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Oral mycosis fungoides: report with immune profile Samuel M. Goldsmith, BDS, DClinDent, Benedict L. Seo, BDS, DClinDent, Rohana Kumara de Silva, BDS, FDSRCPS, FFDRCS, FDSRCS, Praveen Parachuru, BDS, MDS, PhD, Alison M. Rich, BDS, MDSc, PhD, FRACDS, FFOP (RCPA), and Gregory J. Seymour, BDS, MDSc, PhD, FRCPath, FFOP (RCPA) University of Otago, Dunedin, New Zealand
Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that uncommonly involves the oral mucosa. Oral MF is an indication of systemic progression and is often associated with an unfavorable outcome. Any oral mucosal site may be affected. This report describes a case of MF involving the hard palate of a 64-year-old woman with confirmed skin MF. The histology showed intra- and subepithelial atypical lymphocytes. Immunohistochemistry on the tissue sections showed that the CD4:CD8 ratio was high (5.8:1) and the CD8:CD3 ratio was low (0.16:1). FoxP3þ (forkhead box P3epositive) regulatory T cells were conspicuous within the infiltrate, but few interleukin-17 cells were observed. This report is the first to describe a detailed immune profile in oral MF. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;-:e1-e5)
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL) and has been defined as a neoplastic proliferation of epidermotropic, mature CD4þ helper T lymphocytes (TH cells) that has an indolent clinical course.1 The skin lesions are polymorphous and usually begin as scaly or erythematous patches that are followed, often many years later, by well-defined irregular infiltrative plaques, which may progress to form nodules or papules that ulcerate.2,3 At this stage the prognosis for the patient is poor. Concomitant peripheral blood involvement defines the patients as having Sézary syndrome, which is an aggressive type of CTCL.4 The putative cell of origin of MF is the memory CD4þCD45ROþ skin-homing T lymphocyte.5 These cells will be present in the surface epithelium, where they may form focal collections, known as Pautrier microabscesses. The subepidermal infiltrate comprises both malignant CD4þ and reactive CD8þ T lymphocytes with a dominant TH1 cytokine pattern early in the disease. Higher numbers of CD8þ T cells are associated with improved survival.6 As the disease progresses, the CD4:CD8 ratio increases, with a shift to a TH2 cytokine profile.4 The first report of oral involvement in MF was made in 1914,2 and since then fewer than 40 cases have been reported in the literature.2,7 However, on autopsy 7% to 18% of patients with MF have been found to have oral involvement.2,8,9 Oral MF is associated with systemic progression of the malignancy and thus carries a poor prognosis.10 This report describes MF of the palate in Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago. Received for publication Jul 18, 2013; returned for revision Oct 3, 2013; accepted for publication Oct 14, 2013. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.10.005
a 64-year-old woman with confirmed skin MF and provides a discussion of the histologic and immunohistochemical findings in the context of the published literature.
CASE REPORT A 64-year-old woman was referred to the Oral Surgery Clinic, Faculty of Dentistry, University of Otago by her general dental practitioner and dermatologist regarding a firm lump of 3 months’ duration on the hard palate. She had a history of long-standing cutaneous MF, first diagnosed 20 years previously, which had been managed with full-body radiotherapy, PUVA (psoralen combined with ultraviolet A) photochemotherapy and topical corticosteroids. She also had been treated for multinodular goiter with radioactive iodine and was taking methotrexate and an angiotensin-converting enzyme inhibitor. The patient claimed no history of pain, altered sensation, purulent discharge or hemorrhage from the area. On examination she had no palpable cervical or submandibular lymphadenopathy. A diffuse, raised lesion with a broad base (25 mm 10 mm) was observed on the posterior right hard palate adjacent to a mobile first molar tooth (Figure 1). The surface of the lesion showed several focal erosions with superficial ulceration. It was firm on palpation. The rest of the oral mucosa appeared to be normal. An incisional biopsy was performed under local analgesia. Histologically, the sections showed an ulcerated, slightly elevated lesion partially covered by an atrophic stratified squamous epithelium. Much of the submucosa was replaced by sheets of large atypical mononuclear cells (Figure 2, A, B). These cells had pleomorphic nuclei, some of which were vesiculated and some of which showed evidence of nuclear infolding and indentations. Scattered atypical cells were also found within the epithelium without marked Pautrier abscess formation. The neoplastic cells extended to involve all margins and at one end were abutting lobules of mixed minor salivary glands. The histologic appearance was consistent with MF. Further sections were stained with antibodies against CD3, CD4, CD8, CD56, CD68, IL-17 (interleukin-17), and
e1
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OOOO Month 2014 interface of 5.8:1 (Figure 3, A, B). The CD8:CD3 ratio was 0.16:1 (Figure 3, B, C). CD56þ (see Figure 3, D) and CD68þ cells (see Figure 3, E) were scattered throughout the lesion and accounted for 3.4% and 9.4%, respectively, of cells at the epithelialeconnective tissue interface. There was very little expression of IL-17 associated with the lesional cells (see Figure 3, F), whereas FoxP3, which regulates the development and function of regulatory T cells (Tregs), was expressed in cells diffusely scattered throughout the bulk of the lesion (see Figure 3, G). The patient was referred to the Oncology Department of Dunedin Hospital. The management plan involved a 36-Gy dose of radiotherapy delivered to the palate in 15 fractions. Two and a half years later, she remains well.
Fig. 1. Clinical photograph showing the raised firm lesion on the posterior right hard palate at the time of presentation. The surface showed several focal erosions with ulceration.
Table I. Number of positively staining cells expressed as a percentage of total cells counted Antibody CD3 CD4 CD8 CD56 CD68 FoxP3 IL-17
Primary target
% Positive
PaneT cells TH cells TC cells NK cells Macrophages Tregs IL-17-producing cells
49.9% 45.5% 7.8% 3.4% 9.4% 7.9% 0.8%
IL, interleukin; NK, natural killer; TC, cytotoxic T cells; TH, helper T cells.
FoxP3 (forkhead box P3) (Table I) using routine immunohistochemical techniques. Assessment was made of lesional cells in the region of the epithelialeconnective tissue interface both qualitatively and quantitatively. For the quantitation, a grid was superimposed onto photomicrographs, and all cells (negative and positive) in each grid square were counted to give a cumulative score of total cells and total positive cells. Three representative regions across the slide were counted. The results were expressed as the percentage of positive cells within the total cell population in the areas defined by the grid. Lesional cells showed a positive immunoreaction with anti-CD3, anti-CD4, and anti-CD8 antibodies with a CD4:CD8 ratio in the connective tissue immediately adjacent to the epithelialeconnective tissue
DISCUSSION MF occurs most commonly in the fourth or fifth decade of life3 and disproportionately affects black men.11,12 However, persons of any age, gender or race can be affected.12 Oral involvement in MF occurs over a large age range, with an average age of 61 years at diagnosis and without any gender predilection.2 The most commonly involved intraoral sites are the tongue, palate, gingiva, buccal mucosa, lips, and oropharynx, in descending order, and more than one site may be affected.2,10,13-15 Oral lesions generally appear some years (average, 8 years) after cutaneous involvement.2 Oral cavity involvement is associated with poor prognosis, with a 50% mortality rate within 1 year of oral presentation. Almost all patients with such involvement die within 3 years.2 Despite its association with advanced disease, most patients with oral MF do not have lymphadenopathy or visceral involvement.2,10,16 Other extracutaneous sites affected include the lymph nodes, spleen, lungs, liver, kidneys, bones and heart. Diagnosis of MF is based on a thorough history and clinical examination supported by lesional biopsy with histologic and immunohistochemical analysis. The histopathologic features of MF depend on the stage of the disease at the time of biopsy, and in the early phases the microscopic findings may be nonspecific and simulate numerous inflammatory conditions. Histologically the oral lesions appear similar to their cutaneous counterparts, although they tend to present with a deeper infiltrate and more atypical lymphocytes, signifying an advanced stage of the disease, as was seen in the current case.2 With well-established lesions, small well-differentiated lymphocytes with round or cerebriform nuclei are observed within the epidermis, which often shows evidence of basal cell damage and acanthosis. The intraepithelial CD4þ cells are often in close association with Langerhans cells,17 and a dense band-like infiltrate of atypical lymphocytes is seen in the underlying connective tissue. The CD4:CD8 ratio in the subepithelial connective infiltrate and within the
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Fig. 2. Photomicrographs showing the sections from the palatal mass stained with hematoxylin-eosin. A, Low-magnification view (original magnification, 5 objective) showing a relatively atrophic epithelium with an intense infiltrate of mononuclear cells throughout the lamina propria and submucosa. B, Another view (original magnification, 20 objective) shows lymphocytes with nuclear pleomorphism and hyperchromatism in the lamina propria and extending into the epithelium.
epithelium in the current cases was high at 5.8:1. A similar high CD4:CD8 ratio has been previously reported for skin MF.18-20 On the other hand, the CD8:CD3 ratio was low, which is also consistent with prior findings.19 Only a small number of CD56 NK cells were observed, also in accord with advanced cutaneous MF.20 The presence of FoxP3þ Tregs in the infiltrate is of interest in light of their ability to suppress immune responses of other cells. Tregs have been noted in skin MF, with FoxP3 expression being seen in the tumor infiltrating lymphocytes (TILs), but not in the malignant T cells. A high frequency of FoxP3þ TILs has been associated with improved survival,20,21 suggesting that the suppressive FoxP3þ TILs may be able to keep the malignant CD4þ TH cells in check, at least in the early stages of the disease.20 Nevertheless, it is interesting to note that despite the poor prognosis of patients with oral involvement and the relatively advanced stage of the disease, the current patient was still alive 2.5 years after diagnosis of the oral lesion. It is interesting to speculate that this could be associated with high numbers of FoxP3þ Tregs within the lesion. Although it is not possible from a single case report such as this to make any definitive statement, it would nevertheless be interesting to determine if the presence of high numbers of FoxP3þ Tregs within the lesion was related to future prognosis in response to therapy, and it is suggested that this be included in future pathologic reporting. A relative absence of IL-17-producing cells was noted in the current case. IL-17 is a proinflammatory cytokine that is important in immune surveillance. It has been considered to be produced by a specific
subtype of TH cells known as TH17 cells, but it can also be produced by a range of cell populations.22 Variable expression of IL-17 has been reported in the lesions of cutaneous MF,23 but it has not been detected in the blood of patients with MF or Sézary syndrome.4 TH17 cells are thought to be in a reciprocal relationship with FoxP3þ Tregs, such that the low number of TH17 cells seen in the present case is a reflection of the high number of FoxP3þ Tregs. T-cell receptor gene rearrangement analysis using polymerase chain reaction or Southern blotting has been used in diagnosis but is not specific.12,24 A complete blood count and evaluation of the blood to check for the presence of Sézary cells (malignant mononuclear cells with a grooved nucleus and cytoplasmic vacuoles) is necessary to exclude Sézary syndrome.12,25 Plain radiography, computed tomography, and fluorodeoxyglucose positron emission tomography have also proved useful,12 whereas fineneedle aspiration can be used to identify lymph node involvement.13 Once a diagnosis is made, the stage of progression should be identified using the American Joint Committee on Cancer system,26 which has recently been revised by the International Society for Cutaneous Lymphomas and the European Organisation for the Research and Treatment of Cancer.27 The staging system is based on a TNM classification and takes into account the degree and character of cutaneous involvement, lymph node and visceral manifestations, and the presence and number of atypical circulating lymphocytes (Sézary cells).12 The management of MF and Sézary syndrome varies depending on stage of the disease, with consensus
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Fig. 3. Photomicrographs showing the sections reacted with (A) anti-CD4, (B) anti-CD8, (C) anti-CD3, (D) anti-CD56, (E) antiCD68, (F) anti-IL-17, and (G) anti-FoxP3. (Scale bar ¼ 70 mm.)
guidelines suggesting topical therapies in the first instance, with the use of agents such as retinoids and interferons to augment the immune response, rather than immunosuppressants, as necessary. A number of systemic biologic and immune-enhancing therapies are being used in clinical trials.4 Management of an oral lesion is undertaken after consideration of the presence or absence of other active lesions and generally consists of radiotherapy.10 Doses ranging from 20 to 36 Gy have been reported to result in involution of the lesion.28,29 In some cases, systemic chemotherapy has been used.13 Despite this, the prognosis of a patient with oral MF is generally considered poor, and in most cases death will ensue owing to distant disease or susceptibility to infection due to immune suppression.10,20 Further studies will be necessary to determine if the evaluation of the proportion of intralesional FoxP3þ Tregs and TH17 cells can be used as an indicator of prognosis in MF.
REFERENCES 1. Smoller BR. Mycosis fungoides: what do/do not we know? J Cutan Pathol. 2008;35(suppl 2):35-39. 2. de la Fuente EG, Rodriguez-Peralto JL, Ortiz PL, Barrientos N, Vanaclocha F, Iglesias L. Oral involvement in mycosis fungoides: report of two cases and a literature review. Acta Derm Venereol. 2000;80:299-301. 3. Evans GE, Dalziel KL. Mycosis fungoides with oral involvement: a case report and literature review. Int J Oral Maxillofac Surg. 1987;16:634-637. 4. Wong HK, Mishra A, Hake T, Porcu P. Evolving insights in the pathogenesis and therapy of cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome). Brit J Haematol. 2011;155: 150-166. 5. Ginaldi L, De Martinis M, Matutes E, et al. Levels of expression of CD52 in normal and leukemic B and T cells: correlation with in vivo therapeutic responses to Campath-1H. Leukemia Res. 1998;22:185-191. 6. Hoppe RT, Medeiros LJ, Warnke RA, Wood GS. CD8-positive tumor-infiltrating lymphocytes influence the long-term survival of patients with mycosis fungoides. J Amer Acad Dermatol. 1995;32:448-453.
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7. Sirois DA, Miller AS, Harwick RD, Vonderheid EC. Oral manifestations of cutaneous T-cell lymphoma: a report of eight cases. Oral Surg Oral Med Oral Pathol. 1993;75:700-705. 8. Long JC, Mihm MC. Mycosis fungoides with extracutaneous dissemination: a distinct clinicopathologic entity. Cancer. 1974;34: 1745-1755. 9. Epstein EH Jr, Levin DL, Croft JD Jr, Lutzner MA. Mycosis fungoides. Survival, prognostic features, response to therapy, and autopsy findings. Medicine (Baltimore). 1972;51:61-72. 10. Chua MS, Veness MJ. Mycosis fungoides involving the oral cavity. Austral Radiol. 2002;46:336-339. 11. Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol. 2007;143:854-859. 12. Galper SL, Smith BD, Wilson LD. Diagnosis and management of mycosis fungoides. Oncology (Williston Park). 2010;24:491-501. 13. Hata T, Aikoh T, Hirokawa M, Hosoda M. Mycosis fungoides with involvement of the oral mucosa. Int J Oral Maxillofac Surg. 1998;27:127-128. 14. Wain EM, Setterfield J, Judge MR, Harper JI, Pemberton MN, Russell-Jones R. Mycosis fungoides involving the oral mucosa in a child. Clin Exp Dermatol. 2003;28:499-501. 15. Le BT, Setlur J, Sikora AG, Lee KC. Mycosis fungoides: a case of tonsil involvement. Arch Otolaryngol Head Neck Surg. 2006;132:794-796. 16. Laskaris GC, Nicolis GD, Capetanakis JP. Mycosis fungoides with oral manifestations. Oral Surg Oral Med Oral Pathol. 1978;46:40-42. 17. Edelson RL. Cutaneous T cell lymphoma: the helping hand of dendritic cells. Ann New York Acad Sciences. 2001;941:1-11. 18. Izban KF, Hsi ED, Alkan S. Immunohistochemical analysis of mycosis fungoides on paraffin-embedded tissue sections. Mod Pathol. 1998;11:978-982. 19. Ortonne N, Buyukbabani N, Delfau-Larue MH, Bagot M, Wechsler J. Value of the CD8-CD3 ratio for the diagnosis of mycosis fungoides. Mod Pathol. 2003;16:857-862. 20. Krejsgaard T, Odum N, Geisler C, Wasik MA, Woetmann A. Regulatory T cells and immunodeficiency in mycosis fungoides and Sezary syndrome. Leukemia. 2012;26:424-432.
21. Solomon GJ, Magro CM. FoxP3 expression in cutaneous T-cell lymphocytic infiltrates. J Cut Pathol. 2008;35:1032-1039. 22. Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nature Rev Immunology. 2010;10: 479-489. 23. Ciree A, Michel L, Camilleri-Broet S, et al. Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome). Int J Cancer J. 2004;112(1): 113-120. 24. Keehn CA, Belongie IP, Shistik G, Fenske NA, Glass LF. The diagnosis, staging, and treatment options for mycosis fungoides. Cancer Control. 2007;14:102-111. 25. Cyriac MJ, Kurian A. Sezary cell. Indian J Dermatol Venereol Leprol. 2004;70:321-324. 26. Greene FL, Page DL, Fleming ID, eds. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer; 2002. 27. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110:1713-1722. 28. Reynolds WR, Feldman MI, Bricout PB, Potdar GG. Mycosis fungoides in the maxillary sinus and oral cavity: report of two cases. J Oral Surg. 1981;39:373-377. 29. Crane RM Jr, Heydt S. Gingival involvement in mycosis fungoides: report of case. J Oral Surg. 1979;37:585-587.
Reprint requests: Alison M. Rich Sir John Walsh Research Institute Faculty of Dentistry University of Otago PO Box 647 Dunedin 9054 New Zealand [email protected]
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Oral mycosis fungoides: report with immune profile Samuel M. Goldsmith, BDS, DClinDent, Benedict L. Seo, BDS, DClinDent, Rohana Kumara de Silva, BDS, FDSRCPS, FFDRCS, FDSRCS, Praveen Parachuru, BDS, MDS, PhD, Alison M. Rich, BDS, MDSc, PhD, FRACDS, FFOP (RCPA), and Gregory J. Seymour, BDS, MDSc, PhD, FRCPath, FFOP (RCPA) University of Otago, Dunedin, New Zealand
Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that uncommonly involves the oral mucosa. Oral MF is an indication of systemic progression and is often associated with an unfavorable outcome. Any oral mucosal site may be affected. This report describes a case of MF involving the hard palate of a 64-year-old woman with confirmed skin MF. The histology showed intra- and subepithelial atypical lymphocytes. Immunohistochemistry on the tissue sections showed that the CD4:CD8 ratio was high (5.8:1) and the CD8:CD3 ratio was low (0.16:1). FoxP3þ (forkhead box P3epositive) regulatory T cells were conspicuous within the infiltrate, but few interleukin-17 cells were observed. This report is the first to describe a detailed immune profile in oral MF. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;-:e1-e5)
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL) and has been defined as a neoplastic proliferation of epidermotropic, mature CD4þ helper T lymphocytes (TH cells) that has an indolent clinical course.1 The skin lesions are polymorphous and usually begin as scaly or erythematous patches that are followed, often many years later, by well-defined irregular infiltrative plaques, which may progress to form nodules or papules that ulcerate.2,3 At this stage the prognosis for the patient is poor. Concomitant peripheral blood involvement defines the patients as having Sézary syndrome, which is an aggressive type of CTCL.4 The putative cell of origin of MF is the memory CD4þCD45ROþ skin-homing T lymphocyte.5 These cells will be present in the surface epithelium, where they may form focal collections, known as Pautrier microabscesses. The subepidermal infiltrate comprises both malignant CD4þ and reactive CD8þ T lymphocytes with a dominant TH1 cytokine pattern early in the disease. Higher numbers of CD8þ T cells are associated with improved survival.6 As the disease progresses, the CD4:CD8 ratio increases, with a shift to a TH2 cytokine profile.4 The first report of oral involvement in MF was made in 1914,2 and since then fewer than 40 cases have been reported in the literature.2,7 However, on autopsy 7% to 18% of patients with MF have been found to have oral involvement.2,8,9 Oral MF is associated with systemic progression of the malignancy and thus carries a poor prognosis.10 This report describes MF of the palate in Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago. Received for publication Jul 18, 2013; returned for revision Oct 3, 2013; accepted for publication Oct 14, 2013. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.10.005
a 64-year-old woman with confirmed skin MF and provides a discussion of the histologic and immunohistochemical findings in the context of the published literature.
CASE REPORT A 64-year-old woman was referred to the Oral Surgery Clinic, Faculty of Dentistry, University of Otago by her general dental practitioner and dermatologist regarding a firm lump of 3 months’ duration on the hard palate. She had a history of long-standing cutaneous MF, first diagnosed 20 years previously, which had been managed with full-body radiotherapy, PUVA (psoralen combined with ultraviolet A) photochemotherapy and topical corticosteroids. She also had been treated for multinodular goiter with radioactive iodine and was taking methotrexate and an angiotensin-converting enzyme inhibitor. The patient claimed no history of pain, altered sensation, purulent discharge or hemorrhage from the area. On examination she had no palpable cervical or submandibular lymphadenopathy. A diffuse, raised lesion with a broad base (25 mm 10 mm) was observed on the posterior right hard palate adjacent to a mobile first molar tooth (Figure 1). The surface of the lesion showed several focal erosions with superficial ulceration. It was firm on palpation. The rest of the oral mucosa appeared to be normal. An incisional biopsy was performed under local analgesia. Histologically, the sections showed an ulcerated, slightly elevated lesion partially covered by an atrophic stratified squamous epithelium. Much of the submucosa was replaced by sheets of large atypical mononuclear cells (Figure 2, A, B). These cells had pleomorphic nuclei, some of which were vesiculated and some of which showed evidence of nuclear infolding and indentations. Scattered atypical cells were also found within the epithelium without marked Pautrier abscess formation. The neoplastic cells extended to involve all margins and at one end were abutting lobules of mixed minor salivary glands. The histologic appearance was consistent with MF. Further sections were stained with antibodies against CD3, CD4, CD8, CD56, CD68, IL-17 (interleukin-17), and
e1
ORAL AND MAXILLOFACIAL PATHOLOGY e2 Goldsmith et al.
OOOO Month 2014 interface of 5.8:1 (Figure 3, A, B). The CD8:CD3 ratio was 0.16:1 (Figure 3, B, C). CD56þ (see Figure 3, D) and CD68þ cells (see Figure 3, E) were scattered throughout the lesion and accounted for 3.4% and 9.4%, respectively, of cells at the epithelialeconnective tissue interface. There was very little expression of IL-17 associated with the lesional cells (see Figure 3, F), whereas FoxP3, which regulates the development and function of regulatory T cells (Tregs), was expressed in cells diffusely scattered throughout the bulk of the lesion (see Figure 3, G). The patient was referred to the Oncology Department of Dunedin Hospital. The management plan involved a 36-Gy dose of radiotherapy delivered to the palate in 15 fractions. Two and a half years later, she remains well.
Fig. 1. Clinical photograph showing the raised firm lesion on the posterior right hard palate at the time of presentation. The surface showed several focal erosions with ulceration.
Table I. Number of positively staining cells expressed as a percentage of total cells counted Antibody CD3 CD4 CD8 CD56 CD68 FoxP3 IL-17
Primary target
% Positive
PaneT cells TH cells TC cells NK cells Macrophages Tregs IL-17-producing cells
49.9% 45.5% 7.8% 3.4% 9.4% 7.9% 0.8%
IL, interleukin; NK, natural killer; TC, cytotoxic T cells; TH, helper T cells.
FoxP3 (forkhead box P3) (Table I) using routine immunohistochemical techniques. Assessment was made of lesional cells in the region of the epithelialeconnective tissue interface both qualitatively and quantitatively. For the quantitation, a grid was superimposed onto photomicrographs, and all cells (negative and positive) in each grid square were counted to give a cumulative score of total cells and total positive cells. Three representative regions across the slide were counted. The results were expressed as the percentage of positive cells within the total cell population in the areas defined by the grid. Lesional cells showed a positive immunoreaction with anti-CD3, anti-CD4, and anti-CD8 antibodies with a CD4:CD8 ratio in the connective tissue immediately adjacent to the epithelialeconnective tissue
DISCUSSION MF occurs most commonly in the fourth or fifth decade of life3 and disproportionately affects black men.11,12 However, persons of any age, gender or race can be affected.12 Oral involvement in MF occurs over a large age range, with an average age of 61 years at diagnosis and without any gender predilection.2 The most commonly involved intraoral sites are the tongue, palate, gingiva, buccal mucosa, lips, and oropharynx, in descending order, and more than one site may be affected.2,10,13-15 Oral lesions generally appear some years (average, 8 years) after cutaneous involvement.2 Oral cavity involvement is associated with poor prognosis, with a 50% mortality rate within 1 year of oral presentation. Almost all patients with such involvement die within 3 years.2 Despite its association with advanced disease, most patients with oral MF do not have lymphadenopathy or visceral involvement.2,10,16 Other extracutaneous sites affected include the lymph nodes, spleen, lungs, liver, kidneys, bones and heart. Diagnosis of MF is based on a thorough history and clinical examination supported by lesional biopsy with histologic and immunohistochemical analysis. The histopathologic features of MF depend on the stage of the disease at the time of biopsy, and in the early phases the microscopic findings may be nonspecific and simulate numerous inflammatory conditions. Histologically the oral lesions appear similar to their cutaneous counterparts, although they tend to present with a deeper infiltrate and more atypical lymphocytes, signifying an advanced stage of the disease, as was seen in the current case.2 With well-established lesions, small well-differentiated lymphocytes with round or cerebriform nuclei are observed within the epidermis, which often shows evidence of basal cell damage and acanthosis. The intraepithelial CD4þ cells are often in close association with Langerhans cells,17 and a dense band-like infiltrate of atypical lymphocytes is seen in the underlying connective tissue. The CD4:CD8 ratio in the subepithelial connective infiltrate and within the
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Fig. 2. Photomicrographs showing the sections from the palatal mass stained with hematoxylin-eosin. A, Low-magnification view (original magnification, 5 objective) showing a relatively atrophic epithelium with an intense infiltrate of mononuclear cells throughout the lamina propria and submucosa. B, Another view (original magnification, 20 objective) shows lymphocytes with nuclear pleomorphism and hyperchromatism in the lamina propria and extending into the epithelium.
epithelium in the current cases was high at 5.8:1. A similar high CD4:CD8 ratio has been previously reported for skin MF.18-20 On the other hand, the CD8:CD3 ratio was low, which is also consistent with prior findings.19 Only a small number of CD56 NK cells were observed, also in accord with advanced cutaneous MF.20 The presence of FoxP3þ Tregs in the infiltrate is of interest in light of their ability to suppress immune responses of other cells. Tregs have been noted in skin MF, with FoxP3 expression being seen in the tumor infiltrating lymphocytes (TILs), but not in the malignant T cells. A high frequency of FoxP3þ TILs has been associated with improved survival,20,21 suggesting that the suppressive FoxP3þ TILs may be able to keep the malignant CD4þ TH cells in check, at least in the early stages of the disease.20 Nevertheless, it is interesting to note that despite the poor prognosis of patients with oral involvement and the relatively advanced stage of the disease, the current patient was still alive 2.5 years after diagnosis of the oral lesion. It is interesting to speculate that this could be associated with high numbers of FoxP3þ Tregs within the lesion. Although it is not possible from a single case report such as this to make any definitive statement, it would nevertheless be interesting to determine if the presence of high numbers of FoxP3þ Tregs within the lesion was related to future prognosis in response to therapy, and it is suggested that this be included in future pathologic reporting. A relative absence of IL-17-producing cells was noted in the current case. IL-17 is a proinflammatory cytokine that is important in immune surveillance. It has been considered to be produced by a specific
subtype of TH cells known as TH17 cells, but it can also be produced by a range of cell populations.22 Variable expression of IL-17 has been reported in the lesions of cutaneous MF,23 but it has not been detected in the blood of patients with MF or Sézary syndrome.4 TH17 cells are thought to be in a reciprocal relationship with FoxP3þ Tregs, such that the low number of TH17 cells seen in the present case is a reflection of the high number of FoxP3þ Tregs. T-cell receptor gene rearrangement analysis using polymerase chain reaction or Southern blotting has been used in diagnosis but is not specific.12,24 A complete blood count and evaluation of the blood to check for the presence of Sézary cells (malignant mononuclear cells with a grooved nucleus and cytoplasmic vacuoles) is necessary to exclude Sézary syndrome.12,25 Plain radiography, computed tomography, and fluorodeoxyglucose positron emission tomography have also proved useful,12 whereas fineneedle aspiration can be used to identify lymph node involvement.13 Once a diagnosis is made, the stage of progression should be identified using the American Joint Committee on Cancer system,26 which has recently been revised by the International Society for Cutaneous Lymphomas and the European Organisation for the Research and Treatment of Cancer.27 The staging system is based on a TNM classification and takes into account the degree and character of cutaneous involvement, lymph node and visceral manifestations, and the presence and number of atypical circulating lymphocytes (Sézary cells).12 The management of MF and Sézary syndrome varies depending on stage of the disease, with consensus
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Fig. 3. Photomicrographs showing the sections reacted with (A) anti-CD4, (B) anti-CD8, (C) anti-CD3, (D) anti-CD56, (E) antiCD68, (F) anti-IL-17, and (G) anti-FoxP3. (Scale bar ¼ 70 mm.)
guidelines suggesting topical therapies in the first instance, with the use of agents such as retinoids and interferons to augment the immune response, rather than immunosuppressants, as necessary. A number of systemic biologic and immune-enhancing therapies are being used in clinical trials.4 Management of an oral lesion is undertaken after consideration of the presence or absence of other active lesions and generally consists of radiotherapy.10 Doses ranging from 20 to 36 Gy have been reported to result in involution of the lesion.28,29 In some cases, systemic chemotherapy has been used.13 Despite this, the prognosis of a patient with oral MF is generally considered poor, and in most cases death will ensue owing to distant disease or susceptibility to infection due to immune suppression.10,20 Further studies will be necessary to determine if the evaluation of the proportion of intralesional FoxP3þ Tregs and TH17 cells can be used as an indicator of prognosis in MF.
REFERENCES 1. Smoller BR. Mycosis fungoides: what do/do not we know? J Cutan Pathol. 2008;35(suppl 2):35-39. 2. de la Fuente EG, Rodriguez-Peralto JL, Ortiz PL, Barrientos N, Vanaclocha F, Iglesias L. Oral involvement in mycosis fungoides: report of two cases and a literature review. Acta Derm Venereol. 2000;80:299-301. 3. Evans GE, Dalziel KL. Mycosis fungoides with oral involvement: a case report and literature review. Int J Oral Maxillofac Surg. 1987;16:634-637. 4. Wong HK, Mishra A, Hake T, Porcu P. Evolving insights in the pathogenesis and therapy of cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome). Brit J Haematol. 2011;155: 150-166. 5. Ginaldi L, De Martinis M, Matutes E, et al. Levels of expression of CD52 in normal and leukemic B and T cells: correlation with in vivo therapeutic responses to Campath-1H. Leukemia Res. 1998;22:185-191. 6. Hoppe RT, Medeiros LJ, Warnke RA, Wood GS. CD8-positive tumor-infiltrating lymphocytes influence the long-term survival of patients with mycosis fungoides. J Amer Acad Dermatol. 1995;32:448-453.
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7. Sirois DA, Miller AS, Harwick RD, Vonderheid EC. Oral manifestations of cutaneous T-cell lymphoma: a report of eight cases. Oral Surg Oral Med Oral Pathol. 1993;75:700-705. 8. Long JC, Mihm MC. Mycosis fungoides with extracutaneous dissemination: a distinct clinicopathologic entity. Cancer. 1974;34: 1745-1755. 9. Epstein EH Jr, Levin DL, Croft JD Jr, Lutzner MA. Mycosis fungoides. Survival, prognostic features, response to therapy, and autopsy findings. Medicine (Baltimore). 1972;51:61-72. 10. Chua MS, Veness MJ. Mycosis fungoides involving the oral cavity. Austral Radiol. 2002;46:336-339. 11. Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol. 2007;143:854-859. 12. Galper SL, Smith BD, Wilson LD. Diagnosis and management of mycosis fungoides. Oncology (Williston Park). 2010;24:491-501. 13. Hata T, Aikoh T, Hirokawa M, Hosoda M. Mycosis fungoides with involvement of the oral mucosa. Int J Oral Maxillofac Surg. 1998;27:127-128. 14. Wain EM, Setterfield J, Judge MR, Harper JI, Pemberton MN, Russell-Jones R. Mycosis fungoides involving the oral mucosa in a child. Clin Exp Dermatol. 2003;28:499-501. 15. Le BT, Setlur J, Sikora AG, Lee KC. Mycosis fungoides: a case of tonsil involvement. Arch Otolaryngol Head Neck Surg. 2006;132:794-796. 16. Laskaris GC, Nicolis GD, Capetanakis JP. Mycosis fungoides with oral manifestations. Oral Surg Oral Med Oral Pathol. 1978;46:40-42. 17. Edelson RL. Cutaneous T cell lymphoma: the helping hand of dendritic cells. Ann New York Acad Sciences. 2001;941:1-11. 18. Izban KF, Hsi ED, Alkan S. Immunohistochemical analysis of mycosis fungoides on paraffin-embedded tissue sections. Mod Pathol. 1998;11:978-982. 19. Ortonne N, Buyukbabani N, Delfau-Larue MH, Bagot M, Wechsler J. Value of the CD8-CD3 ratio for the diagnosis of mycosis fungoides. Mod Pathol. 2003;16:857-862. 20. Krejsgaard T, Odum N, Geisler C, Wasik MA, Woetmann A. Regulatory T cells and immunodeficiency in mycosis fungoides and Sezary syndrome. Leukemia. 2012;26:424-432.
21. Solomon GJ, Magro CM. FoxP3 expression in cutaneous T-cell lymphocytic infiltrates. J Cut Pathol. 2008;35:1032-1039. 22. Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nature Rev Immunology. 2010;10: 479-489. 23. Ciree A, Michel L, Camilleri-Broet S, et al. Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome). Int J Cancer J. 2004;112(1): 113-120. 24. Keehn CA, Belongie IP, Shistik G, Fenske NA, Glass LF. The diagnosis, staging, and treatment options for mycosis fungoides. Cancer Control. 2007;14:102-111. 25. Cyriac MJ, Kurian A. Sezary cell. Indian J Dermatol Venereol Leprol. 2004;70:321-324. 26. Greene FL, Page DL, Fleming ID, eds. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer; 2002. 27. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110:1713-1722. 28. Reynolds WR, Feldman MI, Bricout PB, Potdar GG. Mycosis fungoides in the maxillary sinus and oral cavity: report of two cases. J Oral Surg. 1981;39:373-377. 29. Crane RM Jr, Heydt S. Gingival involvement in mycosis fungoides: report of case. J Oral Surg. 1979;37:585-587.
Reprint requests: Alison M. Rich Sir John Walsh Research Institute Faculty of Dentistry University of Otago PO Box 647 Dunedin 9054 New Zealand [email protected]
