Cutaneous lymphoproliferative disorders: Back to the future

In the 1980s, immunohistochemistry and clonality analyses became instrumental in the recognition and definition of new types of cutaneous T‐cell lymphoma (CTCL) and cutaneous B‐cell lymphoma (CBCL) and the development of new classifications. By accepting loss of pan‐T‐cell antigens and clonal T‐cell receptor gene rearrangements as important criteria to differentiate between benign and malignant T‐cell proliferations, and monotypic immunoglobulin light‐chain expression and clonal immunoglobulin gene rearrangements as crucial criteria to distinguish between benign and malignant B‐cell proliferations, many cases, until then diagnosed as cutaneous lymphoid hyperplasia or pseudolymphoma, were reclassified as primary cutaneous CD4+ small/medium T‐cell lymphoma (PCSM‐TCL) or primary cutaneous marginal zone lymphoma (PCMZL), respectively. However, in recent years there is growing awareness that neither these immunohistochemical criteria nor demonstration of T‐cell or B‐cell clonality is specific for malignant lymphomas. In addition, many studies have reported that these low‐grade malignant CTCL and CBCL have an indolent clinical behavior and an excellent prognosis with disease‐specific survival rates of or close to 100%. As a result, recent classifications have downgraded several low‐grade malignant cutaneous lymphomas to lymphoproliferative disorder (LPD). Both the 5th edition of the WHO classification (2022) and the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms reclassified PCSM‐TCL as primary cutaneous CD4+ small/medium T‐cell LPD and primary cutaneous acral CD8+ T‐cell lymphoma as primary cutaneous acral CD8+ T cell LPD. While the 2022 ICC introduced the term “primary cutaneous marginal zone LPD,” in the 5th edition of the WHO classification PCMZL is maintained. In this review we describe the background and rationale of the continually changing terminology of these conditions and discuss the clinical consequences of downgrading malignant lymphomas to LPDs.

With the introduction of new diagnostic techniques in the 1980s, many cases previously classified as pseudolymphoma, cutaneous lymphoid hyperplasia, or lymphomatoid reaction were reclassified as lowgrade malignant T-cell or B-cell lymphoma.Clonal T-cell receptor (TCR) gene rearrangements and/or loss of T-cell markers were introduced as important criteria to differentiate between benign and malignant T-cell infiltrates.Clonal IgH gene rearrangements and/or demonstration of monotypic immunoglobulin light-chain expression became major criteria to differentiate between benign and malignant B-cell infiltrates and became instrumental in the definition of primary cutaneous immunocytoma, later renamed primary cutaneous marginal zone lymphoma (PCMZL).
Based on long-term follow-up studies of large cohorts of patients collected in national or international databases showing a benign clinical course in virtually all cases, recent systems have reclassified several of these low-grade cutaneous lymphomas as lymphoproliferative disorder (LPD).[3][4] In this review we will describe the background and rationale of the continual changes in terminology of these conditions and discuss the clinical consequences of this new terminology.

| PRIMARY CUTANEOUS CD4+ SMALL/ MEDIUM T-CELL LYMPHOMA/ LYMPHOPROLIFERATIVE DISORDER
In the 1980s in Leiden, cases with histopathologic features suggesting a CTCL, but with a clinical presentation and clinical course more consistent with a benign condition, including cases now classified as PCSM-TCLPD, were referred to as lymphomatoid reaction or cutaneous T-cell pseudolymphoma.Histopathologic evaluation of 20 of such cases showed atypical infiltrates with a predominance of small to medium-sized lymphocytes and scattered CD3+, CD4+, CD8-blast cells, a considerable admixture with small CD8+ T-cells, B-cells, and histiocytes, including almost without exception multinucleated giant cells. 5Two histopathologic patterns were distinguished: a superficial band-like pattern simulating plaque-stage mycosis fungoides (MF), and a nodular/diffuse pattern. 5][8][9][10] Additional studies on these cutaneous T-cell pseudolymphomas showed that, in contrast to genuine CTCL, they did not show loss of pan-T-cell markers other than CD7 and-with the techniques used at that timedid not contain clonal TCR gene rearrangements. 11These two criteria became crucial in the selection of patients in studies aimed to define new types of CTCL, including PCSM-TCL. 12,13e term "small pleomorphic T-cell lymphoma" was derived from the updated Kiel classification and, in the setting of CTCL, first used in several European studies in the early 1990s. 12,14,15It should, however, be emphasized that in the last 30 years the definition of these PCSM-TCL has changed several times.Using the updated Kiel classification, these early studies found that cases classified as pleomorphic, small, or small/medium-sized had a significantly better survival than cases classified as pleomorphic, large cell, or immunoblastic lymphoma. 12,14,15Distinction between small/medium-sized cell pleomorphic and large cell pleomorphic was based on the presence of less or more than 30% large T-cells. 12These observations formed the basis for inclusion of PCSM-TCL as a provisional entity in the EORTC classification for cutaneous lymphomas. 16 studies using the EORTC classification, it was found that patients with a PCSM-TCL had a significantly better prognosis (5-year overall survival [OS] = 45%) than patients with a primary cutaneous CD30-negative large T-cell lymphoma (5-year OS = 12%) or patients presenting with concurrent cutaneous and extracutaneous disease (5-year OS = 12%). 13It should be emphasized that the group of PCSM-TCL was quite heterogeneous, which explains the OS of only 45%.It contained CD4+ cases, CD8+ cases, and cases classified as angiocentric lymphomas, and 10 of 19 patients had presented with generalized skin lesions. 13The favorable prognosis of this group was particularly found in patients presenting with solitary or localized skin lesions and a CD3+, CD4+, CD8-T-cell phenotype.As a result of this study, in the WHO-EORTC classification for primary cutaneous lymphomas published in 2005, PCSM-TCL was restricted to CD4+ cases and the excellent prognosis of patients presenting with a solitary or localized skin lesion was emphasized. 17 retrospect, in the above-mentioned early studies of our group, several cases classified as PCSM-TCL showed the characteristic clinicopathologic features of cases classified as cutaneous T-cell pseudolymphoma in the past, but demonstration of T-cell clonality has probably been decisive to classify these cases as a malignant lymphoma. 12,13At that time, the clinicopathologic similarities between PCSM-TCL and cutaneous T-cell pseudolymphomas had not been recognized, and a diagnosis of cutaneous pseudo-T-cell lymphoma had not been considered.
[3][4] The term PCSM-TCLPD should only be used for cases that present with a solitary or sometimes localized skin lesions without prior or concurrent patches and/or plaques typical of MF (Table 1).[10] The proliferation rate is usually low (≤25%), but higher percentages have been reported in rare cases. 6In some cases, monotypic plasma cells may be present, and in such cases differentiation from PCMZL may be challenging 18,19 (Figure 1; see also paragraph on PCMZL).
Caution is warranted in rare patients who present with generalized skin lesions, large and rapidly growing tumors, and/or histopathologically show significant loss of T-cell markers, very few reactive CD8+ T-cells or B-cells, or a high proliferation rate. 20In such cases that may run a more aggressive clinical course, a diagnosis of "peripheral T-cell lymphoma not otherwise specified," should be considered.

| PRIMARY CUTANEOUS ACRAL CD8+ T-CELL LYMPHOMA/ LYMPHOPROLIFERATIVE DISEASE
In 2007, Petrella et al. described four patients presenting with a solitary nodule on one or both ears, histopathologically characterized by a diffuse infiltrate of medium-sized CD8+ cytotoxic T-cells, suggesting an aggressive malignant lymphoma, but with an indolent clinical behavior. 21Subsequent studies reported similar cases arising on other acral sites including the nose, face, hands, and feet. 22,23In contrast to PCSM-TCLPD (with its mixed inflammatory infiltrate with relatively few atypical cells), these cases show all histopathologic characteristics of a malignant lymphoma: a diffuse proliferation of medium-sized CD3+, CD4-, CD8+ blast cells with few admixed inflammatory cells, clonal T-cell rearrangements and loss of pan-T-cell markers in almost all cases, and a very characteristic CD68+ perinuclear Golgi-dot staining, similar to that observed in blastic PDC neoplasms. 24The atypical cells are positive for TIA-1, but unlike other types of CD8+ CTCL, negative for other cytotoxic proteins (granzyme B, perforin).[23] From the very beginning, there has been discussion about the most appropriate term for this condition.Because of their benign clinical course, Petrella suggested the term "indolent CD8+ lymphoid T A B L E 1 Summary of main clinical, histopathologic, and immunophenotypical characteristics of three cutaneous lymphoproliferative disorders.proliferation of the ear" for this condition. 21However, because of the alarming histopathologic characteristics and presentation also at other acral sites, in the revised 4th edition of the WHO classification of Tumors of Hematopoietic and Lymphoid Tissues and in the 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas, this new entity was included as a provisional entity termed "primary cutaneous acral CD8+ T-cell lymphoma." 1,2Recent studies have shown that cutaneous relapses may occur, but dissemination to extracutaneous sites is exceptional. 25 between benign and malignant B-cell infiltrates, many cases diagnosed previously as cutaneous lymphoid hyperplasia or B-cell pseudolymphoma were then classified as primary cutaneous immunocytoma (Kiel classification) and later renamed PCMZL. 16In the EORTC classification (1997) and the 2005 WHO-EORTC classification, PCMZL was included as a distinct type of CBCL. 16,17In contrast, in the 3rd (2001), 4th (2008), and revised 4th edition (2016) of the WHO classification, these cases were not listed separately but included in the broad group of extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma). 1However, PCMZL show significant differences in histopathology, immunophenotype, genetic profile, and clinical behavior compared to MZL arising at other extranodal sites. 2 It is therefore fortunate that both the 5th edition of the WHO classification and the 2022 ICC now recognize that PCMZL is a distinct entity, separate from other MALT lymphomas. 3,47][28] Histopathologically, PCMZL are characterized by the presence of a population of small B-cells, lymphoplasmacytoid cells, and monotypic plasma cells, often follicles with reactive germinal centers, and, in most cases, an abundant T-cell infiltrate.[31] Mutations in the FAS gene are found in more than 60% of PCMZL, but they are uncommon in non-cutaneous marginal zone lymphomas. 32o types of PCMZL can be recognized. 33,34[35][36] There is a small group of non-class-switched PCMZL (≈10%) that present with large sheets of B-cells including monocytoid B-cells, which express IgM and often CXCR3 and IRTA1, and contain a much lower number of admixed T-cells. 18,33,34,37  positive) PCMZLPD, but not in common class-switched (IgG+) cases. 38These IgM+ cases more likely have extracutaneous disease. 33,34However, if staging is negative, they have the same excellent prognosis as the more common class-switched cases.
There are many clinical and histological similarities between PCMZL and cutaneous lymphoid hyperplasia (pseudo-B-cell lymphoma).Both may develop from chronic stimulation by intradermally applied antigens (e.g., tattoo pigments, tick bites, and antigen injections) and both have an excellent prognosis. 39,40Because of the extremely indolent clinical behavior with disease-specific survival rates approaching 100%, consensus is growing that PCMZL should be considered as a clonal lymphoproliferative disorder rather than an overt malignant lymphoma. 18,41The 2022 ICC, but not the 5th edition of the WHO classification, adopted this new terminology and introduced the term "primary cutaneous marginal zone LPD (PCMZLPD)" rather than PCMZL for this condition. 3,4cent studies also show overlapping features between PCMZL and PCSM-TCL. 18,19,42Clinically, both conditions present with a soli- Similarly, in 1993 we introduced the term "primary cutaneous CD30+ lymphoproliferative disorder" not for a clinical entity but for a spectrum of diseases with overlapping clinicopathologic features including benign (lymphomatoid papulosis) and malignant (cutaneous anaplastic large-cell lymphoma) conditions.The final diagnosis, either benign or malignant, is dependent on the clinical presentation and clinical behavior of the skin lesions. 43To avoid the confusing acronym PCSM-TCLPD in our patient information, in Leiden we have started to use the term "T-cell pseudolymphoma" again for this condition, because this term communicates much better to our patients that their skin lesion may look like a lymphoma but essentially is a benign condition.
What are the clinical consequences of this new terminology?Previous studies had already emphasized that in typical cases of PCSM-TCLPD and acral CD8+ T-cell lymphoma, staging is not recommended and aggressive treatment is not required. 2,23First choice of treatment includes topical or intralesional steroids, surgical excision, and local radiotherapy. 2,6,9,10,23The downgrading of PCMZL to PCMZLPD, at least in the 2022 ICC, is very recent, and optimal staging procedures and treatment in these patients have still to be determined.Interestingly, only 19 of 30 surveyed expert centers report changes in staging, treatment, and/or follow-up policy in one or more of these conditions,

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Therefore, in the 5th edition of the WHO classification (2022) and in the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms the term "primary cutaneous acral CD8+ T-cell lymphoproliferative disorder" rather than "primary cutaneous CD8+ T-cell lymphoma" is preferred. 3,PRIMARY CUTANEOUS MARGINAL ZONE LYMPHOMA/LYMPHOPROLIFERATIVE DISORDER Using monotypic Ig light-chain expression on paraffin sections and clonal Ig gene rearrangements as crucial criteria to differentiate Overlap case with histopathologic features of both a primary cutaneous CD4+ T-cell lymphoproliferative disorder and a primary cutaneous marginal zone lymphoma.(A) Clinical presentation with tumorous lesion on the left cheek.(B) Nodular to diffuse infiltrate throughout the entire dermis.(C) Detail of dermal infiltrates with scattered medium-sized atypical lymphocytes.(D) CD3 staining of T-cell areas.(E) Detail of marked area in panel D, showing a predominance of CD4+ T cells, and (F) small clusters of PD-1+ cells.(G) CD79a staining of B cell areas.(H) Detail of marked area in panel G, showing cluster of monotypic plasma cells with positive staining for lambda light chains, and (I) negative staining for kappa light chains.Clonality analysis showed both a T-cell and a B-cell clone (original magnifications: B, D, G: Â10; C, E, F, H, I: Â200).

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Primary cutaneous marginal zone lymphoma/lymphoproliferative disorder.(A) Typical clinical presentation with multiple nodules on the back.(B) Dense non-epidermotropic infiltrate throughout the dermis.(C) CD79a+ B-cells and plasma cells.(D) CD3 staining shows many admixed reactive T-cells.(E) Subepidermal monotypic plasma cells with positive staining for kappa light chains.(F) Negative staining for lambda light chains (original magnifications: B, C, D: Â50; E, F: Â100).
tary or multiple papules or plaques and show an indolent clinical course.Histopathologically, they both show polymorphous dermal infiltrates with mixed populations of B-cells and T-cells.Some cases of PCSM-TCLPD may show monotypic plasma cells and/or clonal IgH gene rearrangements characteristic of PCMZL, while PCMZL often contain clusters or rosettes of PD-1+ T-cells considered characteristic of PCSM-LPD. 10,42After adding PD-1 to our routine diagnostic panel for low-grade malignant CBCL, and kappa and lambda stains to our routine diagnostic panel for PCSM-TCLPD, cases showing features of both PCMZL(PD) and PCSM-TCLPD are increasingly observed.These cases may show either a B-cell clone or a T-cell clone or occasionally both B-and T-cell clones (Figure 1).These overlap cases contribute to the view that both PCSM-TCLPD and PCMZL(PD) represent clonal expansions of T-cells and/or B-cells to known or in most cases unknown antigens. 18,19,425 | CONSEQUENCES FOR MANAGEMENT AND PATIENT INFORMATION Because of their indolent clinical behavior and excellent prognosis, together with growing awareness that neither clonal TCR or Ig gene rearrangements nor aberrant T-cell phenotypes or monotypic Ig light-chain expression are specific for malignant lymphomas, recent classifications have reclassified several low-grade malignant cutane-ous lymphomas as LPD.However, for patients this term may not be very reassuring and can be even confusing.When searching the Internet, they may still wonder whether they have a benign or malignant disease.Also among dermatologists, this term is interpreted in different ways.In a recent survey among 30 cutaneous lymphoma expert centers, LPD was considered a benign condition in 20 of 30 centers, although an exception was made for acral CD8+ TCLPD and particularly PCMZL(PD) by some of them.The other centers considered LPD an indolent malignant lymphoma or something between benign and malignant (Willemze R, unpublished data).It is also confusing that in scientific literature LPD is often used as an encompassing term for both benign and malignant lymphoproliferations and may include both cases with an indolent and cases with an aggressive clinical behavior.
while 11 centers do not report any change in clinical management, suggesting considerable heterogeneity in clinical management of patients with cutaneous LPD.International consensus meetings to develop uniform guidelines for the management and treatment of these cutaneous lymphoproliferative disorders are currently under preparation.