Article Evaluation of Melanocyte Loss in Using SOX10 Immunohistochemistry

Cynthia Reyes Barron and Bruce R. Smoller *

Department of and Laboratory , University of Rochester Medical Center, Rochester, NY 14642, USA; [email protected] * Correspondence: [email protected]

Abstract: Mycosis fungoides (MF) is a subtype of primary cutaneous T-cell (CTCL) with an indolent course that rarely progresses. Histologically, the lesions display a superficial lymphocytic infiltrate with epidermotropism of neoplastic T-cells. Hypopigmented MF is a rare variant that presents with hypopigmented lesions and is more likely to affect young patients. The etiology of the hypopigmentation is unclear. The aim of this study was to assess melanocyte loss in MF through immunohistochemistry (IHC) with SOX10. Twenty cases were evaluated, including seven of the hypopigmented subtype. The neoplastic epidermotropic infiltrate consisted predominantly of CD4+ T-cells in 65% of cases; CD8+ T-cells were present in moderate to abundant numbers in most cases. SOX10 IHC showed a decrease or focal complete loss of melanocytes in 50% of the cases. The predominant neoplastic cell type (CD4+/CD8+), age, race, gender, histologic features, and reported clinical pigmentation of the lesions were not predictive of melanocyte loss. A significant loss of melanocytes was observed in 43% of hypopigmented cases and 54% of conventional cases. Additional   studies will increase our understanding of the relationship between observed pigmentation and the loss of melanocytes in MF. Citation: Barron, C.R.; Smoller, B.R. Evaluation of Melanocyte Loss in Keywords: mycosis fungoides; hypopigmented mycosis fungoides; SOX10; cutaneous T-cell lymphoma Mycosis Fungoides Using SOX10 Immunohistochemistry. Dermatopathology 2021, 8, 277–284. https://doi.org/10.3390/ 1. Introduction dermatopathology8030034 Mycosis fungoides (MF) is the most common subtype of primary cutaneous T-cell Academic Editor: Gürkan Kaya lymphoma and is characterized by the presence of malignant T-cells within the (epidermotropism) [1]. The neoplastic T-cells often have a phenotype that is CD3 positive, Received: 7 June 2021 CD4 positive, and CD8 negative with a frequent loss of other T-cell markers such as CD5 Accepted: 6 July 2021 and/or CD7 [2]. Clonal T-cell receptor (TCR) gamma gene rearrangements, that may be Published: 8 July 2021 determined by PCR-based amplification and gel electrophoresis, support the diagnosis [2]. MF usually follows an indolent course but may progress from a patch stage to plaque to Publisher’s Note: MDPI stays neutral tumor and disseminated disease [3]. There is generally good clinicopathologic correlation with regard to jurisdictional claims in for these stages of disease and they display distinct findings histologically [4]. Although published maps and institutional affil- mortality is low, MF may undergo large cell transformation with significant reduction in iations. survival [5]. MF is a disease primarily affecting adults, and patients typically present with per- sistent erythematous patches and plaques in skin that is sun protected such as the trunk (see Figure1). However, the presentation may be quite variable and non-specific with a Copyright: © 2021 by the authors. clinical differential including and eczema, among others. Multiple biopsies are Licensee MDPI, Basel, Switzerland. often required for diagnosis. Reflectance confocal microscopy, a non-invasive method of This article is an open access article visualizing the skin in horizontal planes, may be a useful tool for initial screening in the distributed under the terms and clinic because the findings correlate well with histologic findings including the identifica- conditions of the Creative Commons tion of epidermotropic lymphocytes [6]. Dermoscopy for the evaluation of inflammatory Attribution (CC BY) license (https:// lesions is also becoming more common and frequent findings in MF include the presence creativecommons.org/licenses/by/ of white scales and predominantly patchy vessel arrangements [7]. The clinical findings, 4.0/).

Dermatopathology 2021, 8, 277–284. https://doi.org/10.3390/dermatopathology8030034 https://www.mdpi.com/journal/dermatopathology Dermatopathology 2021, 8 2 Dermatopathology 2021, 8 278

scales and predominantly patchy vessel arrangements [7]. The clinical findings, including includingfeatures observed features observedusing confocal using microscopy confocal microscopy and dermoscopy, and dermoscopy, may help may guide help the guide deci- thesion decision to biopsy. to biopsy.

FigureFigure 1.1.Mycosis Mycosis fungoidesfungoides presentingpresenting asas a a scaly, scaly, erythematous erythematous patch patch in in a a Caucasian Caucasian patient. patient.

ThereThere areare numerousnumerous subtypes of of MF MF with with di differentfferent clinical clinical presentations presentations adding adding to tothe the diagnostic diagnostic challenge. challenge. These These subtypes subtypes include include pagetoid , reticulosis, folliculotropic, folliculotropic, poi- poikilodermatous,kilodermatous, bullous, bullous, granulomatous, granulomatous, an andd hypopigmented hypopigmented [8]. [8 ].Hypopigmented Hypopigmented MF MF is isa arare rare variant variant that that is is more more likely likely than than other other types types of of cutaneous T-cell lymphomalymphoma toto affect affect youngyoung patients patients and and patients patients of Africanof African American American or Hispanic or Hispanic descent descent [9,10]. [9,10]. A recent A studyrecent ofstudy Chinese of Chinese patients patients found that found the age that of the patients age of with patients hypopigmented with hypopigmented MF was significantly MF was youngersignificantly than younger for other than variants for withother a variants median ofwith 13.4 a yearsmedian and of these 13.4 patientsyears and had these a good pa- responsetients had to a treatmentgood response [11]. to Clinically, treatment patients [11]. Clinically, present withpatients patches present or plaqueswith patches in sun- or protectedplaques in areas, sun-protected as in other areas, types as of in MF, other but ty thepes lesionsof MF, but have the lighter lesions coloration have lighter than color- the surroundingation than the skin surrounding (see Figure 2skin). There (see mayFigure also 2). be There a mixed may presentation also be a mixed with the presentation presence ofwith both the hypopigmented presence of both and hypopigmented erythematous lesionsand erythematous [11]. The clinical lesions differential [11]. The clinical diagnosis dif- isferential broad and diagnosis includes is ,broad and pityriasis includes alba, viti post-inflammatoryligo, , hypopigmentation, post-inflammatory and hy- leprosypopigmentation, [8]. Biopsy and and histopathologic [8]. Biopsy analysis and histopathologic are imperative inanalysis making are the imperative diagnosis. in makingSOX10 the isdiagnosis. a protein that functions as a transcription factor that is essential to the differentiation of neural crest cells. One of its many functions involves promoting the de- velopment and survival of melanocytes by regulating the expression of multiple genes [12]. An immunohistochemical (IHC) stain with an antibody to the SOX10 protein is widely available in many laboratories and is an important tool for the evaluation of melanocytic lesions. SOX10 strongly stains the nuclei of melanocytes including melanocytes in benign nevi and [13]. The absence of staining indicates the absence of melanocytes as is seen in depigmented lesions of vitiligo. SOX10 may be a helpful stain in further understanding the etiology of the loss of pigment in hypopigmented MF. Preliminary stud- ies have shown that other melanocyte IHC markers including Melan-A, tyrosinase, stem cell factor receptor (CD117), and microphthalmia-associated transcription factor (MiTF) appear to be diminished in hypopigmented MF [14]. The sensitivity and specificity of

Dermatopathology 2021, 8 279

SOX10 for melanocytes may make it a useful stain to further study the pathophysiology of hypopigmentation in this disease. The diagnosis of hypopigmented MF requires clinical observation. Determining whether hypopigmentation results from the loss of the melanin Dermatopathology 2021, 8 3 pigment only or true loss of melanocytes will require an assessment of lesions from both conventional MF and the rare hypopigmented subtype.

FigureFigure 2. MycosisMycosis fungoides fungoides presenting presenting as hypopigmented as hypopigmented macules macules and patches andpatches in the upper in the extremity upper of an African American patient. extremity of an African American patient.

2. MaterialsSOX10 andis a protein Methods that functions as a transcription factor that is essential to the dif- ferentiationA search of was neural conducted crest cells. to One identify of its cases many of functions MF with involves a clinical promoting presentation the ofdevel- hy- popigmentationopment and survival in the of pathology melanocytes archives by regulating at the Department the expression of Pathology of multiple and Laboratory genes [12]. MedicineAn immunohistochemical of the University (IHC) of Rochester stain with Medical an antibody Center. Sevento the casesSOX10 that protein were hypopig-is widely mentedavailable clinically in many were laboratories identified and from is Januaryan impo 2010rtant totool March for the 2020. evaluation An additional of melanocytic 13 cases oflesions. conventional SOX10 strongly MF were stains selected the fromnuclei the ofsame melanocytes period to including include casesmelanocytes from a widein benign age rangenevi and and melanoma cases where [13]. the The malignant absence T-cells of staining were indicates predominantly the absence CD8+. of The melanocytes histopatho- as logicis seen findings in depigmented for each case lesions were of reviewed vitiligo. SOX10 including may previously be a helpful performed stain in further IHC studies under- forstanding CD4 and the CD8. etiology All casesof the but loss one of had pigment previously in hypopigmented reported clonal MF. T-cell Preliminary receptor gamma studies genehave rearrangements shown that other assessed melanocyte by PCR IHC and markers gel electrophoresis. including Melan-A, The clinical tyrosinase, presentation stem cell as wellfactor as receptor patient gender, (CD117), age, and and microphthalmia-associated ethnicity were reviewed for transcription each case. factor (MiTF) ap- pearThe to be paraffin diminished tissue in blockshypopigmented were retrieved MF [14]. from The the sensitivity archives and for specificity the selected of SOX10 cases andfor melanocytes new tissue sections may make were it a cut. useful SOX10 stain IHC to further was performed study the to pathophysiology evaluate melanocyte of hy- losspopigmentation using the mouse in this monoclonal disease. The IgG diagnosi antibodys of BC34 hypopigmented from Biocare MF (1:200 requires dilution) clinical on the ob- Leicaservation. BOND Determining stainer with whether Bond Polymer hypopigmentation Refine Red detection results from kit. Thethe antibodyloss of the had melanin been previouslypigment only validated or true forloss clinical of melanocytes use. The will staining require results an assessment were assessed of lesions using from standard both lightconventional microscopy. MF Appropriate and the rare positive hypopigmented controls weresubtype. confirmed as well as internal controls for each case. Cases were classified as having melanocyte loss if there was an absence of SOX102. Materials staining and in Methods at least one contiguous 2 mm section of epidermis. A search was conducted to identify cases of MF with a clinical presentation of hy- popigmentation in the pathology archives at the Department of Pathology and Laboratory Medicine of the University of Rochester Medical Center. Seven cases that were hypopig- mented clinically were identified from January 2010 to March 2020. An additional 13 cases of conventional MF were selected from the same period to include cases from a wide age

Dermatopathology 2021, 8 4

range and cases where the malignant T-cells were predominantly CD8+. The histopatho- logic findings for each case were reviewed including previously performed IHC studies for CD4 and CD8. All cases but one had previously reported clonal T-cell receptor gamma gene rearrangements assessed by PCR and gel electrophoresis. The clinical presentation as well as patient gender, age, and ethnicity were reviewed for each case. The paraffin tissue blocks were retrieved from the archives for the selected cases and new tissue sections were cut. SOX10 IHC was performed to evaluate melanocyte loss us- ing the mouse monoclonal IgG antibody BC34 from Biocare (1:200 dilution) on the Leica BOND stainer with Bond Polymer Refine Red detection kit. The antibody had been previ- ously validated for clinical use. The staining results were assessed using standard light Dermatopathology 2021, 8 microscopy. Appropriate positive controls were confirmed as well as internal controls for280 each case. Cases were classified as having melanocyte loss if there was an absence of SOX10 staining in at least one contiguous 2 mm section of epidermis.

3.3. Results Results OnlyOnly seven seven cases with clinically diagnosed hypopigmentation were were identified identified in a ten-yearten-year period. period. The The average average patient patient age age of these of these cases cases was was 43 years 43 years (range (range 30 to 30 62). to The 62). The majority of the hypopigmented cases were female (71%). The ethnicity of 86% of the majority of the hypopigmented cases were female (71%). The ethnicity of 86% of the hy- hypopigmented cases was non-Caucasian and only 15% of the conventional cases. Of the popigmented cases was non-Caucasian and only 15% of the conventional cases. Of the hypopigmented cases, 57% were CD4 predominant (see Table1). hypopigmented cases, 57% were CD4 predominant (see Table 1).

Table 1. Analysis of 20 cases of mycosis fungoides with features observed in hypopigmented and Table 1. Analysis of 20 cases of mycosis fungoides with features observed in hypopigmented and conventionalconventional cases. cases.

ResultsResults Hypopigmented Hypopigmented Conventional Conventional All All MelanocyteMelanocyte loss loss 3 (43%) 3 (43%) 7 (54%) 7 (54%) 10 (50%) 10 (50%) CD4CD4 predominant predominant 4 (57%) 4 (57%) 9 (69%) 9 (69%) 13 (65%) 13 (65%) EthnicityEthnicity non-Caucasian non-Caucasian 6 (86%) 6 (86%) 2 (15%) 2 (15%) 8 (40%) 8 (40%) GenderGender (female) (female) 5 (71%) 5 (71%) 4 (31%) 4 (31%) 9 (45%) 9 (45%) AgeAge (Average) (Average) 43 43 54 54 50 50 RangeRange 30–62 30–62 15–86 15–8615–86 15–86

AnAn abnormal abnormal SOX10 SOX10 staining staining pattern pattern indicating indicating melanocyte melanocyte loss loss was was observed observed in 10 in cases10 cases (50%). (50%). Seven Seven of ofthese these cases cases were were conv conventionalentional MF MF and and had had no no clinically clinically observed observed hypopigmentation;hypopigmentation; however, inin fourfour ofof these, these, the the epidermotropic epidermotropic malignant malignant population population of ofT-cells T-cells was was predominantly predominantly CD8+ CD8+ (see (see Figure Figure3). 3).

Cases with Melanocyte Loss Cases with Melanocyte Loss

30% CD8 Conventional 40% Predominant Hypopigmented 60% CD4 70% Predominant

(a) (b)

Figure 3. Ten cases displayed melanocyte loss by SOX10 IHC. The loss was observed in in both both conventional conventional and and hypopig- hypopig- mented cases ( a) and in CD8 or CD4 predominant cases (b).

The remaining three cases that were predominantly CD8+ displayed melanocytes in normal quantities and distribution by SOX10 IHC (see Figure4). Of the thirteen CD4 predominant cases, six had melanocyte loss by SOX10 IHC (see Figure5). Dermatopathology 2021, 8 5

The remaining three cases that were predominantly CD8+ displayed melanocytes in Dermatopathology 2021, 8 281 normal quantities and distribution by SOX10 IHC (see Figure 4). Of the thirteen CD4 pre- dominant cases, six had melanocyte loss by SOX10 IHC (see Figure 5).

(a) (b)

(c) (d)

Figure 4. Sample casecase withwith a a predominant predominant CD8+ CD8+ epidermotropic epidermotropic T-cell T-cell infiltrate infiltrate with with melanocytes melanocytes in normal in normal quantities quantities and distributionand distribution highlighted highlighted by SOX10 by SOX10 IHC. TheIHC. patient The patient was a 40-year-oldwas a 40-year-old male with male persistent with persistent pink to pink hyperpigmented to hyperpigmented patches inpatches sun-protected in sun-protected areas. (a )areas. Hematoxylin (a) Hematoxylin and eosin and stained eosin section, stained original section, magnification original magnification 100×.(b) 100×. T-cells (b highlighted) T-cells high- by lighted by a CD4 IHC stain, original magnification 100×. (c) T-cells highlighted by a CD8 IHC stain, original magnification a CD4 IHC stain, original magnification 100×.(c) T-cells highlighted by a CD8 IHC stain, original magnification 100×. 100×. (d) SOX10 IHC highlighting melanocytes, original magnification 100×. (d) SOX10 IHC highlighting melanocytes, original magnification 100×.

Dermatopathology 2021, 8 282 Dermatopathology 2021, 8 6

(a) (b)

(c) (d)

Figure 5. Sample case with a predominant predominant CD4+ epidermotropic epidermotropic T-ce T-cellll infiltrate infiltrate with melanocyte loss shown by complete focal loss loss of of SOX10 SOX10 IHC IHC staining. staining. The The patient patient was was an an86-year-old 86-year-old male male with with a long a long history history of hyperpigmented of hyperpigmented rashin sun- in protected areas. (a) Hematoxylin and eosin-stained section, original magnification 100×. (b) T-cells highlighted by a CD4 sun-protected areas. (a) Hematoxylin and eosin-stained section, original magnification 100×.(b) T-cells highlighted by IHC stain, original magnification 100×. (c) T-cells highlighted by a CD8 IHC stain, original magnification 100×. (d) Negative a CD4 IHC stain, original magnification 100×.(c) T-cells highlighted by a CD8 IHC stain, original magnification 100×. SOX10 IHC staining, original magnification 100×. (d) Negative SOX10 IHC staining, original magnification 100×. 4. Discussion 4. Discussion The diagnosis of MF depends on the synthesis of pertinent histopathologic, molecu- The diagnosis of MF depends on the synthesis of pertinent histopathologic, molecular, lar, and clinical findings [15]. The clinicopathological correlation is imperative. Hypopig- and clinical findings [15]. The clinicopathological correlation is imperative. Hypopig- mented MF is a rare subtype classified as such by clinical exam. Hypopigmentation is not mented MF is a rare subtype classified as such by clinical exam. Hypopigmentation is not merelymerely anan interestinginteresting clinical clinical observation observation but but designates designates the the disease disease as a as specific a specific entity entity with withbetter better prognosis prognosis than than other other variants. variants. Moreover, Moreover, repigmentation repigmentation of lesions of lesions may may indicate indi- cateeffective effective treatment treatment response response and remission and remi whilession recurrentwhile recurrent hypopigmentation hypopigmentation may indicate may indicaterelapse [ relapse10]. Hypopigmented [10]. Hypopigmented MF may MF have may features have features that distinguish that distinguish it from other it from variants other variantsof MF histopathologically of MF histopathologically as well, including as well, including the abundance the abundance of pigmentary of pigmentary incontinence incon- [4] tinenceand melanocyte [4] and melanocyte loss [14]. Some loss have[14]. arguedSome have that argued it is a separate that it is disease a separate from disease conventional from conventionalMF altogether MF because altogether the neoplastic because T-cellsthe neopla are morestic T-cells frequently are more CD8+ frequently cytotoxic T-cells CD8+ andcy- totoxic T-cells and the disease affects younger patients. Although hypopigmented MF

Dermatopathology 2021, 8 283

the disease affects younger patients. Although hypopigmented MF generally has a better prognosis than conventional MF, rare cases of disease progression have been reported [16]. In this study, the average age was younger (43 years versus 54) and all but one case occurred in non-Caucasian patients including African Americans and South Asians. The population of malignant T-cells was CD4+ not CD8+ in the majority of the hypopigmented cases (57%). However, moderate to abundant numbers of CD8+ cytotoxic T-cells were present in the inflammatory infiltrate whether they were the malignant T-cell population or not. Recent studies have shown that CD8+ cytotoxic T-cells play an important role in disease regulation in conventional MF when they form part of the antitumor immune response [17]. Tumor infiltrating lymphocytes (TILs) and the cytotoxic molecules they produce may be distinct from the molecules produced by the malignant T-cell population in MF. For example, granzyme B may be expressed in TILs but not in malignant cells [17]. Tumor necrosis factor alpha (TNFα) may be another important cytokine with high levels in stable lesions. Cases of CTCL disease progression or unmasking in previously undiagnosed patients who take TNFα inhibitors have been reported illustrating the potential critical role of TNFα in the immunologic control of MF and other types of CTCL [18,19]. The damage to melanocytes in cases of conventional and hypopigmented MF as shown by decreased SOX10 IHC staining in this study may be the result of collateral damage caused by the host immune response to malignancy and not damage caused directly by the malignant population of T-cells. Although hypopigmented MF may be more frequently seen in tumors with neoplastic cells that express CD8, we observed hypopigmentation in cases in which the neoplastic cells express CD4, as well. Likewise, other studies have reported a significant number of hypopigmented MF with malignant T-cells of the CD4+ phenotype indicating that CD8 positivity is insufficient for predicting the clinical findings of hypopigmentation and histologic melanocyte damage [17]. Patient age, race, and gender were not sufficient to predict melanocyte loss by SOX10 IHC. Using hypopigmentation as a marker of active immune response has been pro- posed [17]. The clinical observation of hypopigmentation may be difficult in patients with fair skin tones such as Fitzpatrick types I and II. Furthermore, pigment loss may be clinically obscured by from inflammation, trauma from scratching, background skin pigmentation, and partial treatment. Histologically, distinguishing between malignant T-cells and T-cells that are part of the tumor response is very difficult and grading the extent of tumor infiltrating lymphocytes in MF is not feasible. Although cytologic atypia may be identified, an attempt to distinguish atypical malignant T-cells from reactive T-cells in the tumor response histologically is unlikely to be accurate. SOX10 IHC, as a sensitive and specific method of assessing melanocyte loss, has the potential to be a surrogate marker for tumor immune response. It may provide the ability to categorize MF as the hypopigmented variant or a variant with better prognosis by histopathological means. Additional studies with a greater number of cases having substantial clinical information would be helpful in determining the utility of SOX10 IHC in further categorizing MF.

Author Contributions: All authors contributed to conceptualization, methodology, formal analysis, and investigation. Writing of the original draft was performed by C.R.B. Supervision and project administration were conducted by B.R.S. Both authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Acknowledgments: Special thanks to Sierra Kovar for the technical support. Conflicts of Interest: The authors declare no conflict of interest. Dermatopathology 2021, 8 284

References 1. Bagherani, N.; Smoller, B.R. An overview of cutaneous . F1000Res 2016, 5.[CrossRef] 2. Hristov, A.C.; Tejasvi, T.; Wilcox, R.A. Mycosis fungoides and Sezary syndrome: 2019 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 2019, 94, 1027–1041. [CrossRef] 3. Kaufman, A.E.; Patel, K.; Goyal, K.; O’Leary, D.; Rubin, N.; Pearson, D.; Bohjanen, K.; Goyal, A. Mycosis fungoides: Developments in incidence, treatment and survival. J. Eur. Acad. Dermatol. Venereol. 2020, 34, 2288–2294. [CrossRef][PubMed] 4. Smoller, B.R. Mycosis fungoides: What do/do not we know? J. Cutan. Pathol. 2008, 35 (Suppl. 2), 35–39. [CrossRef][PubMed] 5. Agar, N.S.; Wedgeworth, E.; Crichton, S.; Mitchell, T.J.; Cox, M.; Ferreira, S.; Robson, A.; Calonje, E.; Stefanato, C.M.; Wain, E.M.; et al. Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: Validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of proposal. J. Clin. Oncol. 2010, 28, 4730–4739. [CrossRef][PubMed] 6. Broggi, G.; Lacarrubba, F.; Verzi, A.E.; Micali, G.; Caltabiano, R. Confocal microscopy features of patch-stage mycosis fungoides and their correlation with horizontal histopathological sections. A case series. J. Cutan. Pathol. 2019, 46, 163–165. [CrossRef] [PubMed] 7. Bilgic, S.A.; Cicek, D.; Demir, B. Dermoscopy in differential diagnosis of inflammatory dermatoses and mycosis fungoides. Int. J. Dermatol. 2020, 59, 843–850. [CrossRef][PubMed] 8. Hodak, E.; Amitay-Laish, I. Mycosis fungoides: A great imitator. Clin. Dermatol. 2019, 37, 255–267. [CrossRef][PubMed] 9. Castano, E.; Glick, S.; Wolgast, L.; Naeem, R.; Sunkara, J.; Elston, D.; Jacobson, M. Hypopigmented mycosis fungoides in childhood and adolescence: A long-term retrospective study. J. Cutan. Pathol. 2013, 40, 924–934. [CrossRef][PubMed] 10. Rodney, I.J.; Kindred, C.; Angra, K.; Qutub, O.N.; Villanueva, A.R.; Halder, R.M. Hypopigmented mycosis fungoides: A retrospective clinicohistopathologic study. J. Eur. Acad. Dermatol. Venereol. 2017, 31, 808–814. [CrossRef][PubMed] 11. Luo, Y.; Liu, Z.; Liu, J.; Liu, Y.; Zhang, W.; Zhang, Y. Mycosis Fungoides and Variants of Mycosis Fungoides: A Retrospective Study of 93 Patients in a Chinese Population at a Single Center. Ann. Dermatol. 2020, 32, 14–20. [CrossRef][PubMed] 12. Mollaaghababa, R.; Pavan, W.J. The importance of having your SOX on: Role of SOX10 in the development of neural crest-derived melanocytes and glia. Oncogene 2003, 22, 3024–3034. [CrossRef][PubMed] 13. Shakhova, O.; Zingg, D.; Schaefer, S.M.; Hari, L.; Civenni, G.; Blunschi, J.; Claudinot, S.; Okoniewski, M.; Beermann, F.; Mihic- Probst, D.; et al. Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma. Nat. Cell Biol. 2012, 14, 882–890. [CrossRef][PubMed] 14. Furlan, F.C.; de Paula Pereira, B.A.; da Silva, L.F.; Sanches, J.A. Loss of melanocytes in hypopigmented mycosis fungoides: A study of 18 patients. J. Cutan. Pathol. 2014, 41, 101–107. [CrossRef][PubMed] 15. Pimpinelli, N.; Olsen, E.A.; Santucci, M.; Vonderheid, E.; Haeffner, A.C.; Stevens, S.; Burg, G.; Cerroni, L.; Dreno, B.; Glusac, E.; et al. Defining early mycosis fungoides. J. Am. Acad. Dermatol. 2005, 53, 1053–1063. [CrossRef][PubMed] 16. Amorim, G.M.; Niemeyer-Corbellini, J.P.; Quintella, D.C.; Cuzzi, T.; Ramos, E.S.M. Hypopigmented mycosis fungoides: A 20-case retrospective series. Int. J. Dermatol. 2018, 57, 306–312. [CrossRef][PubMed] 17. Martinez Villarreal, A.; Gantchev, J.; Lagace, F.; Barolet, A.; Sasseville, D.; Odum, N.; Charli-Joseph, Y.V.; Hernandez Salazar, A.; Litvinov, I.V. Hypopigmented Mycosis Fungoides: Loss of Pigmentation Reflects Antitumor Immune Response in Young Patients. Cancers 2020, 12, 2007. [CrossRef][PubMed] 18. Chuang, G.S.; Wasserman, D.I.; Byers, H.R.; Demierre, M.F. Hypopigmented T-cell dyscrasia evolving to hypopigmented mycosis fungoides during etanercept . J. Am. Acad. Dermatol. 2008, 59, S121–S122. [CrossRef][PubMed] 19. Martinez-Escala, M.E.; Posligua, A.L.; Wickless, H.; Rutherford, A.; Sable, K.A.; Rubio-Gonzalez, B.; Zhou, X.A.; Kaplan, J.B.; Pro, B.; Choi, J.; et al. Progression of undiagnosed cutaneous lymphoma after anti-tumor necrosis factor-alpha therapy. J. Am. Acad. Dermatol. 2018, 78, 1068–1076. [CrossRef][PubMed]