Pediatric CD4⁺ Small Medium Sized Pleomorphic T-cell Lymphoproliferative Disorder: A Unique Indolent Lymphoproliferative Lesion With Consistent Reproducible Clinical and Phenotypic Features

Abstract:

Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoproliferative disorder (CD4⁺ PCSM-LPD) is characterized by its indolent course and favorable prognosis, distinguishing it from multifocal variants or other peripheral T-cell lymphomas. Pediatric cases are exceptionally rare, with only 9 pediatric cases documented, limiting understanding of their clinical, pathological, and molecular characteristics. Although recent studies propose a T follicular helper cell (TFH) origin, further investigation is necessary to substantiate this hypothesis and elucidate the pathogenesis of CD4⁺ PCSM-LPD in pediatric patients. We conducted a systematic literature review (6 studies documenting 9 cases) and retrospective chart review of pediatric CD4⁺ PCSM-LPD cases (≤21 years) diagnosed at Weill Cornell Medicine between 2010 and 2024 (4 cases). All 13 cases presented with solitary lesions, lacking the head and neck predominance observed in adult patients. Treatments included intralesional steroids, excision, and local radiation, with no recurrences. Histopathology mirrored adult cases, showing characteristic features of CD4⁺ PCSM-LPD. Nonspecific TFH markers (PD-1, BCL-6, ICOS) exhibited variable positivity, whereas specific markers (CD10, CXCL13) were predominantly negative. CD4⁺ PCSM-LPD is a rare entity that can potentially occur in pediatric patients, exhibiting clinical, histopathological, and phenotypic features similar to adult cases. However, the hypothesis of follicular helper T-cell ontogeny is questioned, as specific markers are usually absent, whereas commonly reported positive stains are not specific for follicular helper T cells. This suggests a malleable CD4⁺ T-cell phenotype influenced by the microenvironment.

LEARNING OBJECTIVES

After participating in this CME activity, learners will be better able to

1. Identify the clinical and histopathological features of pediatric CD4⁺ PCSM-LPD.

2. Explain the diagnostic markers and immunophenotypic characteristics of pediatric CD4⁺ PCSM-LPD.

3. Evaluate the current treatment options and prognosis for pediatric patients with CD4⁺ PCSM-LPD.

INTRODUCTION

Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoproliferative disorder (CD4⁺ PCSM-LPD) represents the indolent end of the spectrum of lymphoproliferative disorders of the skin, which were formerly designated as primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma, an entity that was originally introduced as a cutaneous variant of peripheral T-cell lymphoma, not otherwise specified. In the seminal paper by Bekkenk and coworkers,¹ the authors presented 46 cases of CD30 negative large T-cell lymphoma, 17 cases of small- and medium-sized pleomorphic T-cell lymphomas and 17 cases of patients with cutaneous T-cell lymphoma and concurrent extracutaneous lymphoma. They found that the overall 5-year survival in the small/medium group was much better than the other subtypes of T-cell neoplasia with a 45% 5-year survival. They recognized that within that group, the patients who had localized disease demonstrated the best prognosis. As the findings clinically and light microscopically were very reproducible, this lymphoproliferative disorder was designated as a provisional entity in the latest World Health Organization-European Organization for the Research and Treatment of Cancer classification and the World Health Organization classification of tumors of hematopoietic and lymphoid tissues as CD4⁺ PCSM-LPD.^2,3

CD4⁺ PCSM-LPD manifests as a solitary,⁴ slow-growing erythematous or purplish skin lesion, typically found on the face, neck, upper trunk, or ear in the adult patients. Other name designations include indolent CD4⁺ lymphoid proliferation versus the designation of so called cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance. The multifocal equivalent is considered a form of peripheral T-cell lymphoma including those cases that have been categorized as primary cutaneous follicular helper T-cell lymphoma where the clinical course and overall prognosis is more variable. Extracutaneous dissemination can occur, and the cutaneous eruption may be recalcitrant to most systemic therapies.^1,4–7 From a light microscopic perspective, biopsies procured from a lesion of CD4⁺ PCSM-LPD typically show a pan dermal diffuse and nodular lymphocytic infiltrate oftentimes with many admixed histiocytes. The lymphocytes are small to intermediate in size and show significant noncerebriform atypia. There can be an admixture of larger atypical cells although this cell population does not exceed 30% of the infiltrate. The infiltrates are frequently juxtaposed to adnexal structures. Although significant epidermotropism is not a characteristic finding, some degree of infiltration of the epidermis can be seen and does not exclude the diagnosis or suggest an alternative diagnosis such as mycosis fungoides.¹ Immunophenotypically, the infiltrate consists mainly of CD3-positive alpha-beta T cells. The CD4 to CD8 ratio is characteristically significantly skewed, and there is variable loss of select pan T-cell markers, most notably CD5 and/or CD7. The concept of T follicular helper cell(TFH) differentiation has been emphasized based on positivity of the lymphocytes for PD1, ICOS, and BCL6 although the more specific follicular helper markers such as CXCL13 and CD10 are usually negative or minimally positive. The prognosis is excellent with a near 100% 5-year survival rate,^3,5 minimal recurrence. Pediatric CD4⁺ PCSM-LPD is extremely rare, with a total of 9 cases^5,7–11 reported before our paper with the first case reported in 2008.⁸ Given its rarity, it is not surprising that there is limited understanding on the oncogenic, clinical, pathological, and molecular characteristics of CD4⁺ PCSM-LPD in pediatric patients. We report the clinical and pathological features of 4 pediatric patients presenting with skin lesions consistent with a diagnosis of CD4⁺ PCSM-LPD. We also review other previously published cases of pediatric CD4⁺ PCSM-LPD.

MATERIALS AND METHODS

We conducted a retrospective cohort study at Weill Cornell Medicine, including 4 cases of pediatric primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoproliferative disorder diagnosed between 2010 and 2024. The cases were among those patients diagnosed with this lymphoproliferative disorder up to the age of 21 years. Clinical data, including age at diagnosis, gender, clinical presentations, treatment modalities, duration of follow-up, and outcome, were systematically gathered. Skin biopsy specimens from all cases underwent diagnostic evaluation, involving routine light microscopic analysis and phenotypic studies on formalin-fixed, paraffin-embedded tissue. In each case, a comprehensive phenotypic panel was employed, including CD2, CD3, CD4, CD5, CD7, and CD8, and BCL-6, PD-1, CD10, ICOS, CXCL13, nuclear factor of activated T cells (NFAT), and TOX, to further investigate potential follicular helper T-cell origin. None of the 4 cases had a standard T-cell receptor γ gene rearrangement assay performed. The study was covered by Weill Cornell Medicine IRB study protocol Number: 20-02021524.

RESULTS

Clinic Summary

Four cases were uncovered; each was received in consultation. The patients were represented by 1 male, age 11 and 3 females, ages 11, 14, and 20, respectively. Each patient presented with a solitary lesion and was otherwise in excellent health. The lesions were located on the buttock in 1 patient, the pretibial region in another, the right arm in the third, and the forehead in the fourth. In each case, the patient underwent complete excision without subsequent recurrence. The clinical features of all 4 cases are summarized in Table 1.

TABLE 1.

Clinical Features of All 4 Cases

Case No.	Age	Gender	Clinical Presentation	Treatment	Outcome
1	11	F	A solitary infiltrative lesion on the buttock	Complete excision	No recurrence
2	11	M	A solitary nodule in the pretibial region	Complete excision	No recurrence
3	14	F	A solitary plaque on the right arm (1 cm)	Complete excision	No recurrence
4	20	F	A solitary nodule on the forehead (1 cm)	Complete excision	No recurrence

Histopathology Features

In all 4 cases, an extensive diffuse and nodular lymphocytic infiltrate was seen in dermis, with extension to the deeper reticular dermis and focally into the subcutaneous fat in 2 out of 4 cases (Fig. 1A). A significant degree of histiocytic infiltration was present in all 4 cases (Fig. 1F), imparting a distinctly granulomatous quality to the infiltrate in 2 of 4 cases. Well-defined sarcoid-like granulomas and germinal centers were absent. Adnexal infiltration was consistently observed across all cases, whereas epidermotropism was notably absent (Fig. 1B). Syringotropism was evident in each case, characterized by lymphocytic infiltration of the perieccrine adventitial dermis, eccrine ducts, and eccrine glands of the eccrine coil (Figs. 1C, D). In addition, focal folliculotropism was identified in 3 of the cases (Fig. 1E). Cytomorphologically, the lymphocytes were predominantly small to intermediate in size, exhibiting nuclear contour irregularity and hyperchromasia. However, they lacked the classic cerebriform gyrate appearance typically seen in mycosis fungoides. Larger atypical lymphocytes were also dispersed throughout the infiltrate comprising 10%–30% of the infiltrate (Fig. 1F). In 2 out of 4 cases, the infiltrate surrounding blood vessels was observed with 1 case associated with neovascularization and hemorrhage; however, no cases exhibited angiodestructive alterations. The histopathologic features of all 4 cases are summarized in Table 2.

FIGURE 1.

The excision specimen for case #4 revealed a tumefactive lymphocytic infiltrate within the dermis and subcutis (A). There was a narrow Grenz zone that separated this massive infiltrate from the overlying epidermis (B). Focal syringotropism (C, D) and folliculotropism (E) were identified. Although the infiltrate was predominantly composed of small lymphocytes, scattered large, atypical cells were noted, in addition to a prominent histiocytic infiltrate (F) (hematoxylin–eosin stain: A, ×2; B, ×4; C, ×10; D, ×20; E, ×20; F, ×100).

TABLE 2.

Histopathology Characteristics of All 4 Cases

Case No.	Epidermotropism	Syringotropism	Folliculotropism	Infiltrate Surrouding Nerves	Infiltrate Surrouding Blood Vessels	Neovascularization	Angiodestructive Features	Germinal Center Formation
(A)
1	Absent	Significant	Moderate	Absent	Absent	Absent	Absent	Absent
2	Absent	Significant	Moderate/focal	Absent	Present	Present with hemorrhage	Absent	Absent
3	Absent	Focal	Absent	Absent	Present	Absent	Absent	Absent
4	Absent	Focal	Focal	Absent	Absent	Absent	Absent	Absent

Case No.	Histiocytic Infiltrate	Granulomatous Quality	Larger Atypical Cells	B-Cell Hyperplasia	T-Cell to B-Cell Ratio	Plasma Cell	Light Chain–Restricted Plasma Cells	Eosinophils
(B)
1	Significant	Absent	<30%	Significant	4:1	A number of cells	Absent	Absent
2	Significant	Present	A few larger atypical cells	Present	Not reported	A number of cells	Absent	Absent
3	Significant	Present with multinucleated giant cells	5%–10%	Significant	5:1	Many cells	Absent	Absent
4	Significant	Absent	A smattering of larger atypical cells	Minor	Not reported	Some cells	Absent	Absent

Phenotypic Profile

Comprehensive phenotypic studies were conducted for all 4 cases. This extensive, well-differentiated, but atypical lymphocytic infiltrate was predominantly comprised of T cells, which were highlighted by CD2, CD3, and beta F1 (Fig. 2A). Significant staining for CD5 was also observed although 1 case there was a modest reduction of 15%–20%, and the other 3 cases showed no significant reduction. In contrast, a substantial reduction in CD7 staining was noted in all 4 cases, estimated at approximately 60%, 50%, 80%, and 15%–20% in each of the 4 cases, respectively. CD4 T cells were predominant over the CD8 subset (Figs. 2B, C), with CD4/CD8 ratios of approximately 5:1, 4:1, 5:1 and a normal ratio in the 4 cases respectively. The large, atypical cells present in each of the cases were typically highlighted by CD30 and did not exceed 30% of the infiltrate in any of the 4 cases.

FIGURE 2.

The phenotypic studies in case #4 revealed the infiltrate is predominantly T cells of the alpha beta subset highlighted by beta F1 (A), with CD4 positive T cells dominant (B) and a component of CD8 positive reactive lymphoid hyperplasia (C). Approximately 20% of the infiltrate stained positive for PD1 (D), largely corresponding to the intermediate and larger cell populace. BCL-6 and TOX showed a similar staining pattern with PD1 to a lesser extent, and they both showed the greater tendency to stain more superficially. (A, BF1; B, CD4; C, CD8; D, PD1; E, BCL-6; F, TOX).

In each of the 4 cases, there was a significant degree of positivity of PD-1, ranging from 20% to >50% (Fig. 2D). ICOS was positive in a number of lymphocytes in case 1, whereas the stain was not conducted in other 3 cases. There was a tendency for the PD1 and ICOS stain to highlight the intermediate and large lymphoid elements. BCL6 was significantly positive and mirrored PD1 although in 1 case it was less quantitatively; the distribution of staining was similar to PD1 suggesting that the BCL6 positive cells were among those that were PD1 positive (Fig. 2E). CXCL13 showed a number of atypical lymphocytes positive in 1 case, whereas in another case, the CD10 was found to be predominantly negative. Nuclear staining for NFAT and TOX are characteristic findings in follicular helper T cells and indeed a subset of lymphocytes showed nuclear staining for NFAT in all 4 cases and for TOX in the 1 case where it was performed (Fig. 2F).

A B-cell component was also identified, highlighted by the pan B-cell markers CD20 and/or CD79a, with T-cell to B-cell ratios of approximately around 4:1 to 5:1 in all cases. A number of plasma cells were observed in each of the 4 cases, without any cases showing light chain–restricted plasmocytic infiltrates. Numerous histiocytes were noted throughout the infiltrate, exhibiting dendritic cell (DC) features as characterized by the striking degree of positivity for CD11c. The phenotypic features of the 4 cases are summarized in Table 3.

TABLE 3.

Phenotypic Profile of All 4 Cases

Case No.	CD30	CD5	CD7	CD4:CD8	CD11c	CD21 and CD23	CD 20 and CD79a
(A) Pan T-cell and B-cell markers
1	<30%	No significant reduction	60% reduction	5:1	Striking degree of positivity	Not done	Significant degree of positivity
2	Not done	15%–20% reduction	50% reduction	4:1	Not done	Not done	Not done
3	5%–10%	No significant reduction	80% reduction	5:1	Not done	Negative	Significant degree of positivity
4	Rare positive staining cells	No significant reduction	15%–20% reduction	2:1	Not done	Not done	Significant degree of positivity

Case No.	PD1	ICOS	CXCL13	NFATc1 (Nuclear Stain)	BCL6	CD10	Beta F1	TOX
(B) Follicular helper T-cell markers
1	>50%	>50%	A number of atypical lymphocytes positive	Many atypical lymphocytes positive	50%	Not done	Not done	Not done
2	30%	Not done	Not done	A number of atypical lymphocytes positive	30%	Not done	Not done	Not done
3	30%–50%	Not done	Not done	20%	30%–50%	Primarily negative	Not done	Not done
4	20%	Not done	Not done	20%	20%	Not done	Most T cells	20%

Molecular Profile

All 4 cases were received in consultation. Material was not available to pursue clonality studies.

DISCUSSION

We have presented 4 pediatric patients who presented with solitary lesions that light microscopically and phenotypically was consistent with a low-grade form of CD4⁺ T-cell lymphoproliferative disease, specifically aligning with the characteristics of CD4⁺ PCSM-LPD. This designation is reserved for cases presenting with a distinctive histomorphology and to some extent phenotypic profile but where the clinical presentation is in the context of a solitary lesion. At least in our data base, a presentation characterized by multiple discontinuous sites of skin involvement precludes categorization as CD4⁺ PCSM-LPD. Cases sharing a similar light microscopic and phenotypic profile to CD4⁺ PCSM-LPD but presenting with significant multifocal cutaneous disease are likely better categorized as a form of peripheral T-cell lymphoma including cases where the follicular helper T-cell profile establishes a diagnosis of follicular helper T-cell lymphoma.

Pediatric T-cell lymphoproliferative disorders of the skin encompass a spectrum of lesions with most cases represented by prelymphomatous T-cell dyscrasia. The principle T-cell dyscrasias in the pediatric setting are pityriasis lichenoides, the hypopigmented interface T-cell dyscrasia, and alopecia mucinosis.^12–15 The second most common lymphoproliferative lesion affecting this age group would be lymphomatoid papulosis.^16–20 Both lymphomatoid papulosis and pityriasis lichenoides present similarly with papular lesions, with a critical requisite for diagnosis being one of spontaneous regression. The histologic findings are of cardinal importance in distinguishing lymphomatoid papulosis from pityriasis lichenoides, although some cases exhibit overlapping morphology between type B lymphomatoid papulosis and pityriasis lichenoides. Mycosis fungoides can develop in childhood, oftentimes in the setting of a precursor T-cell dyscrasia such as pityriasis lichenoides or the hypopigmented interface T-cell dyscrasia. Consequently, morphologic variants, such as pityriasis lichenoides like mycosis fungoides and hypopigmented mycosis fungoides, are frequent histologic subtypes that reflect the potential for tumor progression in the setting of a prelymphomatous T-cell dyscrasia.^21,22 The least common form of T-cell lymphoproliferative disease is CD4⁺ PCSM-LPD, with only 13 pediatric cases reported, including the present 4 cases.

The classic phenotypic profile of CD4⁺ PCSM-LPD shows a significant loss of CD7, markedly skewed CD4:CD8 ratio, and as well partially developed TFH phenotype as revealed by variable positivity in staining of PD1, ICOS, BCL6, CD10, CXCL13, and nuclear staining for NFAT.

Regarding CD4⁺ PCSM-LPD in pediatric patients, the main differential diagnosis includes pseudolymphoma, T-cell–rich marginal zone lymphoma (MZL), and unilesional follicular mycosis fungoides. In pediatric patients, the first alternative diagnosis that needs to be considered is pseudolymphoma/reactive lymphoid hyperplasia. Pseudolymphoma typically exhibits a multinodular growth pattern similar to CD4⁺ PCSM-LPD; however, the individual nodules exhibit a characteristic zonation pattern with germinal center foci predominating centrally while T cells typically assume a more peripheral disposition. The germinal centers are highlighted by BCL6 and CD21. Follicular helper T cells are found within the germinal centers. There may be a mantle zone of naïve B cells expressing IgD and CD23 that demarcates the peripheral rim of T cells from the germinal center foci hence recapitulating a benign lymph node architecture with the T cells being a paracortical equivalent.²³ This structured lymph node-like architecture is absent in CD4⁺ PCSM-LPD. In addition, there are a number of atypical features seen in CD4⁺ PCSM-LPD, including the density of the infiltrate, the inherent cytologic atypia amidst the lymphocytes most evident in the abnormal larger lymphoid forms, and the abnormal phenotypic profile such as the extent of loss of CD7 or the skewed CD4 to CD8 ratio.

Distinguishing CD4⁺ PCSM-LPD from T-cell–rich MZL can be challenging, especially when light chain restriction is noted in plasma cells within CD4⁺ PCSM-LPD. The presence of reactive germinal centers is a key differentiator, as B-cell hyperplasia in CD4⁺ PCSM-LPD typically involves postgerminal center B cells distributed singly or in small clusters, accompanied by a plasmacytic infiltrate without germinal centers. Furthermore, T cells in T-cell–rich MZL are generally bland and lack the cytologic atypia seen in CD4⁺ PCSM-LPD. A normal CD4 to CD8 ratio and preservation of pan–T-cell markers further support a diagnosis of T-cell–rich MZL.²⁴ Finally, in follicular mycosis fungoides, the infiltrate is primarily perifollicular, with minimal interadnexal involvement, at least in early cases.^25,26 The neoplastic T cells display a distinctive cerebriform appearance, differing from the cytomorphology observed in CD4⁺ PCSM-LPD.

A review of the literature identified 9 definitive cases of pediatric CD4⁺ PCSM-LPD that have been reported (Table 4). Among the 9 pediatric cases with available lesion locations and our 4 cases, 7 had lesions on the head and neck region, whereas 5 had lesions on the trunk and extremities. In contrast, approximately 75% of adult cases have lesions on the head and neck region.⁸ Notably, in our 4 cases, 3 lesions were localized to the extremities. The only case involving the head and neck region occurred in a 20-year-old patient, potentially exhibiting characteristics intermediate between pediatric and adult cases. Four pediatric cases from literature presenting with extensive multifocal cutaneous disease were not considered as representing CD4⁺ PCSM-LPD.^1,4–7

TABLE 4.

Reported 9 Pediatric CD4+ PCSM‐LPD Cases

Author	Age	Gender	Clinical Presentation	Phenotypic Aberrancy and Clonality in CD3, CD4+ T Cells	Treatment	Prognosis	Follow-Up Duration (mo)
Grogg et al5	14	M	A solitary lesion on the upper arm	Absent CD7	Radiation therapy	No relapse	10
Leinweber et al9	6	M	A solitary tumor on the cheek	Unknown	Excision	No relapse	90
Beltraminelli et al8	3	Unknown	A solitary/oligo lesion	Unknown	Unknown	Unknown	Unknown
Baum et al7	6	M	A solitary plaque on the cheek	D4:CD8 = 4:1 CD30+ <1% of the infiltrate	Topical steroids, excision	No relapse	29
	9	M	A solitary plaque on the left cheek	D4:CD8 = 10:1	Topical steroids, doxycycline, prednisone	No relapse	5
	13	M	A solitary plaque on the neck	CD4:CD8 = 8:1 CD30+ <1% of the infiltrate	Excision	No relapse	27
James et al10	12	Unknown	A solitary lesion on the trunk	CD3+, CD4+, CD2+, CD5+/−, CD7−	Unknown	Unknown	30
	15	Unknown	A solitary lesion on the head	CD3+, CD4+, CD2+, CD5−, CD7−, clonal	Excision	No relapse	26
Kim et al11	13	M	A solitary tumor on the temporal head	CD3+, CD4:CD8 = 6:1, partial loss of CD7, PD1 + in 30% of the infiltrate, CXCL13 + in subset of cells, CD30+ in 5% of the infiltrate	Radiation	No relapse	3

The 13 pediatric cases (9 cases from literature and 4 cases from our cohort) showed a uniform clinical presentation although with site variation. Treatments included intralesional steroids, complete excision, and local radiation. Regardless of the therapeutic intervention (ie, conservative vs. extirpative approach), the outcome was lesional resolution without recurrence. Furthermore, some cases in our adult cohort, and those reported in the literature can regress after the initial biopsy.

The former designation of what we now call CD4⁺ PCSM LPD was that of primary cutaneous CD4⁺ small medium sized T-cell lymphoma, and it recognized the 2 clinical variants namely 1 that was unilesional and another that was multifocal. Not surprisingly, the cases presenting as solitary lesions had an indolent clinical course similar to pseudolymphoma, whereas the multifocal variant could be associated with progressive and refractory disease and the potential for extracutaneous dissemination. Despite the differences in the anatomic site distribution between the pediatric cases versus the adult cases, there are no discriminating light microscopic and phenotypic findings. Upon examining our 4 pediatric cases and comparing them with cases from our adult cohort, both exhibit a dense, predominantly dermal superficial and deep coalescing diffuse and nodular lymphocytic infiltrate. The presence of epidermotropism to some extent is not uncommon, which does not exclude the diagnosis of CD4⁺ PCSM-LPD or suggest an alternative diagnosis, such as mycosis fungoides.¹ In addition, the infiltrates are characteristically juxtaposed to adnexal structures whereby there can be infiltration into the follicular outer root sheath epithelium and frank syringotropism with atypical lymphocytes extending into the ducts and glands of the eccrine coil. In addition, significant infiltration of the adventitial dermis of the eccrine coil and hair follicles can be seen. Accentuation of inflammation around nerves and vessels is observed although without angiodestructive alterations. The lymphocytes are heterogeneous in size, with larger atypical cells typically constituting <30% of the infiltrate.²⁷ The cells show hyperchromasia and nuclear irregularity although cerebriform atypia is not seen. Other inflammatory cells can be seen and are represented by eosinophils and plasma cells.¹³ Plasma cells can be numerous and may exhibit light chain restriction without other features suggesting concurrent B-cell lymphoproliferative disease. Phenotypically, most cases showed a clear-cut predominance of CD4 T cells with a minor CD8⁺ T-cell infiltrate. A highly skewed CD4 to CD8 ratio is a useful diagnostic indicator. When this ratio exceeds 10:1, it can serve as a very important clue regarding a diagnosis of CD4⁺ PCSM-LPD, rather than T-cell pseudolymphomas.²⁸ CD8 lymphoid hyperplasia was observed in one of our 4 cases. Similarly, Beltraminelli et al⁸ reported CD8 positivity in majority cells in the infiltrate in 3 out of 85 cases. Other follicular helper T-cell dyscrasias, particularly angioimmunoblastic T-cell lymphoma (AITL), have also demonstrated significant CD8-positive T-cell hyperplasia. Thus, CD8 lymphoid hyperplasia should not be considered an exclusion criterion for CD4⁺ PCSM-LPD. The loss of select pan T-cell markers, most notably CD5 and CD7, is variable, and they can be preserved. In particular, the retention of the expression of various pan T-cell markers is not uncommon in CD4⁺ PCSM-LPD and is not an exclusionary criterion.¹⁰

Comprehension of this rare, provisional, and heterogeneous entity may lie in elucidating its oncogenic mechanism, which remains under investigation. Some studies propose that the potential cell of origin for this lymphoma is the follicular helper T cell, the same cell type implicated in AITL. This hypothesis is based on findings that neoplastic cells in this lymphoma express TFH markers such as PD-1, Bcl-6, CD10, ICOS, and CXCL-13.^28–30 Although TFH cells require interactions with DCs and B cells for full differentiation, markers like PD-1, Bcl-6, and ICOS, although crucial for TFH differentiation,³¹ are not specific to TFH cells and can indicate general T-cell activation.³² In contrast, CD10 and CXCL13 are more specific markers for TFH cells.^31,33 In our 4 cases, PD-1 and BCL-6 demonstrated variable degree of positivity, ranging from 20% to over 50% of the infiltrate. In contrast, CD10 and CXCL13 showed minimal positivity of the lymphocytes in the infiltrate, significantly lower than that observed for PD-1 and ICOS. A similar pattern was observed in a pediatric case reported by Kim et al,¹¹ where about 30% of atypical cells expressed PD-1, and CXCL13 was only granularly expressed in a subset of cells. Other studies in the literature review did not describe the phenotypical profile of pediatric cases separately from adult cases, suggesting a similar phenotypical profile across age groups. Our findings in adult cohort of CD4⁺ PCSM-LPD also indicate variable expression (20%–80% of lymphocytes in the infiltrate) of nonspecific TFH markers (PD-1, Bcl-6, ICOS) and frequently primarily negativity or minimal positivity in most lymphocytes in the infiltrate for specific TFH markers (CD10, CXCL13). This challenges the assumption that CD4⁺ PCSM-LPD originates from follicular helper T cells, as these cases do not fully exhibit a TFH phenotype. In contrast, AITL, which is hypothesized to originate from TFH cells, consistently shows a fully developed TFH phenotype, including CD10 and CXCL13 expression.²⁸ In a study by Magro et al,³⁴ all 3 cases with CXCL13 results available were negative, and in our present cases, CXCL13 positivity was observed in only a subset of neoplastic cells in 1 case. Considering that PD1 and ICOS are general activating makers for lymphocytes, not truly specific markers for follicular helper T cells, and that CXCL13, a truly specific marker for follicular helper T cells, is typically negative or only limitedly positive, this suggests an alternative cell origin for CD4⁺ PCSM-LPD. In addition, the absence of reactive germinal centers and the lack of significant mast cell infiltration in CD4⁺ PCSM-LPD further argue against the follicular helper T-cell origin. In AITL, CXCL13 produced by neoplastic lymphocytes attracts mastocytes, a large number of mastocytes were not observed in CD4⁺ PCSM-LPD lesions in any studies. Therefore, based on the phenotype of the neoplastic cells, it is premature to definitively conclude that the cell origin of CD4⁺ PCSM-LPD is follicular helper T cell. It is more plausible that the TFH phenotype of CD4⁺ PCSM-LPD is an acquired phenotype that occurs in the setting of a particular cytokine microenvironment oftentimes induced by monocyte-derived DCs that course through the inflammatory milieu.

In our experience, the main markers that are positive in CD4+PCSM-LPD are ICOS, PD1, BCL6, and nuclear staining for NFAT. Neither ICOS nor PD1 are unique for a follicular helper T-cell ontogeny, whereas the most specific TFH markers, namely CXCL13 and CD10, are predominantly negative amid lymphocytes in our experience. In this series of pediatric patients, we did not conduct CXCL13 and CD10 on 3 of the 4 cases. However, we routinely conduct all TFH markers on adult cases, and the most frequent markers that are positive are ICOS, PD1, and BCL6 recognizing that most lymphocytes do not stain positively for these markers (ie, typically <50% of the infiltrate is positive), whereas the CXCL13 and CD10 are negative in most lymphocytes (ie, in excess of 90% of the lymphocytes). In addition to TFH markers, the nuclear staining pattern of calcineurin/NFAT emerges as a crucial marker in CD4⁺ PCSM-LPD. NFAT plays a critical role in controlling peripheral T-lymphocyte proliferation and survival after T-cell receptor engagement.³⁵ NFAT can serve as a valuable diagnostic tool for identifying lymphomas with a TFH phenotype, especially in differentiating CD4⁺ PCSM-LPD from conditions such as pseudolymphoma, unilesional follicular mycosis fungoides, and T-cell–rich MZL. Unlike the cytoplasmic staining observed in most reactive states (eg, pseudolymphoma) and other cutaneous T-cell lymphomas/lymphoproliferative disorders (eg, mycosis fungoides, anaplastic large-cell lymphoma, lymphomatoid papulosis), the nuclear staining pattern of NFAT is relatively unique to CD4⁺ PCSM-LPD, making it highly useful in clinical practice.³⁶

It could be argued that at least a minor subset of the clonally restricted T-cell infiltrate shows what could be deemed as a TFH phenotype although not a fully evolved as seen in those follicular helper T cells that reside in a germinal center. In addition, the extent of B-cell hyperplasia including the emerging light chain–restricted infiltrates that can be seen in some cases is a feature of a follicular helper T-cell milieu. The frequent presence of CD11c-positive monocyte-derived DCs and B cells in biopsies of CD4⁺ PCSM-LPD might explain the variability in TFH marker expression. CD11c-positive monocyte-derived DCs can induce a TFH phenotype in CD4⁺ T cells. CD4⁺ PCSM-LPD can be viewed as a low-grade CD4⁺ clonal T-cell LPD that is potentially enriched in histiocytes that promotes a TFH phenotype and result in an emerging follicular helper T-cell population amid the neoplastic T cells, potentially accounting for this variable staining ranging from positive to negative. The overall staining pattern could be interpreted as a somewhat abortive follicular helper T-cell profile emphasizing that the acquisition of TFH markers is a dynamic event occurring in neoplastic T cells residing in this follicular helper T-cell conducive microenvironment. Consequently, the TFH phenotype does not definitively indicate that CD4⁺ PCSM-LPD originates from follicular helper T cells, so this phenotype should not be a mandatory diagnostic criterion.

In conclusion, CD4⁺ PCSM-LPD represents a distinct form of primary cutaneous T-cell lymphoproliferative disease that occurs in the pediatric setting. The overall clinical presentation and light microscopic findings and the phenotypic profile in pediatric patients are similar to what are seen in adults. The concept of a follicular helper T-cell ontogeny, however, has to be questioned not only in pediatric cases but adult cases as well because the specific TFH markers are typically negative, whereas the most commonly reported positive stains are not specific for follicular helper T cells. One has to view the clonally restricted CD4⁺ T-cell population as one that has a malleable phenotype whereby in the setting of a monocyte enriched microenvironment there can be progressive acquisition of a TFH phenotype. Our 4 cases contribute substantially to our overall understanding of this provisional entity in pediatric patients, enabling a reassessment of the distinct characteristics of CD4⁺ PCSM-LPD between adult and pediatric patients. This, in turn, enhances clinical diagnosis and management strategies.

INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITS^TM

The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational needs of its readers.

An annual total of 12 AMA PRA Category 1 Credits™ is available through the twelve 2025 issues of The American Journal of Dermatopathology. This activity is available for credit through September 30, 2027.

• Accreditation Statement

Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

• Credit Designation Statement

Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of 1 (1) AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

To earn CME credit, you must read the article in The American Journal of Dermatopathology and complete the quiz, answering at least 80 percent of the questions correctly. Mail the Answer Sheet along with a check or money order for the $15 processing fee, to Lippincott CME Institute, Inc., Wolters Kluwer Health, Two Commerce Square, 2001 Market Street, 3rd Floor, Philadelphia, PA 19103. Only the first entry will be considered for credit and must be postmarked by the expiration date. Answer sheets will be graded and certificates will be mailed to each participant within 6 to 8 weeks of participation. Visit http://cme.lww.com for immediate results, other CME activities, and your personalized CME planner tool.

CME EXAMINATION

October 2025

Please mark your answers on the ANSWER SHEET.

Upon completion of this CME activity, participants will be better able to: 1. Identify the clinical and histopathological features of pediatric CD4⁺ PCSM-LPD. 2. Explain the diagnostic markers and immunophenotypic characteristics of pediatric CD4⁺ PCSM-LPD. 3. Evaluate the current treatment options and prognosis for pediatric patients with CD4⁺ PCSM-LPD.

CME QUESTIONS

1. Which of the following best describes the typical clinical presentation of pediatric CD4⁺ PCSM-LPD?

   • a. Multiple widespread cutaneous lesions

   • b. Solitary lesion without systemic symptoms

   • c. Systemic lymphadenopathy and hepatosplenomegaly

   • d. Rapidly progressing ulcerative skin lesions

2. How do pediatric CD4⁺ PCSM-LPD cases differ from adult cases in anatomical location?

   • a. Pediatric cases show a predominance in the head and neck region

   • b. Pediatric cases lack a predominance in the head and neck region

   • c. Pediatric cases are more likely to have extracutaneous involvement

   • d. There is no significant difference in lesion distribution between pediatric and adult cases

3. Which immunophenotypic marker is least likely to be positive in pediatric CD4⁺ PCSM-LPD?

   • a. PD-1

   • b. BCL-6

   • c. CXCL13

   • d. ICOS

4. What does the immunophenotypic profile of pediatric CD4⁺ PCSM-LPD suggest about its pathogenesis?

   • a. A definitive follicular helper T-cell origin

   • b. It defines an immunohistochemical profile indistinguishable from angioimmunoblastic T cell lymphoma

   • c. A not fully developed follicular helper T-cell phenotype influenced by the microenvironment

   • d. A strong association with Epstein–Barr Virus (EBV)

5. Which of the following treatment options has been used successfully in pediatric CD4⁺ PCSM-LPD cases?

   • a. Systemic chemotherapy

   • b. Complete excision, intralesional steroids and local radiation

   • c. High-dose corticosteroids and rituximab

   • d. Bone marrow transplantation

6. What is the prognosis for pediatric patients diagnosed with CD4⁺ PCSM-LPD?

   • a. Poor, with high recurrence and risk of systemic spread

   • b. Moderate, requiring lifelong immunosuppressive therapy

   • c. Favorable, with an indolent course and no recurrences reported

   • d. Variable, with cases progressing to aggressive lymphoma