroded plaque. The biopsy showed a moderately dense lymphocytic infiltrate with many eosinophils and extravasated erythrocytes, edema in the papillary dermis, and intraepidermal vesiculation. No clinical follow-up was provided for this patient.5 In 1998, McBride et al reported another patient with vesicular MF; a 64-year-old woman with a change in presentation from a nonweeping scaly eruption to a blistering vesicular weepy one when she developed an aggressive clinical course. The patient eventually died of lymphoma. This case, however, had concomitant features of tumor stage MF with a number of large transformed lymphocytes within the biopsy.6 Gantcheva et al described a 62-year-old man with a rapidly progressive MF in 2005. The skin lesions of the face, head, trunk, and limbs exhibited numerous vesicles and erosions. Histopathology showed marked spongiosis and intraepidermal blisters, as well as invasion of the epidermis by atypical lymphocytes. Axillary and inguinal lymphadenopathy was also identified; however, the patient refused a lymph node biopsy. Despite intense chemophototherapy, the patient died after an aggressive clinical course.7 In 2006, Vermeer et al reported another patient with vesicular MF. The patient was a 62-year-old man who presented with a generalized eruption of sharply demarcated, erythematous small vesicles with yellow content. The lesions had started 1 year before presentation spreading to the trunk and extremities. Although initial photochemotherapy was associated with a partial response, 2 years after the diagnosis of vesicular MF, peripheral lymphadenopathy developed and despite intensive chemotherapy the patient developed a generalized herpes zoster infection and died.8 Bernardini et al reported a vesicular MF case in 2009. The patient was a 67-year-old man who had an unusual eruption characterized by vesiculobullous lesions on an annular background. It was unclear if MF arose in a background of a reactive eczematous process or was an ab initio presentation of MF. Similar to 2 cases in our study, this www.amjdermatopathology.com |
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Momtahen et al
TABLE 1. Summary of the Reported Cases of Vesicular MF Gender/Age
Extension of Disease
Treatment
Outcome After Therapy
Lund et al4 Shapiro and Pinto5 McBride et al6
M/64 M/NA F/64 M/62 M/62 M/67 F/83 M/46 M/74 M/73
Electron beam therapy NA PUVA electron beam therapy chemotherapy UV-A chemotherapy UV-A chemotherapy PUVA UV-A UV-A chemotherapy Narrowband UV phototherapy UV-B chemotherapy
Responded to therapy NA Death within weeks
Gantcheva et al7 Vermeer et al8 Bernardini et al9 Case 1 of current Case 2 of current Case 3 of current Case 4 of current
Bilateral extremities NA Extensive dissemination with mucosal involvement Extensive dissemination Extensive dissemination Extensive dissemination Bilateral extremities Extensive dissemination Unilateral upper extremity Extensive dissemination
series series series series
Death within weeks Death within weeks Responded to therapy Responded to therapy Partially responded to therapy Responded to therapy Partially responded to therapy
M, male; F, female; NA, no information available; PUVA, psoralen–UV-A.
patient’s clinical course was not as aggressive as the other cases described in the literature.9 In summary, among the 10 patients with vesicular MF reviewed in this article, 7 patients had vesicular skin lesions clinically. Acquisition of a vesicular morphology either clinically and or histologically corresponded to the onset of an aggressive clinical disease in at least 6 patients. Three patients died within few weeks after the diagnosis, whereas 2 patients responded partially to chemophototherapy. The other patients responded to phototherapy and had a stable clinical course (Table 1). The basis of the vesiculation could be reflective of a Th2-dominant cytokine microenvironment analogous to that seen in the setting of atopic eczema. It is well established that conversion from a Th1-dominant microenvironment to one associated with a Th2 profile correlates with a more aggressive clinical course in the setting of MF and hence could explain the association between vesicular MF and a more aggressive clinical course. When there is a Th2-dominant cytokine milieu, there is elaboration of IL-10, which suppresses natural killer (NK) and dendritic cell function resulting in a relative state of immunosuppression. Studies on MF immunophenotypes revealed that in early stages of the disease the production of IL-2 and IFN-g by a predominant population of reactive Th1 cells inhibits the expansion of neoplastic Th2 lymphocytes. In more advanced stages of MF, intensive activation of T cells is present and the neoplastic lymphocytes express a Th2 phenotype. Productions of Th2-specific cytokines (IL-4, IL-5, and IL-10) and concentration of other cytokines (IL-15, IL-16, IL-23, IL-26, IL-31, and IL-32) outweigh the main Th1 cytokine and lead to the increase of IgE and IgA, eosinophilia, and impaired delayed-type reactivity. Systemic changes associated with MF because of the constellation of immune abnormalities are observed mainly in advanced stages of MF.10–16 In conclusion, although the diagnosis of vesicular MF is among the most difficult ones to make, useful clues include the basilar pattern of passive colonization of cerebriform lymphocytes that is actually best highlighted by pan-T-cell markers, a finding that would not be seen in a reactive eczematous dermatitis. As well, in examining the vesicles,
they contain significant mucin hyaluronic acid analogous to the follicular mucinosis that is observed in the pilotropic T-cell dyscrasias of alopecia mucinosa and follicular MF. It is quite likely that the cytokine milieu contributes to the vesicular changes. Langerhans cells are integral cells in maintaining the intraepidermal neoplastic lymphocytic populace including a role for presenting apoptotic neoplastic T-cell fragments to viable T cells as a growth stimulus defining an almost cannibalistic phenomenon. When there are both clinical and histological features of vesicular MF, an aggressive clinical course seems characteristic. The role of dysregulated Th2 cytokine milieu should be explored further.
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ACKNOWLEDGMENTS The authors thank Dr. David Ramsay from New York University Medical Center for providing clinical information on one of the reported cases. REFERENCES 1. Nuovo GJ, Garofalo M, Valeri N, et al. Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples. Mod Pathol. 2012;25:1333–1344. 2. Nickoloff BJ. Epidermal mucinosis in mycosis fungoides. J Am Acad Dermatol. 1986;15:83–86. 3. Böer A, Guo Y, Ackerman AB. Alopecia mucinosa is mycosis fungoides. Am J Dermatopathol. 2004;26:33–52. 4. Lund KA, Parker CM, Norris AL, et al. Vesicular cutaneous T cell lymphoma presenting with gangrene. J Am Acad Dermatol. 1990;23: 1169–1171. 5. Shapiro PE, Pinto FJ. The histologic spectrum of mycosis fungoides/ Sézary syndrome (cutaneous T-cell lymphoma). A review of 222 biopsies, including newly described patterns and the earliest pathologic changes. Am J Surg Pathol. 1994;18:645–667. 6. McBride SR, Dahl MGC, Slater DN, et al. Vesicular MF. Br J Dermatol. 1998;138:141–144. 7. Gantcheva M, Lalova A, Broshtilova V, et al. Vesicular mycosis fungoides. J Dtsch Dermatol Ges. 2005;3:898–900. 8. Vermeer MH, Bekkenk MW, Jansen PM, et al. Vesicular mycosis fungoides. In: Michaelis S, Feit J, Burg G, Kempf W, editors. Cutaneous lymphomas: unusual cases 2. [electronic resource] Darmstadt: Steinkopff; 2006:6–7.
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9. Bernardini ML, Brandozzi G, Campanati A, et al. Bullous-vesicular variant of mycosis fungoides presenting as erythema annulare centrifugum: a case report. J Eur Acad Dermatol Venereol. 2009;23:835–862. 10. Van Kester MS, Borg MK, Zoutman WH, et al. A meta-analysis of gene expression data identifies a molecular signature characteristic for tumorstage mycosis fungoides. J Invest Dermatol. 2012;132:2050–2059. 11. Ohmatsu H, Sugaya M, Suga H, et al. Serum IL-31 levels are increased in patients with cutaneous T-cell lymphoma. Acta Derm Venereol. 2012;92: 282–283. 12. Doherty SD, Ni X, Doherty CB, et al. Abnormal expression of interleukin-23 in mycosis fungoides/Sézary syndrome lesions. Arch Dermatol Res. 2006;298:353–356.
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Vesicular Mycosis Fungoides
13. Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol. 2004;18:397–415. 14. Harwix S, Zachmann K, Neumann C. T-cell clones from early-stage cutaneous T-cell lymphoma show no polarized Th-1 or Th-2 cytokine profile. Arch Dermatol Res. 2000;292:1–8. 15. Pawlaczyk M, Sobieska M. A correlation between acute phase proteins and cytokines in patients suffering from mycosis fungoides. Acta Dermatovenerol Alp Pannonica Adriat. 2006;15:107–112. 16. Asadullah K, Haeussler-Quade A, Gellrich S, et al. IL-15 and IL-16 overexpression in cutaneous T-cell lymphomas: stage-dependent increase in mycosis fungoides progression. Exp Dermatol. 2000;9: 248–251.
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Vesicular Mycosis Fungoides Shabnam Momtahen, MD,* Gerard J. Nuovo, MD,† and Cynthia M. Magro, MD*
Abstract: Mycosis fungoides (MF), the most common form of cutaneous lymphoma is derived from postthymic T cells that migrate to the skin likely under the influence of chronic antigen stimulation. Less common histomorphologic variants are diagnostically challenging because of their resemblance to reactive conditions. Three men aged 46, 73, and 74 years and one 83-year-old woman were encountered in the files of one of the authors and represented the patients. The patients had a longstanding eruption for several years. In 2 cases, the clinical course was aggressive with extracutaneous lymph node and/or peripheral blood dissemination. One patient had vesicles noted clinically. In all cases, vesiculation was a prominent feature histologically, which lead to an erroneous categorization initially as a reactive process. Basilar colonization by cerebriform lymphocytes along with the mucinous quality of the vesicle was diagnostic clue histologically, whereas the phenotypic and molecular profile was typical for MF. Strong expression of interleukin 5 and interleukin 10 in atypical lymphocytes in comparison with interferon gamma suggested a T-helper type 2–dominant cytokine microenvironment. In reviewing the literature of the 6 previously reported cases, 3 patients died of the disease; all these patients had vesicular lesions both clinically and histologically. We concluded that vesicular MF is a distinct histological and in some instances clinical variant of MF. The correlation of the vesicular eczematous quality of the eruption and a more aggressive clinical course may reflect the skewing toward a T-helper type 2–dominant cytokine milieu typical of advanced disease. Key Words: mycosis fungoides, vesicular mycosis fungoides, cutaneous lymphoma (Am J Dermatopathol 2015;37:724–729)
INTRODUCTION Mycosis fungoides (MF), the most common form of cutaneous lymphoma is derived from postthymic T cells that migrate to the skin likely under the influence of chronic antigen stimulation. There is considerable heterogeneity in regards to the clinical and histological subtypes of MF including follicular, granulomatous, syringotropic, and unilesional variants of MF. From the *Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York, NY; and †Ohio State University Comprehensive Cancer Center Core Lab, Powell, OH. The authors declare no conflicts of interest. Reprints: Cynthia M. Magro, MD, Professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, Room F309-B, New York, NY 10065 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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When one considers the prototypic morphology encountered in MF, it is in the context of passive infiltration of the epidermis by atypical hyperchromatic cerebriform lymphocytes. The designation of “passive” is used to emphasize the lack of spongiosis and/or keratinocyte necrosis that one might observe in inflammatory dermatoses such as eczema and the interface dermatitis of type 4 hypersensitivity. It is not entirely a passive phenomenon as there is an epidermal response, which is usually hyperplasia but may be attenuation in poikilodermatous variants. Histomorphologic patterns of MF that emphasize those seen in reactive conditions pose the greatest problems for dermatopathologists, perhaps best exemplified by lichenoid MF. However, a distinct pattern accompanied by vesiculation defines an additional uncommon morphologic expression of MF and likely reflects a unique cytokine milieu attributable to the nature of the infiltrating neoplastic T cells. It falls under the designation of vesicular MF. The purpose of this article was to present 4 cases of vesicular MF and review all cases of vesicular MF reported to date.
MATERIALS AND METHODS Four cases of vesicular MF comprising 3 men and 1 woman, ranging in age from 46 to 83 years, were encountered in the files of one of the authors. The paraffin-embedded samples were examined by routine hematoxylin and eosin for all 4 cases followed by phenotypic studies to assess the expression of CD3, CD4, CD5, CD7, and CD8. In 2 cases (case 1 and 2), the expression of interferon g (IFN-g), interleukin 5 (IL-5), and IL-10 was also evaluated by immunohistochemical analysis. Our immunohistochemical protocol has been previously described and used the Leica BOND-MAX (Leica Biosystems, Buffalo Grove, IL).1 Serial sections were tested after optimizing each antibody with formalin-fixed paraffin-embedded tonsils. Each antibody (obtained from Abcam) was optimized with antigen retrieval for 30 minutes. Alcian blue special staining were performed on 3 cases for better visualization of mucin deposits.
RESULTS Case 1 An 83-year-old woman presented with a 3-year history of erythematous and vesicular skin eruptions on her lower extremities with no other accompanying clinical signs or symptoms. On examination, she had erythematous, vesicular and scaly eruptions with oozing over the lower extremities. The initial biopsies were interpreted as a reactive eczematous process. Laboratory analysis including hemoglobin, white blood cell, platelet, and comprehensive metabolic profile were within normal limits. The human T-cell lymphotropic virus Am J Dermatopathol Volume 37, Number 9, September 2015
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Am J Dermatopathol Volume 37, Number 9, September 2015
(HTLV) 1 and 2 antibodies were not detected. The skin eruptions were treated with a variety of topical medications with only a transient improvement. Subsequent repeat biopsies and review of the earlier biopsies were held to be diagnostic of vesicular MF. A peripheral blood flow cytometry revealed 34% lymphoid cells including a minor B-cell population with expression of the pan-B-cell markers, and coexpression of CD5 and CD23, as well as a T-cell population with pan-T-cell antigen expression in a nonaberrant fashion. UV phototherapy was started 3 times per week with complete response within 5 months. Follow-up examination after 1 year showed that the patient was still in remission and phototherapy continued every other week.
Case 2
Vesicular Mycosis Fungoides
A narrowband UV-B phototherapy was initiated and the patient showed a significant improvement within the next 3 years. However, after 3 years, he was found to have a cervical lymphadenopathy. A biopsy of the lymph node showed CD30+ large T-cell lymphoma. Chemotherapy was initiated while the UV-B phototherapy was withheld. After few weeks, he developed new rashes on the arms, trunk, and legs. A second skin biopsy showed recurrent plaque stage MF. The patient continued to receive UV-B and topical corticosteroids. A third skin biopsy demonstrated significant spongiosis, frank vesiculation, and exocytosis of atypical lymphocytes into the epidermis, highly characteristic for vesicular MF. Given the fact that the patient was refractory to standard therapy, he was enrolled in a clinical trial for chemotherapy.
A 46-year-old man presented with a pruritic rash over his body along with waxing and waning lymphadenopathy in the inguinal and cervical regions for many years. His biopsies had always been interpreted as an eczematous dermatitis likely reflective of an atopic diathesis. He was treated with various topical treatments with no improvement. On examination, he had diffuse, dry, and scaling skin, erythematous plaques on his feet and a significant posterior cervical, axillary, and inguinal lymphadenopathy. Laboratory analysis revealed normal values for hemoglobin, white blood cell, platelet, and comprehensive metabolic profile. The HTLV 1 and 2 antibodies were not detected. The peripheral blood flow cytometry revealed 74% circulating Sezary cells. The cells expressed CD4 (90%) and showed a loss of CD7. There was a minor T-cell population representing 14% of the lymphocytes, which appeared to be double negative for CD4 and CD8 and demonstrated a loss of CD7. The initial biopsy was consistent with plaque stage MF. Biopsies of the bone marrow and right inguinal lymph node were unremarkable. He was treated with various chemotherapy regiments along with UV phototherapy with no improvement after 6 months. Physical examination showed new forming papules and plaques on his face, upper body, and arms, affecting more than 75% of his body surface area. A repeat biopsy of the right dorsal wrist was highly characteristic for vesicular MF and a new chemotherapy regimen was initiated.
Pathological Findings
Case 3
Immunophenotypic Studies
A 74-year-old man presented with poikilodermatous patches with scales localized to the left forearm for few years. Additional smaller plaques had arisen in this vicinity over the years. The patient was otherwise asymptomatic. Earlier biopsies had been interpreted as an eczematous dermatitis. After a diagnosis of vesicular MF was established, the patient was treated conservatively with narrowband UV phototherapy.
Cytokine expression analysis was performed on case 1 and case 2. The IFN-g showed no expression in atypical lymphocytes and a weak expression in the superficial squamous cells (Fig. 3). The IL-5 and IL-10 were strongly expressed in atypical lymphocytes with a high IL-5 or IL10-to-IFN-g ratio.
Case 4 A 73-year-old man presented with a history of erythematous and scaly rash on the trunk and extremities for 4 to 5 years. He was initially treated with a course of topical steroids with temporary improvement. A skin biopsy of the lower extremity was characteristic for plaque stage MF. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
In all cases, the biopsies appeared similar. The skin biopsy showed a superficial interstitial and perivascular lymphocytic infiltrate that focally assumed a band-like disposition (Fig. 1). In addition, there was infiltration of the epidermis by lymphocytes in a relatively passive pattern. There were multiple intraepidermal vesicles remarkable for an accumulation of atypical lymphocytes, Langerhans cells, and abundant intraepidermal mucin essentially equivalent to follicular mucinosis but involving the interfollicular epidermis. There was some accentuation of lymphocytic infiltration around the straight eccrine duct. From a cytomorphologic perspective, the lymphocytes were small to intermediate in size with hyperchromatic nuclei and significant nuclear contour irregularity whereby the atypia appeared to be greater in the epidermis compared with the dermal compartment. A large cell component was identified in 1 case. Alcian blue special stain revealed striking intraepidermal and follicular mucin deposits in 2 cases.
Phenotypic Studies The lymphocytes that defined these lesions were cerebriform and phenotypically exhibited a very high CD4to-CD8 ratio in excess of 10:1 along with a marked reduction of CD7 (Fig. 2). In 1 case, 30% of the infiltrate was positive for CD30. There was preservation of the other pan-T-cell markers namely CD2, CD3, and CD5.
DISCUSSION We have presented 4 cases of MF associated with prominent vesiculation histologically. In 1 case, there was both clinical and histological evidence of a vesicular process, whereas in the other 3 cases the designation of vesicular referred to the histological findings of vesiculation as opposed www.amjdermatopathology.com |
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FIGURE 1. Hematoxylin and eosin on case 1. A, Superficial interstitial and perivascular lymphocytic infiltrate in a band-like disposition. B, The intraepidermal vesicles are remarkable for an accumulation of atypical hyperchromatic lymphocytes with significant nuclear contour irregularity. C, Alician blue stain shows intraepidermal mucin deposit.
to vesiculation clinically. In 3 cases, earlier biopsies were interpreted as a reactive eczematous dermatitis. Retrospective review of those biopsies showed classic changes of vesicular MF, emphasizing the great diagnostic difficulty posed by such cases. The clinical course and diagnostic criteria of vesicular MF will be reviewed. Our patient cohort was represented by 3 men and 1 woman with an age range of 46–83 years and an average age of 69 years. All 4 patients had a longstanding eruption for at least 3 years. In 2 cases, the clinical course was aggressive with extracutaneous lymph node and/or peripheral blood dissemination. The other 2 patients had limited disease response to UV phototherapy. Although most patients had biopsies interpreted as a reactive process, even in the earlier biopsies the changes were diagnostic of vesicular MF. Although the diagnosis was obscured by vesiculation, there were important clues pointing to the correct diagnosis. In all cases, a very atypical cerebriform epitheliotropic lymphocytic infiltrate was present. The background architectural disposition of basilar colonization of the epidermis by atypical lymphocytes was noted in every case. When one considers a conventional eczematous dermatitis, this pattern of passive interface dermatitis is not a feature. An additional clue, although not identified in every case, was the mucinous quality of the vesicles essentially recapitulating follicular mucinosis. Although epidermal mucinosis has been previously described in patch-plague stage MF, mucinosis in
the context of vesiculation has not been described.2 In 2004, Böer et al3 reviewed 54 skin biopsies that were initially diagnosed as “follicular mucinosis” along with a comprehensive review of the literature concerning the terms “follicular mucinosis” and “alopecia mucinosa.” The authors proposed a concept to use the terminology “MF with epithelial mucinosis” rather than “follicular mucinosis” or “alopecia mucinosa.” They did not specifically allude to the presence of intraepidermal mucin but rather only emphasized the localization of mucin to the follicular apparatus. The phenotypic profile was typical for MF; however, without an appropriate index of suspicion, such studies would not be routinely conducted on a process that has the histological semblance of a reactive eczematous process. Hence, the recognition of the salient features by routine hematoxylin and eosin assessment are of cardinal importance. The abnormal lymphoid populace was of the CD4 subset exhibiting striking reductions in the expression of CD7 typical for plaque stage MF. At variance with classic MF was the very extensive vesiculation, whereby there were frank intraepidermal Langerhans cell–rich microvesicles that recapitulated those encountered in a reactive eczematoid process. We showed that in 2 cases in our study, the IL-10 and IL-5 were strongly positive, whereas the IFN-g revealed no expression in the atypical lymphocytes. This is highly suggestive of a T-helper type 2 (Th2)–dominant cytokine microenvironment.
FIGURE 2. Immunohistochemical phenotypic studies on case 1: (A) CD4; (B) CD8; (C) CD7. The lymphocytes exhibit a very high CD4 to CD8 ratio in excess of 10:1 along with a marked reduction of CD7.
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Vesicular Mycosis Fungoides
FIGURE 3. Immunophenotypic studies on case 2: (A) IL-5; (B) IFN-g. The atypical CD3-positive lymphocytes exhibit a very high IL-5-to-IFN-g ratio.
With regards to vesicular bullous MF, we are limiting the diagnosis to cases showing intraepidermal vesiculation histologically with or without a clinical correlate of vesiculobullous lesions. In addition, we consider pustular MF to be distinct from vesicular MF. In reviewing the literature, there are only few earlier reports falling under the designation of vesicular MF. In most cases, there was extensive disease noted clinically with a clinical course that was very aggressive, and all the patients showed frank erosive oozing vesicles. However, in our study, only 1 patient had vesicular lesions clinically. The question arises regarding the pathogenesis of vesicular MF including the basis for the apparently more aggressive clinical course associated with vesicular MF. It is very possible that true vesicular MF arises in the background of an atopic diathesis; however, that particular theoretical construction would not explain its more aggressive clinical behavior at least in the few cases reported. It has been suggested that the bullous variant of MF has a worse prognosis; however, the bullous variants of MF really represent accumulations of malignant lymphocytes within the epidermis resulting in the separation of the epidermis from the dermis and hence is really not synonymous with vesicular MF. Whether vesicular MF exists as an initial process and/or develops in a background of a preceding eczematoid eruption is not known because of the infrequency with which this variant of MF has been reported. There are 6 earlier cases of vesicular MF reported in the literature. Lund et al described the first case in 1990. The patient was a 66-year-old man who had a history of dermatitis for 12 years before presenting with a necrotic finger and a vesicular eruption. The digit was amputated and the histology showed inflammation and necrosis. During the next month, the grafted base of the finger became necrotic again and the subsequent biopsy showed microabscesses and an extensive infiltrate of numerous large lymphocytes. A diagnosis of tumor stage MF was made. Retrospective review of the amputated specimen revealed lymphoma within the necrotic tissue. The patient received electron beam therapy with a very good response. However, after 2–3 years, he developed large, erythematous, and scaly patches on his legs along with vesiculopustular erosive dermatitis on both hands. All biopsy showed intraepidermal vesicles with spongiosis, epidermotropism, and a lichenoid infiltrate of atypical lymphocytes consistent with vesicular MF. Electron beam Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
therapy was restarted and the patient remained asymptomatic for 14 months.4 In a review of 222 skin biopsies of patients with MF by Shapiro and Pinto in 1994, there was 1 case of “subepidermal vesicular MF.” The patient was a man with MF who developed a blister on his leg within a chronic large, ovoid, and eroded plaque. The biopsy showed a moderately dense lymphocytic infiltrate with many eosinophils and extravasated erythrocytes, edema in the papillary dermis, and intraepidermal vesiculation. No clinical follow-up was provided for this patient.5 In 1998, McBride et al reported another patient with vesicular MF; a 64-year-old woman with a change in presentation from a nonweeping scaly eruption to a blistering vesicular weepy one when she developed an aggressive clinical course. The patient eventually died of lymphoma. This case, however, had concomitant features of tumor stage MF with a number of large transformed lymphocytes within the biopsy.6 Gantcheva et al described a 62-year-old man with a rapidly progressive MF in 2005. The skin lesions of the face, head, trunk, and limbs exhibited numerous vesicles and erosions. Histopathology showed marked spongiosis and intraepidermal blisters, as well as invasion of the epidermis by atypical lymphocytes. Axillary and inguinal lymphadenopathy was also identified; however, the patient refused a lymph node biopsy. Despite intense chemophototherapy, the patient died after an aggressive clinical course.7 In 2006, Vermeer et al reported another patient with vesicular MF. The patient was a 62-year-old man who presented with a generalized eruption of sharply demarcated, erythematous small vesicles with yellow content. The lesions had started 1 year before presentation spreading to the trunk and extremities. Although initial photochemotherapy was associated with a partial response, 2 years after the diagnosis of vesicular MF, peripheral lymphadenopathy developed and despite intensive chemotherapy the patient developed a generalized herpes zoster infection and died.8 Bernardini et al reported a vesicular MF case in 2009. The patient was a 67-year-old man who had an unusual eruption characterized by vesiculobullous lesions on an annular background. It was unclear if MF arose in a background of a reactive eczematous process or was an ab initio presentation of MF. Similar to 2 cases in our study, this www.amjdermatopathology.com |
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TABLE 1. Summary of the Reported Cases of Vesicular MF Gender/Age
Extension of Disease
Treatment
Outcome After Therapy
Lund et al4 Shapiro and Pinto5 McBride et al6
M/64 M/NA F/64 M/62 M/62 M/67 F/83 M/46 M/74 M/73
Electron beam therapy NA PUVA electron beam therapy chemotherapy UV-A chemotherapy UV-A chemotherapy PUVA UV-A UV-A chemotherapy Narrowband UV phototherapy UV-B chemotherapy
Responded to therapy NA Death within weeks
Gantcheva et al7 Vermeer et al8 Bernardini et al9 Case 1 of current Case 2 of current Case 3 of current Case 4 of current
Bilateral extremities NA Extensive dissemination with mucosal involvement Extensive dissemination Extensive dissemination Extensive dissemination Bilateral extremities Extensive dissemination Unilateral upper extremity Extensive dissemination
series series series series
Death within weeks Death within weeks Responded to therapy Responded to therapy Partially responded to therapy Responded to therapy Partially responded to therapy
M, male; F, female; NA, no information available; PUVA, psoralen–UV-A.
patient’s clinical course was not as aggressive as the other cases described in the literature.9 In summary, among the 10 patients with vesicular MF reviewed in this article, 7 patients had vesicular skin lesions clinically. Acquisition of a vesicular morphology either clinically and or histologically corresponded to the onset of an aggressive clinical disease in at least 6 patients. Three patients died within few weeks after the diagnosis, whereas 2 patients responded partially to chemophototherapy. The other patients responded to phototherapy and had a stable clinical course (Table 1). The basis of the vesiculation could be reflective of a Th2-dominant cytokine microenvironment analogous to that seen in the setting of atopic eczema. It is well established that conversion from a Th1-dominant microenvironment to one associated with a Th2 profile correlates with a more aggressive clinical course in the setting of MF and hence could explain the association between vesicular MF and a more aggressive clinical course. When there is a Th2-dominant cytokine milieu, there is elaboration of IL-10, which suppresses natural killer (NK) and dendritic cell function resulting in a relative state of immunosuppression. Studies on MF immunophenotypes revealed that in early stages of the disease the production of IL-2 and IFN-g by a predominant population of reactive Th1 cells inhibits the expansion of neoplastic Th2 lymphocytes. In more advanced stages of MF, intensive activation of T cells is present and the neoplastic lymphocytes express a Th2 phenotype. Productions of Th2-specific cytokines (IL-4, IL-5, and IL-10) and concentration of other cytokines (IL-15, IL-16, IL-23, IL-26, IL-31, and IL-32) outweigh the main Th1 cytokine and lead to the increase of IgE and IgA, eosinophilia, and impaired delayed-type reactivity. Systemic changes associated with MF because of the constellation of immune abnormalities are observed mainly in advanced stages of MF.10–16 In conclusion, although the diagnosis of vesicular MF is among the most difficult ones to make, useful clues include the basilar pattern of passive colonization of cerebriform lymphocytes that is actually best highlighted by pan-T-cell markers, a finding that would not be seen in a reactive eczematous dermatitis. As well, in examining the vesicles,
they contain significant mucin hyaluronic acid analogous to the follicular mucinosis that is observed in the pilotropic T-cell dyscrasias of alopecia mucinosa and follicular MF. It is quite likely that the cytokine milieu contributes to the vesicular changes. Langerhans cells are integral cells in maintaining the intraepidermal neoplastic lymphocytic populace including a role for presenting apoptotic neoplastic T-cell fragments to viable T cells as a growth stimulus defining an almost cannibalistic phenomenon. When there are both clinical and histological features of vesicular MF, an aggressive clinical course seems characteristic. The role of dysregulated Th2 cytokine milieu should be explored further.
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ACKNOWLEDGMENTS The authors thank Dr. David Ramsay from New York University Medical Center for providing clinical information on one of the reported cases. REFERENCES 1. Nuovo GJ, Garofalo M, Valeri N, et al. Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples. Mod Pathol. 2012;25:1333–1344. 2. Nickoloff BJ. Epidermal mucinosis in mycosis fungoides. J Am Acad Dermatol. 1986;15:83–86. 3. Böer A, Guo Y, Ackerman AB. Alopecia mucinosa is mycosis fungoides. Am J Dermatopathol. 2004;26:33–52. 4. Lund KA, Parker CM, Norris AL, et al. Vesicular cutaneous T cell lymphoma presenting with gangrene. J Am Acad Dermatol. 1990;23: 1169–1171. 5. Shapiro PE, Pinto FJ. The histologic spectrum of mycosis fungoides/ Sézary syndrome (cutaneous T-cell lymphoma). A review of 222 biopsies, including newly described patterns and the earliest pathologic changes. Am J Surg Pathol. 1994;18:645–667. 6. McBride SR, Dahl MGC, Slater DN, et al. Vesicular MF. Br J Dermatol. 1998;138:141–144. 7. Gantcheva M, Lalova A, Broshtilova V, et al. Vesicular mycosis fungoides. J Dtsch Dermatol Ges. 2005;3:898–900. 8. Vermeer MH, Bekkenk MW, Jansen PM, et al. Vesicular mycosis fungoides. In: Michaelis S, Feit J, Burg G, Kempf W, editors. Cutaneous lymphomas: unusual cases 2. [electronic resource] Darmstadt: Steinkopff; 2006:6–7.
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9. Bernardini ML, Brandozzi G, Campanati A, et al. Bullous-vesicular variant of mycosis fungoides presenting as erythema annulare centrifugum: a case report. J Eur Acad Dermatol Venereol. 2009;23:835–862. 10. Van Kester MS, Borg MK, Zoutman WH, et al. A meta-analysis of gene expression data identifies a molecular signature characteristic for tumorstage mycosis fungoides. J Invest Dermatol. 2012;132:2050–2059. 11. Ohmatsu H, Sugaya M, Suga H, et al. Serum IL-31 levels are increased in patients with cutaneous T-cell lymphoma. Acta Derm Venereol. 2012;92: 282–283. 12. Doherty SD, Ni X, Doherty CB, et al. Abnormal expression of interleukin-23 in mycosis fungoides/Sézary syndrome lesions. Arch Dermatol Res. 2006;298:353–356.
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13. Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol. 2004;18:397–415. 14. Harwix S, Zachmann K, Neumann C. T-cell clones from early-stage cutaneous T-cell lymphoma show no polarized Th-1 or Th-2 cytokine profile. Arch Dermatol Res. 2000;292:1–8. 15. Pawlaczyk M, Sobieska M. A correlation between acute phase proteins and cytokines in patients suffering from mycosis fungoides. Acta Dermatovenerol Alp Pannonica Adriat. 2006;15:107–112. 16. Asadullah K, Haeussler-Quade A, Gellrich S, et al. IL-15 and IL-16 overexpression in cutaneous T-cell lymphomas: stage-dependent increase in mycosis fungoides progression. Exp Dermatol. 2000;9: 248–251.
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