CD30 Pseudolymphomas
Jacqueline M. Junkins-Hopkins
DEFINITION
Cutaneous pseudolymphomas (CPLs) are benign lymphocytic infiltrates of the skin, which microscopically and immunophenotypically simulate cutaneous lymphoma, and yet do not have clinical corroboration to confirm a malignant designation. CPLs may mimic many of the B- or T-cell lymphomas recognized by the World Health Organization–European Organization for Research and Treatment of Cancer (WHO–EORTC) classification scheme,1 especially those falling under the subtype of CD30+ lymphoproliferative disorder (LPD). These include lymphomatoid papulosis (LyP) and anaplastic large cell lymphoma (ALCL). Other lymphoproliferative disorders may express CD30,1 such as mycosis fungoides (MF) that has undergone large cell transformation or the folliculotropic subtype, pagetoid reticulosis, NK-/T-cell lymphoma, nasal type, subcutaneous panniculitis-like T-cell lymphoma, intravascular T-cell lymphoma,2 some B-cell lymphomas,3 and hematologic malignancies that may affect the skin secondarily, such as Hodgkin lymphoma, hydroa vacciniforme-like lymphoma,4 adult T-cell leukemia/lymphoma, and angioimmunoblastic-like T-cell lymphoma.5 Of these, CD30 CPL most frequently mimics either LyP or ALCL. CD30+ expression is seen on activated CD45RO+ memory T cells,6 and as would be expected, scattered atypical CD30+ cells are found in a variety of benign inflammatory infiltrates, but do not usually present with critical mass to specifically mimic malignancy. Nevertheless, these may be met with anxiety and concern for a malignant process such as LyP; thus, this will also be discussed in this chapter.
EPIDEMIOLOGY
The epidemiology of CD30 CPL has not been formally evaluated. It is reported more frequently in adults of all ages; however, it may occur in children, including infants.7 Several patients with herpes virus-induced CPL have had a prior hematologic malignancy,8 but this may be related to a tendency for this population to develop herpes infections. Additionally, HIV-infected individuals have been reported to have CD30 CPL,9 and CD30 can be induced by stimulation with viruses, such as Epstein–Barr virus (EBV) and human T-cell lymphotropic virus types 1 and 2 (HTLV-1/2), suggesting susceptibility for CD30 expression by reactive infiltrates in virally infected individuals.6 In fact, CD30+ cells were frequently noted in skin biopsies from individuals with HIV, especially in later-stage disease.10 A number of patients reported to have CD30 CPL have had autoimmune disorders, but it is not clear whether this is related to immune dysregulation from their disease or their medications.
ETIOLOGY
CD30 CPLs may be caused by or associated with a variety of benign inflammatory conditions.7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44 A list of these conditions is provided in Table 40-1. CD30 expression has also been documented in benign and malignant nonhematopoietic neoplasms.3,45 The specific details of the immune dysregulation leading to the lymphoid dyscrasia in CD30 CPL have not been elucidated. Furthermore, the pathogenesis may differ among the entities. CD30 antigen, a cytokine receptor and transmembrane glycoprotein of the tumor necrosis factor superfamily, may be expressed in normal lymphoid tissue (germinal center B cells and some T and B peri/interfollicular blasts)3 and by activated CD45+ RO memory T and B lymphocytes, in response to induction by various mitogens and virus stimulation.6 CD30 is especially expressed by T lymphocytes producing T helper-2 (TH2) type cytokines,10,46 and investigators have shown a relationship between some TH2 diseases and CD30 expression.46,47 Overexpression of CD30 and its ligand (CD153 or CD30L) has been documented in the dermal infiltrate of atopic dermatitis (AD), a TH2-mediated disease (in contrast to infiltrates of allergic dermatitis),46 and soluble CD30 has been shown to be increased in the serum of atopic patients with active dermatitis.47 Mast cells are also increased in AD biopsies, as well as other chronic inflammatory conditions, and in Hodgkin disease, a malignancy characterized by increased numbers of CD30 cells, cells expressing CD30L, and CD30+ Reed–Sternberg cells. In fact, mast cells represent a significant portion of these CD30L-expressing cells, and are felt to play a role in tumor progression, through CD30–CD30L interactions. CD30L transduces signaling downstream that leads to cytokine production.46 Mast cells have been shown to release chemokines through a pathway distinct from the IgE-mediated degranulation pathway,46 thus possibly playing a role in AD via interactions with CD30. The release of chemokines by mast cells may also play a role in defense against a variety of pathogens,46 possibly explaining the presence of CD30 cells in other inflammatory and infectious conditions. HIV infection may also play a role in promoting the proliferation of activated T lymphocytes, due to induction of a TH2 cytokine profile by the virus.10 The observation of CD30 lymphocytes in many biopsies from HIV patients supports a possible relationship.10 CD30 CPL has been associated with drugs that share a common structural feature of two noncoplanar rings, that includes a heterocyclic amine ring and carbonyl group, which bridges or is external to the rings.44 This suggests that certain molecular structures may contribute to the etiology of CD30 CPL.
TABLE 40-1 Inflammatory Conditions Associated With Expression of CD30 | ||||||||||||||||||
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CLINICAL PRESENTATION, COURSE, ANDPROGNOSIS
The clinical presentation of CD30 CPL is determined by the cause. Papules, nodules, plaques, patches, hemangioma-like lesions, and rarely tumors have been reported. These may be crusted or ulcerated, and in the cases of drug, an exanthem may be present. A critical clinical feature is the lack of systemic “B” symptoms, negative laboratory/radiologic workup, and absence of other clinical features that are otherwise seen in lymphoma. The clinical course of the cutaneous lesions is also key, as these lesions tend to regress when the instigating agent is removed, or do not recur after surgical removal/medical therapy. This is in contrast to LyP, which waxes and wanes, before and after therapy is discontinued, despite complete response. In general, the prognosis for CD30 CPL is excellent, provided there is no ongoing or significant immunosuppression that was responsible for theCPL.
HISTOLOGY
The histologic features are determined by the cause of the CD30 CPL. Selected presentations are discussed separately in this chapter. In general, scattered large atypical cells reside in a background of a variably dense dermal lymphocytic infiltrate (T more often than B) (Fig. 40-1). These have large vesicular nuclei, variably prominent nucleoli, and ample cytoplasm. Reed–Sternberg cytomorphology may be seen (see Chapter 14). Exocytosis into a variably acanthotic epidermis, or involvement of adnexae, especially in the cases of herpes virus infections, may be seen (Fig. 40-2). Angiocentricity frequently occurs in some CD30 CPL, but angiodestruction is rare. There is a subtype that simulates intravascular lymphoma31,32,33,34 (Fig. 40-3).
 FIGURE 40-1. CD30 CPL. There are scattered large atypical lymphocytes amidst a mixed infiltrate of nonatypical lymphocytes and eosinophils. |
 FIGURE 40-2. CD30 CPL. There is a mixed dermal infiltrate of lymphocytes, eosinophils, and large atypical cells. There is exocytosis into the epidermis and adnexal epithelium. |
 FIGURE 40-3. Intravascular CD30CPL. Area adjacent to chronic folliculitis with a perifollicular lymphocytic and eosinophilic infiltrate and large atypical intravascular lymphocytes that stained positive for CD30. |
IMMUNOPHENOTYPE
The cells are decorated in a pattern similar to that of CD30 LPDs, characterized by a membranous and Golgi dot pattern of staining (Fig. 40-4). Plasma cells may be highlighted with CD30 antibody, but in a cytoplasmic pattern. Ki-67 is variable, but may reach at least 80%.14 The CD30 staining in CPL is usually less intense than that of LyP and ALCL, and the cells tend to be scattered and are not apposed, nor in large clusters and sheets, in contrast to LyP and ALCL (Fig. 40-4). Nonetheless, exceptions exist, especially in cases of inflammatory molluscum contagiosum7 in which large aggregates may be seen (Fig. 40-5). CD30+ atypical cells may arise in the background of a dense infiltrate rich in neutrophils and eosinophils. This has been reported in insect bite reactions, spider bites, hidradenitis suppurativa, genital herpes virus infection, perirectal abscess, ruptured cyst, and rhynophyma.9 The CD30+ cells tend to associate with T and B lymphocytes (as opposed to the neutrophils and eosinophils) where these cells may represent up to approximately 25% of the lymphoid population. CD30+ cells have not been reported in infections, such as cellulitis and necrotizing fasciitis, and in Sweet’s.9
 FIGURE 40-4. CD30 immunohistochemical stain demonstrating scattered, nonclustered CD30+ atypical lymphocytes in a pseudolymphomatous infiltrate. These have a membranous and cytoplasmic dot-staining pattern. |
 FIGURE 40-5. CD30 CPL due to ruptured molluscum contagiosum. There are large clusters of atypical cells with large vesicular nuclei, conspicuous nucleoli, and ample cytoplasm, simulating LyP-C or ALCL. |
MOLECULAR FINDINGS
INFECTION-ASSOCIATED CD30 PSEUDOLYMPHOMA
Several infections, especially virally induced, have been reported to have CD30+ cells in their infiltrates. These are listed in Table 40-1. Selected subtypes are discussed below.
Herpes Virus Infection
Classical herpes virus infections present as clustered, dermatomal, or occasionally disseminated papules that are in various stages of vesiculation or crusting, with a limited, self-healing course of approximately 2 to 3 weeks. In cases of HSV-associated CD30 CPL, the lesions are often present for a longer period of time, and are not vesicular. Submitted diagnoses for these lesions may include mycotic infection, basal cell carcinoma, lymphoma, or pseudolymphoma.8 Histopathologic features of classical herpes simplex virus/herpes zoster virus (HSV/VZV) infections include acantholytic vesicle or ulcer formation, epidermal and/or pilosebaceous necrosis, epithelial cell alteration that includes balloon-cell degeneration, eosinophilic intranuclear inclusions, ground glass nuclei, and/or multinucleated giant cell formation with molded nuclei, and lymphocytic inflammation that is usually superficial and deep, perifollicular, perineural, and rarely syringotropic. Lichenoid dermatitis and/or leukocytoclastic vasculitis may be seen. Both HSV and VZV may present in a clinically and histologically clandestine fashion, mimicking a variety of hematologic malignancies. These usually simulate LyP, but herpes may mimic other subtypes of T-cell lymphoma, including ALCL, NK-/T-cell lymphoma and other angiocentric presentations, and B-cell lymphoma. Patients with immunocompromised states, especially HIV disease, may be more at risk of such atypical presentations. Some patients have a prior history of hematologic malignancy or eczema herpeticum.8 Pseudolymphomatous reactions are common in both HSV and VZV infections. In nearly half of cases, a dense lymphocytic infiltrate may be seen, and approximately 67% of these will have atypical lymphocytes.8 Atypical lymphocytes can also be identified in less dense perivascular infiltrates of herpes virus infections (Fig. 40-6). These reactions have also occurred at sites of prior VZV vaccination.13 Differentiating the specific viral cause is usually not possible, although the presence of herpes folliculitis may be more indicative of VZV than HSV.8 The lymphocytes may exhibit angiotropism with vessel disruption and erythrocyte extravasation (Fig. 40-6) in at least a third of cases, but significant angiodestruction is rare. Granulomatous infiltrates are also rare, in contrast to post-zoster lesions, which are known to be associated with granulomatous and lymphoid reactions. Numerous eosinophils, while typically not a feature of herpes virus infection, may rarely be numerous. The immunophenotype is usually that of a T-cell-rich infiltrate with CD30 decorating the large atypical cells, but rare cases of CD20-cell rich lymphocytic infiltrates simulating B-cell lymphoma have been reported.12 The presence of scattered CD30+ cells in this context may be a clue to the viral nature of the process. Within the dense infiltrates, CD30+ atypical lymphocytes are usually <5% and scattered (Fig. 40-6), differentiating this from LyP and ALCL, but these may range from 15% to 25% of the infiltrate, and present as clusters.8 CD56/TIA1 positivity may also be seen. PCR is typically yields a polyclonal TCR rearrangement in CD30 CPL; however, rarely, a monoclonal TCR band associated with lymphocytic infiltrates containing clusters of CD30 positivity may be documented,8 truly simulating LyP. Detection of HSV by PCR analysis or correlating with an appropriate clinical presentation, and/or presence of typical herpetic viral changes is required to confirm pseudolymphoma in such instances (Fig. 40-6).
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