Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders
Rebecca L. King
Amy C. Musiek
Andrew L. Feldman
INTRODUCTION
Primary cutaneous CD30+ T-cell lymphoproliferative disorders (TLPDs) are challenging to both pathologists and clinicians owing to their heterogeneous features and overlap with a multitude of reactive and neoplastic conditions. In addition to making the distinction between primary cutaneous anaplastic large-cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP), the two entities within this group of diseases, one must attempt to determine whether a cutaneous lesion has arisen primarily in the skin, represents secondary cutaneous involvement by a systemic lymphoma, or represents transformation of another cutaneous T-cell lymphoma. Just as novel genetic markers emerge and bring us closer to understanding the pathogenesis of these diseases, additional pathologic subtypes are being described, further broadening the morphologic spectrum of these relatively indolent diseases. In addition, although there is evidence that pcALCL and LyP are distinct entities in many ways, there clearly are cases that show overlapping features, highlighting the pathogenic link between the two and supporting their inclusion under one subheading in current classification systems.
DEFINITION
Primary cutaneous CD30+ TLPDs include pcALCL and LyP according to the World Health Organization (WHO) and European Organization for Research and Treatment of Cancer (EORTC) classification systems.1,2 Together, these entities represent around 30% of cutaneous T-cell lymphomas (CTCLs) and are the second most common form of CTCL after mycosis fungoides (MF). LyP and pcALCL exist along a clinical and histopathologic spectrum of diseases, and “borderline” cases in which the features do not easily fit into one entity or the other exist.3 Furthermore, both LyP and pcALCL may occur in the same patient.4
pcALCL is a CD30+ T-cell lymphoma that resembles systemic ALCL but arises primarily in, and is often limited to, the skin. These lesions are almost exclusively negative for anaplastic lymphoma kinase (ALK) fusion proteins and rearrangements involving the ALK gene.5,6,7,8,9,10 Clinically, pcALCLs are typically localized, often solitary lesions that are large in size (>2 cm) and frequently ulcerate. Dissemination within the skin and to locoregional lymph nodes may occur; however, widespread disease is rare. The current WHO and EORTC definitions of pcALCL state that current MF and/or a previous history of MF must be excluded, as in this situation these patients are presumed to have transformed MF.1,2 The definition of pcALCL also requires distinction from secondary cutaneous involvement of systemic ALCL on clinical grounds.
LyP is an indolent, cutaneous TLPD characterized clinically by a recurrent papulonodular eruption with smaller lesions (<2 cm) that show a waxing-and-waning clinical course.11,12,13,14,15 This definition, however, belies the histopathologic complexity of this entity. Three histologic subtypes (A, B, and C) were recognized in the 2008 WHO classification scheme.11,16 As of this writing, three more have been proposed in the literature (type D, type E, and LyP with 6p25.3 rearrangements).16,17,18,19,20 Although most show some degree of CD30+ T-cell proliferation, the histopathologic features of the different subtypes may overlap with pcALCL as well as other cutaneous lymphomas and reactive entities.4 pcALCL is considered a true malignant lymphoma, whereas LyP currently is not considered a malignant disorder clinically.1 Nevertheless, both entities demonstrate an overall favorable prognosis with long-term survival rates of 90% or higher,4,21,22 lending further support to their inclusion under a single classification.
EPIDEMIOLOGY
Primary Cutaneous ALCL
The median age of presentation for pcALCL is 60 years.1 Rarely, cases of ALCL limited to the skin occur in the pediatric setting and in these cases ALK negativity may be especially helpful in recognizing the possibility of a primary cutaneous process.1,9,23,24 Males are affected more often than females, in a ratio of 2–3:1. No geographic or ethnic predilections have been reported. Possible associations with hay fever, celiac disease, and cigarette smoking have been reported.25
Lymphomatoid Papulosis
The incidence of LyP peaks around 45 years, at a slightly younger age than in pcALCL.1 As with pcALCL, cases do occur in children and must be distinguished from systemic ALCL, which most often is ALK+ in this age group.26,27 Cases of LyP with DUSP22 (6p25.3) rearrangements (see later) tend to occur in older individuals (67 to 88 years in one series).20 As with pcALCL, LyP affects males more often than females, in a ratio of 2–3:1.1 Associations between LyP and atopy, especially in young patients, have been reported; however, a definitive causal link between the two conditions has not been established.26,28 Patients with LyP are at increased risk for developing lymphoma and other nonhematolymphoid malignancies.4,12,29,30,31 Up to 20% of patients with LyP in some series have had associated lymphomas, with the most common types reported being MF, ALCL, and Hodgkin lymphoma.11,30,31 Lymphoma may present before, concurrently with, or after a diagnosis of LyP in these patients, though when the lymphoma is systemic ALCL this generally follows LyP.4,29 The ongoing study is warranted to reevaluate these associations, as diagnostic criteria and understanding of the clinicopathologic spectrum of both LyP and the associated lymphomas have changed significantly in the past 10 years.
ETIOLOGY
The etiology of primary cutaneous CD30+ TLPDs is unknown. CD30 expression in lymphocytes is upregulated by viruses such as Epstein–Barr virus (EBV), human herpes virus (HHV), and human T-cell lymphotropic virus (HTLV). However, CD30 expression is also induced by various other stimuli that activate T cells, and a link to viral infection has not been confirmed in primary cutaneous CD30+ TLPDs. Outside of rare cases occurring in the posttransplant setting, pcALCL and LyP are consistently negative for EBV.32
As with systemic ALK− ALCL, the pathogenesis of pcALCL and LyP is poorly understood. The finding of DUSP22 rearrangements in subsets of both pcALCL and LyP (see the section “Genetic and Molecular Findings”) provides further support for the hypothesis that these entities exist along a clinicopathologic spectrum that may include some systemic ALK− ALCLs as well. These rearrangements have been associated with markedly decreased expression of the DUSP22 gene, which encodes a dual-specificity phosphatase known to regulate several mitogen-activated protein kinases (MAPKs).33 In addition to regulating MAPKs, DUSP22 has been shown to diminish IL-6-induced STAT3 activation in vitro.34 Finally, DUSP22 has been shown to inactivate LCK (lymphocyte-specific protein tyrosine kinase) via dephosphorylation, resulting in diminished T cell–mediated immunity and autoimmunity.35 DUSP22, therefore, appears to play an important role in inflammatory disorders, and might represent a tumor suppressor in T-cell lymphomas and lymphoproliferative disorders.
Differential expression of cytokines has been postulated to underlie the skin-homing properties of the neoplastic cells in primary cutaneous CD30+ TLPDs. Studies of gene expression have shown that pcALCL demonstrates higher expression than primary cutaneous PTCL-NOS of CCR7, CCR8, and CCR10, all of which encode chemokine receptors.36 This finding could contribute to clinical finding that pcALCL tends to remain localized rather than disseminating to extracutaneous sites. These findings may also relate to the underlying tumor genetics, as CCR8 expression has recently been shown to correlate closely with the presence of DUSP22 rearrangements in ALCL.29 It has also been proposed that differential expression of chemokine receptors could direct progression or regression of primary cutaneous CD30+ TLPDs. pcALCL, which typically does not demonstrate clinical signs of spontaneous regression, has been shown to express CCR3 and its ligand, whereas LyP, which typically shows a waxing-and-waning clinical course, may preferentially express CXCR3.12,37
The pathogenesis of pcALCL may also relate to defects in apoptotic signaling, which is known to play a critical role in cell fate of mature T cells.36 For example, pcALCL expresses higher levels of FAS (CD95, TNFRSF6), TNFRSF8 (CD30), IRF4, and TRAF1 than primary cutaneous PTCL-NOS.30,36 Although FAS stimulation can induce apoptosis in pcALCL cells, these cells appear resistant to TNF-α- and TRAIL-mediated extrinsic proapoptotic mechanisms.38 The TRAIL resistance might result from overexpression of cellular FLICE-like inhibitory protein (c-FLIP, CFLAR) and diminished expression of the proapoptotic protein, BID. Interestingly, c-FLIP has been shown to be upregulated by NF-κB in pcALCL cells, which in turn is activated by cross-linking of CD30. This upregulation of c-FLIP may enhance the resistance to apoptosis associated with CD95. IRF4 also increases resistance to apoptotic stimuli, as well as activation-induced cell death, in reactive CD4+ T cells.39 Furthermore, IRF4 recently was shown to be important in the proliferation and survival of ALCL cells.40 TRAF1 is involved in intracellular signal transduction from CD30 and other tumor necrosis factor (TNF) receptor superfamily members, and similarly has been implicated in promoting resistance to apoptotic stimuli in T cells.41
CLINICAL PRESENTATION AND PROGNOSIS
Primary Cutaneous ALCL
pcALCL and LyP often have heterogeneous and overlapping features on histopathology, and it is often the clinical history that distinguishes these two conditions. As discussed earlier, patients with pcALCL tend to be male more often than female and in their seventh decade of life.4 The lesions tend to be solitary, often ulcerate tumors (Fig. 14-1), though groups of nodules can also occur (Fig. 14-2). Although spontaneous regression of pcALCL has been reported in up to 20% of cases, pcALCL classically has been described as less likely to self-resolve than LyP. This lack of self-resolution can be used to help distinguish the two entities.4 Survival rates of pcALCL are favorable, with an overall survival rate of 77% at both 5 and 10 years and disease-specific survival of 85% at both 5 and 10 years.21 Despite treatment, relapse is common, but progression to systemic disease is rare. Because of the favorable overall survival, it is important to not overtreat patients with this condition, and patients should be staged with computed tomography or positron emission tomography scans to evaluate for systemic disease. Although there are minimal data to substantiate the use of one treatment modality over another, therapy should be based on tumor burden. For solitary lesions, the mainstay of treatment is excision with or without radiation. Other treatment options include radiation alone, interferon α, and bexarotene. In case of widespread disease, doxorubicin or brentuximab vedotin can be considered.21
 FIGURE 14-1. pcALCL presenting on the forehead, before (A) and after (B) radiation therapy. (Courtesy of Dr. Mark A. Cappel by permission of Mayo Foundation for Medical Education and Research. All rights reserved.) |
 FIGURE 14-2. pcALCL presenting as a group of nodules on the lower leg. |
Lymphomatoid Papulosis
There are many histopathologic variants of LyP (see the section “Histology”); however, their clinical behavior and features are largely identical. As discussed earlier and in contrast to pcALCL, LyP typically occurs early in life, approximately the fifth decade, with a slight male predominance.4 LyP presents as a grouped papular or papulonecrotic eruption (Fig. 14-3). One- to two-centimeter ulcerated nodules and tumor lesions can occur. The lesions tend to develop as relapsing and remitting crops in different stages of evolution. When LyP occurs as papules and nodules within an erythematous, scaly plaque, it has been called persistent agmination of LyP (Fig. 14-4).42 Generally, lesions of LyP resolve without treatment in 6 to 10 weeks (Fig. 14-5). Upon resolution, scarring, atrophy, or hyperpigmentation can result (Fig. 14-6). Overall survival rates for LyP are 100% and 92% at 5 and 10 years, respectively.21 Staging is not required for patients with isolated LyP, but patients should be monitored for the development of additional malignancies including lymphoma, which has been found to be associated with LyP in 20% to 60% of cases.4,21 Observation is an acceptable treatment, but low-dose methotrexate, phototherapy, antibiotics, nitrogen mustard, interferon, and bexarotene have also been used with success.21
 FIGURE 14-3. LyP showing nodules at different stages of evolution. |
 FIGURE 14-4. Persistent agmination of LyP, consisting of papules and nodules within an erythematous, scaly plaque. |
 FIGURE 14-5. Lesions of LyP undergoing spontaneous resolution. A crop of lesions on the forehead is shown at presentation (A) and 3 weeks later without treatment (B). This case had a DUSP22 (6p25.3) rearrangement. (Reprinted from Karai LJ, Kadin ME, Hsi ED, et al. Chromosomal rearrangements of 6p25.3 define a new subtype of lymphomatoid papulosis. Am J Surg Pathol. 2013;37(8):1173-1181.) |
 FIGURE 14-6. Resolving LyP lesion showing scarring and hyperpigmentation. |
HISTOLOGY
Primary Cutaneous ALCL
Lesions of pcALCL are characterized by cohesive sheets of large, pleomorphic tumor cells growing within the dermis and occasionally extending into the subcutaneous tissue (Fig. 14-7). Epidermotropism is not characteristic; however, cases with rearrangements involving the DUSP22-IRF4 locus may show an epidermal component (discussed later).43 Tumor cells of pcALCL show cytologic features similar to systemic ALCL including hallmark cells. A distinction between anaplastic cytology (75% to 80% of cases) and nonanaplastic cytology (pleomorphic or immunoblastic, 20% to 25%) has been described but is not associated with clinical presentation or outcome.2,4,21,44
 FIGURE 14-7. Typical case of pcALCL demonstrating epidermal ulceration and cohesive sheets of large, pleomorphic tumor cells in the dermis (H&E: A, 4×; B, 40×). At high magnification, the tumor cells are pleomorphic and some have the folded or reniform nuclear contours and prominent Golgi zone of the so-called “hallmark” cells (arrows; C, 100). |
The inflammatory background typical of LyP is less often seen in pcALCL, with the exception of a neutrophil-rich variant in which the large cells may be obscured by abundant neutrophils (Fig. 14-8).44,45 Other morphologic variants including lymphohistiocytic, inflammatory, and subcutaneous have been reported, although unlike in systemic ALCL, a morphologic classification scheme has not been accepted widely.45
 FIGURE 14-8. pcALCL with marked inflammatory background. There is an extensive infiltrate in the dermis with overlying epidermal ulceration (H&E: A, 2×). At higher magnification, the tumor cells are admixed with numerous neutrophils, eosinophils, and histiocytes (B, 50×). |
Cases with angiodestructive lesions, morphologically resembling LyP type E (see in the next section), but with solitary lesions and clinical features of pcALCL recently have been described.46 These cases must be distinguished from more aggressive lymphomas such as extranodal NK/T-cell lymphoma that they may mimic pathologically. In addition, a multi-institutional case series has identified a subset of pcALCL cases with a prominent intralymphatic large-cell population and lacking features of systemic disease (Fig. 14-9).47
 FIGURE 14-9. pcALCL with an intralymphatic pattern. The tumor cells are solely present within lymphatic spaces in the upper dermis (H&E: A, 10×; B, 100×). IHC for podoplanin using the D2-40 antibody highlights the lymphatic endothelium (C, 10×). (Case courtesy of Dr. Mark A. Cappel.) |
Cases of pcALCL harboring translocations involving the DUSP22-IRF4 locus may show a unique biphasic histology with sheets of medium-to-large atypical cells within the dermis and a population of smaller, also CD30+, cells infiltrating the epidermis in a pagetoid reticulosis–like pattern.43
Lymphomatoid Papulosis
Histologic features of LyP lesions vary widely depending on the histologic subtype and the age of the lesion biopsied. Early lesions show a superficial dermal and perivascular accumulation of atypical cells in an inflammatory background, whereas more mature lesions typically show a wedge-shaped, more diffuse infiltrate within the dermis.11,12,13,14,15 Epidermal hyperplasia is common, and ulceration, spongiosis, and focal epidermal necrosis may be seen in some cases. Neutrophils within the lumens of dermal blood vessels are common.
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