Hypopigmented Mycosis Fungoides With Childhood‐Onset and Middle‐Aged Onset: Two Case Reports Focusing on the Cutaneous Immune Microenvironment

ABSTRACT

Hypopigmented mycosis fungoides (MF) is a rare clinical variant of MF that often presents in childhood or young adulthood and is typically associated with an indolent course. In contrast to classic MF, hypopigmented MF frequently shows a CD8⁺ T‐cell‐predominant phenotype, and cytotoxic immune responses have been implicated in melanocyte injury; however, the cutaneous immune microenvironment across different ages of onset remains incompletely characterized. We reported two cases of hypopigmented MF with distinct ages of disease onset and evaluated lesional immune profiles by immunohistochemistry, focusing on CD8, FOXP3, CXCL10, and CCL19. In both cases, the epidermotropic infiltrate was CD8‐positive T‐cell dominant, accompanied by scarce FOXP3‐positive cells and increased expression of CXCL10 together with CCL19. These shared features support the concept that a Tc1‐associated cytotoxic immune milieu, accompanied by scarce FOXP3‐positive cells, may be associated with hypopigmentation in hypopigmented MF, irrespective of the age at clinical presentation.

1. Introduction

Hypopigmented mycosis fungoides (MF) is a relatively uncommon variant of MF characterized clinically by hypopigmented patches and immunophenotypically by a predominance of CD8⁺ T cells. This contrasts with classic MF, which more often exhibits a CD4⁺ phenotype. Hypopigmented MF is most commonly observed in children and young adults, and recent consensus recommendations and cohort studies have refined the diagnostic and staging approaches for early‐stage pediatric MF [1, 2].

Although Tc1‐associated cytotoxic immune responses have been suggested to contribute to melanocyte injury and subsequent hypopigmentation, the immunopathological features of hypopigmented MF across different ages of disease onset remain insufficiently defined [3]. CXCL10 (interferon‐γ–inducible protein 10, IP‐10) is a chemokine induced by interferon‐γ and produced by various cell types, including keratinocytes, fibroblasts, and macrophages [4]. It plays a key role in the recruitment of CXCR3‐expressing T cells, particularly activated CD8⁺ cytotoxic T lymphocytes [5]. CCL19, also known as macrophage inflammatory protein‐3β (MIP‐3β), is produced by various cell types, including lymphocytes, fibroblasts, and macrophages, and plays a critical role in the homing and spatial organization of T cells and dendritic cells. In the skin, it is thought to contribute to the formation of structured immune microenvironments, such as inducible skin‐associated lymphoid tissue (iSALT) [6]. Taken together, CXCL10 and CCL19 may reflect both the recruitment of cytotoxic T cells and the organization of local immune responses in the skin; however, their roles in hypopigmented MF remain unclear. Here, we report two cases of hypopigmented MF with childhood‐onset and middle‐aged onset and compare their cutaneous immune microenvironments, focusing on CD8 and FOXP3, as well as the chemokines CXCL10 and CCL19.

2. Case 1

An 18‐year‐old woman presented to our outpatient clinic with multiple well‐demarcated depigmented patches on the trunk and extremities. The lesions had first appeared at 11 years of age and had gradually expanded. Topical corticosteroids resulted in only transient improvement, and the eruptions recurred and increased in number at 16 years of age.

On physical examination, numerous irregularly shaped depigmented macules and patches with faint erythema were observed (Figure 1a). Histopathological examination revealed epidermotropic infiltration of atypical lymphocytes predominantly within the epidermis and along the epidermal–dermal junction (Figure 1b). At higher magnification, these lymphocytes exhibited hyperchromatic, irregular nuclei (Figure 1c).

FIGURE 1.

Clinical, histological, and immunohistochemical findings of Case 1. Numerous irregularly shaped depigmented macules and patches with faint erythema on the trunk and extremities (a). Histopathological findings of a hypopigmented lesion show epidermotropic infiltration of atypical lymphocytes within the epidermis and along the epidermal–dermal junction (H&E staining) (b, c). Immunohistochemical staining demonstrates lymphocytic infiltration positive for CD3 (d), CD8 (e), and CD4 (f), with a predominance of CD8‐positive cells. Partial loss of CD7 expression is observed (g). Additional staining shows positivity for granulysin (h). CXCL10 (i) and CCL19 (j) are expressed in the epidermis and dermis, whereas FOXP3‐positive regulatory T cells are rarely observed (k). CCL22 is not observed in lesional skin (l).

Immunohistochemically, the infiltrating lymphocytes were positive for CD3 (Figure 1d). CD8‐positive T cells (Figure 1e) and CD4‐positive T cells (Figure 1f) were observed, with a predominance of CD8‐positive cells. Partial loss of CD7 expression was noted (Figure 1g). Additional staining for cytotoxic molecules demonstrated positivity for granulysin (Figure 1h). Expression of CXCL10 (Figure 1i) and CCL19 (Figure 1j) was observed in both the epidermis and dermis, whereas FOXP3‐positive regulatory T cells were scarcely detected (Figure 1k). In addition, CCL22 expression was not observed (Figure 1l), and CCR7 expression was also not detected (data not shown). Polymerase chain reaction analysis confirmed rearrangement of the T‐cell receptor β‐chain gene. Based on the clinicopathological findings, a diagnosis of hypopigmented MF was made. Treatment with 308‐nm narrowband UVB combined with topical difluprednate ointment was initiated, resulting in gradual improvement of the lesions after 3 months.

3. Case 2

A 63‐year‐old man presented with a 1‐year history of multiple depigmented patches on the left upper limb that had gradually increased in size. On examination, multiple ill‐defined hypopigmented macules up to thumbnail size were observed on the trunk and extremities (Figure 2a). Prominent epidermal atrophy, appearing as fine wrinkled folds, was noted at the centers of the lesions. Histopathological examination revealed epidermotropic infiltration of atypical lymphocytes involving the epidermis and the epidermal–dermal junction (Figure 2b,c). At higher magnification, the lymphocytes exhibited cerebriform nuclei with complex nuclear contours. Immunohistochemical analysis showed that the infiltrating lymphocytes were positive for CD3 (Figure 2d). CD8‐positive T cells (Figure 2e) and CD4‐positive T cells (Figure 2f) were observed, with a predominance of CD8‐positive cells. Partial loss of CD7 expression was noted (Figure 2g). Additional staining demonstrated positivity for granulysin (Figure 2h). Expression of CXCL10 (Figure 2i) and CCL19 (Figure 2j) was observed, while FOXP3‐positive regulatory T cells were scarce (Figure 2k). Furthermore, CCL22 expression was not observed (Figure 2l), and CCR7 expression was also not detected (data not shown).

FIGURE 2.

Clinical, histological, and immunohistochemical findings of Case 2. Prominent epidermal atrophy, appearing as fine, wrinkled folds, is evident at the centers of the hypopigmented lesions (a). Histopathological findings of a hypopigmented lesion reveal epidermotropic infiltration of atypical lymphocytes involving the epidermis and the epidermal–dermal junction (H&E staining) (b, c). Immunohistochemical staining demonstrates lymphocytic infiltration positive for CD3 (d), CD8 (e), and CD4 (f), with a predominance of CD8‐positive cells. Partial loss of CD7 expression is observed (g). Additional staining shows positivity for granulysin (h). CXCL10 (i) and CCL19 (j) are expressed, whereas FOXP3‐positive regulatory T cells are rarely observed (k). CCL22 is not observed in lesional skin (l).

PCR analysis confirmed T‐cell receptor β‐chain gene rearrangement. Based on these findings, a diagnosis of hypopigmented MF was made. Treatment with 308‐nm narrowband UVB combined with topical difluprednate ointment resulted in gradual improvement after 3 months.

4. Discussion

In the present two cases of hypopigmented MF with different ages of onset, immunohistochemical analysis demonstrated a shared immune profile characterized by a predominance of CD8‐positive T cells, granulysin expression, scarce FOXP3‐positive regulatory T cells, and expression of CXCL10 and CCL19 in lesional skin. These findings suggest the presence of a Tc1‐associated cytotoxic immune milieu rather than a Th1‐skewed response [3].

Hypopigmented MF is a heterogeneous entity, and both CD4‐positive and CD8‐positive phenotypes have been reported [3]. In early‐stage MF, neoplastic and reactive T cells are often admixed, making it difficult to determine whether CD8‐positive cells represent the neoplastic population or reactive tumor‐infiltrating lymphocytes [2]. The cytotoxic features observed in the present cases may contribute to melanocyte injury [7]. However, because overt epidermal destruction was absent, hypopigmentation is unlikely to be explained solely by direct cytotoxic effects of neoplastic cells. Instead, it may reflect bystander damage mediated by activated cytotoxic T cells within the local microenvironment.

CXCL10 is an interferon‐inducible chemokine that recruits activated T cells [5], whereas CCL19 is involved in T‐cell trafficking and immune cell organization [6]. Their expression in lesional skin may facilitate the recruitment and retention of cytotoxic T cells. CCL22, also known as macrophage‐derived chemokine (MDC), is a chemokine produced by dendritic cells and macrophages that exerts its effects on target cells through interaction with CCR4. FOXP3‐positive cells were scarce in both lesions; however, because quantitative comparison with appropriate controls was not performed, this finding should be interpreted descriptively and does not prove reduced regulatory T‐cell activity.

An important feature of this report is the difference in age of onset. Although hypopigmented MF is typically observed in children and young adults, Case 2 represented true middle‐aged‐onset disease with a short duration before diagnosis. Despite this difference, both cases showed a similar immune profile, suggesting that a comparable cytotoxic immune microenvironment may be established regardless of age at onset.

This study is limited by the small number of cases and lack of quantitative controls. Further spatial and functional studies are needed. In conclusion, a Tc1‐associated cytotoxic immune microenvironment may be associated with hypopigmentation in hypopigmented MF.

Funding

The authors have nothing to report.

Ethics Statement

Written informed consent was obtained from the patients for publication of this case report and any accompanying images. The publication of this case report was approved by the ethics committee of Tohoku University Graduate School of Medicine, Sendai, Japan (permit no. 2021‐1‐1213).

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.