Lymphomatoid papulosis

INTRODUCTION — Lymphomatoid papulosis (LyP) is a recurrent, self-healing papulonodular skin eruption with histologic features of a CD30⁺ lymphoid proliferation of atypical T cells [1,2]. LyP is part of the group of cutaneous CD30⁺ lymphoproliferative disorders (LPDs) that includes primary cutaneous anaplastic large cell lymphoma (PC-ALCL) and borderline CD30⁺ lesions. Clinicopathologic correlation is essential for establishing the diagnosis of LyP, as there are many clinical and histologic mimics of LyP.

LyP is characterized by a chronic course, lasting years or decades. Grouped or generalized papules and nodules develop and spontaneously regress over weeks to months (picture 3B). Patients with LyP have an excellent prognosis, although they are at increased risk of developing a second cutaneous or nodal lymphoma, such as mycosis fungoides, PC-ALCL, or Hodgkin lymphoma.

This topic will discuss the clinical presentation, diagnosis, and treatment of LyP. Other cutaneous T cell lymphomas are discussed separately.

●(See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

●(See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

EPIDEMIOLOGY — Lymphomatoid papulosis (LyP) is a rare disease. The estimated incidence is 1.2 to 1.9 cases per million persons per year [3]. It occurs in patients of all ethnic groups with a peak incidence in the fifth decade. However, LyP may occur in children and individuals older than 50 years [4-6]. A bimodal distribution by age and sex has been noted, with a male predominance among pediatric cases and a female predominance among adult cases (figure 1) [7]. Most patients with LyP and 6p25.3 gene rearrangement are older adults [8].

ETIOLOGY AND PATHOGENESIS — The cause of lymphomatoid papulosis (LyP) is unknown. The hypothesis of a viral etiology has not been confirmed. In several studies, oncogenic or lymphotropic viruses, including Epstein-Barr virus, herpes viruses 6, 7, and 8, and human T cell leukemia/lymphoma virus were not detected in LyP lesions [9-13]. Atopy may have a role in the pathogenesis of LyP. In a study of 28 patients with LyP and 52 healthy controls, approximately 50 percent of patients with LyP had serologic evidence of atopy compared with 3 percent of controls [14].

Overexpression of CD30 — The overexpression of CD30 on the large atypical T cells found in the skin lesions is the hallmark of LyP and primary cutaneous anaplastic large cell lymphoma (PC-ALCL). CD30 is a cell surface cytokine receptor belonging to the tumor necrosis factor (TNF) receptor superfamily 8, first identified on the Reed-Sternberg cells in Hodgkin lymphoma. CD30 is expressed on activated T and B cells but not on mature circulating T or B cells. The interaction of CD30 with its membrane-associated glycoprotein ligand (CD30L) activates the nuclear factor kappa-B (NFkB) signal transduction pathway, resulting in either cell proliferation or apoptosis [15-17].

The genetic abnormalities underlying the CD30 overexpression in LyP are largely unknown. One study found that two allelic forms of the CD30 promoter microsatellite repressive element, designated 30M377 and 30M362, were associated with the development of LyP and progression to CD30⁺ lymphomas in patients with LyP [18]. These findings suggest that allele-specific differences in the control of CD30 transcription may have a role in the pathogenesis of CD30⁺ cutaneous lymphoproliferative disorders (LPDs).

Clonality of T cells — Monoclonal rearrangement of the T cell receptor (TCR) genes has been detected in 40 to 100 percent of the LyP skin lesions [19-23]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)

In patients with LyP and associated lymphoma, identical rearrangements have been identified in LyP lesions and lymphoma cells [24-32]. (See 'Associated hematologic malignancies' below.)

Several studies indicate that the CD30⁺ cells are the clonal T cells in LyP [19,24,25,33,34]. However, it is not known whether the clonal T cells persist in the skin or in the peripheral blood during the remission periods [22].

In an analysis of the TCR gene rearrangements, multiple skin and blood samples were obtained from patients with LyP at the time of active disease and remission [20]. Overall, clonal T cell populations were detected in 78 percent of the skin samples and in 36 percent of blood samples. The direct comparison of the clonal T cell populations detected in the lesional skin and corresponding blood sample of each patient revealed a different rearrangement pattern in all instances. These findings suggest that T cell clones detected in the peripheral blood of patients with LyP are non-neoplastic and represent a reactive response to an unknown antigen.

Genetic abnormalities — Genetic abnormalities found in LyP by classic cytogenetic studies include aneuploidy and chromosomal aberrations [10,35]. The t(2;5)(p23,q35) translocation characteristic of systemic ALCL has not been found in LyP cells [36]. However, there is immunohistochemical evidence of increased expression in LyP cells of the oncogenic transcription factor gene Fra2 and inhibitor of differentiation gene Id2, which are located in close proximity to the t(2;5) breakpoint, suggesting a pathogenetic relationship between LyP and systemic ALCL [37].

A subset of LyP cases affecting mainly older adult patients has been found to have chromosomal rearrangements involving the DUSP22-IRF4 locus on 6p25.3, a genetic abnormality seen in approximately 28 percent of PC-ALCLs but absent in 97 percent of conventional types of LyP. Histologically, lesions showed a biphasic growth pattern, with small cerebriform lymphocytes in the epidermis and larger transformed lymphocytes in the dermis. All had a T cell immunophenotype but were often negative for both CD4 and CD8. The pathologic features raised the possibility of an aggressive T cell lymphoma such as transformed mycosis fungoides. However, no patient developed disseminated skin disease or extracutaneous spread. Untreated lesions regressed spontaneously, characteristic of LyP [8].

A novel, recurrent NPM1-TYK2 gene fusion has been reported in biopsy samples of LyP and PC-ALCL [38]. This finding supports the hypothesis that NPM1-TYK2 mediates the activation of STAT1/3/5 signaling to promote cell proliferation. The inactivation of TYK2 significantly diminished proliferation, suggesting that TYK2 is an oncogenic driver kinase and a potential therapeutic target in a subset of CD30⁺ cutaneous LPDs.

Spontaneous regression — The mechanisms underlying the spontaneous regression of LyP lesions are unknown. The prevailing hypothesis is that the coexpression of CD30 and the death receptor CD95 (Fas) ligand in LyP lesions may be responsible for the self-regression of LyP lesions by enhanced apoptosis of proliferating cells [39]. This hypothesis is supported by several observations:

●LyP and plaque-stage mycosis fungoides (MF) have a higher apoptosis/proliferation ratio than more aggressive cutaneous lymphomas such as tumor stage MF, cutaneous T cell lymphomas with tumor masses, or cutaneous B cell lymphoma [40,41].

●The large atypical CD30⁺ cells of LyP have a low expression of the anti-apoptotic Bcl-2 protein [42,43].

●The pro-apoptotic protein BAX is expressed at higher levels in LyP and CD30⁺ ALCL than in systemic CD30⁺ lymphoma, which does not undergo spontaneous regression and has an aggressive clinical behavior [41].

PATHOLOGY

Histologic features — The histology of lymphomatoid papulosis (LyP) varies according to the age of the lesion. Early lesions show a limited perivascular collection of lymphocytes with few inflammatory cells and large atypical cells. As lesions evolve, there is accumulation of dermal lymphocytes admixed with large atypical cells resembling immunoblasts, including bi- and multi-nucleated forms similar to Hodgkin/Reed-Sternberg cells of Hodgkin lymphoma (picture 1A).

A variable number of inflammatory cells, mostly neutrophils and eosinophils, are also seen. Neutrophils are usually found within the lumina of small dermal capillaries and serve as a useful diagnostic marker of LyP. Some degree of neutrophilic infiltration of the overlying epidermis is commonly seen, especially in advanced lesions, and may be associated with initial ulceration. Fully developed LyP lesions typically have a wedge-shaped configuration with a deep-lying apex (picture 1B).

There are six major histologic types of LyP lesions:

●Type A – Type A is the most common (approximately 75 percent of cases) and is characterized by a wedge-shaped infiltrate of scattered or clustered large atypical CD30⁺ cells, intermingled with numerous inflammatory cells, such as small lymphocytes, neutrophils, eosinophils, and histiocytes (picture 1B). Type A resembles the polymorphous infiltrates of Hodgkin lymphoma. Mitoses are frequent and may be atypical.

●Type B – Type B lesions show a predominant epidermotropic infiltrate of smaller atypical CD30⁺ or CD30^- cells with cerebriform nuclei that histologically resembles mycosis fungoides (MF). Unlike MF, LyP type B infiltrates are associated with papular lesions that regress spontaneously.

●Type C – Type C lesions contain large dermal clusters or sheets of large atypical CD30⁺ cells with relatively few inflammatory cells. These lesions resemble foci of cutaneous anaplastic large cell lymphoma (ALCL), and the distinction from ALCL is largely based on clinical presentation. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

●Type D – Type D (CD8⁺ cytotoxic T cell lymphoma-like) lesions are characterized by a pagetoid infiltrate of epidermotropic small to medium-sized atypical CD8⁺ and CD30⁺ lymphoid cells that resembles primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T cell lymphoma [44,45]. However, clinically, the lesions appear and behave as LyP.

●Type E – Type E has consistent dermal angiocentric infiltrates of small and medium-sized to large pleomorphic cells expressing uniformly CD30 and focally CD8 that infiltrate the walls of small to medium-sized dermal, and in some cases subcutaneous, blood vessels (picture 2). Vasculitis with fibrin deposition in vessel walls is described. Vascular thrombosis occurs in one-half of cases. Extensive extravasation of erythrocytes from damaged blood vessels also may occur [46].

●LyP with DUSP22:6p25.3 rearrangement – This variant has a distinctive biphasic histology with small to medium-sized epidermotropic cerebriform lymphocytes and large pleomorphic dermal lymphocytes. CD30 staining is biphasic with usual stronger staining of dermal compared with epidermal cells. Atypical cells are often double-negative for CD4 and CD8 or CD8⁺. Most patients with LyP and 6p25.3 gene rearrangement are older adults [8].

Follicular LyP is another rare histopathologic variant characterized by a perifollicular infiltrate of CD30⁺ atypical medium to large lymphoid cells, with variable degree of folliculotropism, follicular mucinosis, and presence of neutrophils in the hair follicle infundibula [47]. Rare, granulomatous and syringotropic variants have been described [48].

Immunophenotype — The large atypical immunoblast-like cells of LyP have the phenotype of activated T cells expressing Hodgkin lymphoma-related antigens [49]. In type A and type C LyP, these cells have an aberrant T cell phenotype lacking one or more common T cell antigens (CD3, CD2, CD5, or CD7) and are usually CD4⁺ and less often CD8⁺. They express CD30, CD25, HLA-DR and CD71, and occasionally CD15 or CD56. In type B LyP, the atypical cells with cerebriform nuclei have a CD3⁺, CD4⁺, CD8^- phenotype and variable expression of CD30. Large cells in types D are CD30⁺ CD8⁺ and in type E are CD30⁺ and CD8⁺ in most cases. In LyP with 6p25.3 rearrangement, large cells are often double-negative for CD4 and CD8, but CD3- and TCR-beta F1-positive. CD30 is positive in both dermal and smaller epidermotropic cells [8].

Cytotoxic granules (granzyme B, perforin, T cell intracellular antigen [TIA]-1) can be found within the cytoplasm in approximately 50 percent of cases [50].

SATB1 (special AT-rich sequence-binding protein 1), a thymocyte nuclear chromatin organizer that plays a crucial role in T cell development, was found to be overexpressed in the CD30⁺ anaplastic T cells in CD30⁺ cutaneous lymphoproliferative disorders (LPDs), including LyP [51]. In a series of 54 patients with CD30⁺ cutaneous LPD (12 with LyP), SATB1⁺ cases demonstrated a T helper (Th)-17 cytokine profile in anaplastic T cells and a marked inflammatory histopathologic response, including more prominent epidermal hyperplasia, epidermotropism, neutrophilic infiltrate, and vasculitic changes [52]. Interestingly, SATB1⁺ cases responded better to combined therapy of low-dose methotrexate and interferon-alfa-2b.

Genetic features — Clonal rearrangement of the TCR genes is observed in 40 to 100 percent of cases of LyP [19-22]. Identical rearrangements have been demonstrated in LyP lesions and associated lymphomas [24-32]. The t(2;5)(p23;q35) translocation involving the anaplastic lymphoma kinase (ALK), a marker of systemic ALCL, is not found in LyP or in cutaneous ALCL. Only one recurrent rearrangement of 6p25.3 has been described in a small group of older adult patients [8].

CLINICAL FEATURES — Lymphomatoid papulosis (LyP) manifests as a chronic, recurrent eruption of papules and nodules that spontaneously regress. Some patients, particularly children, experience pruritus associated with the eruption [23,53]. Other systemic symptoms, including fever, sweats, or weight loss, are absent in patients with uncomplicated LyP. Their presence raises the suspicion of an associated systemic lymphoma and warrants further evaluation. (See 'Further diagnostic evaluation' below.)

The lesions of LyP are grouped or generalized and usually coexist in different developmental stages (picture 3C). Early lesions appear as small erythematous or violaceous papules, which evolve to larger papules or nodules that may develop central hemorrhage, necrosis, and crusting and subsequently disappear in three to eight weeks (picture 3A-C).

The lesions of LyP are generally smaller than 2 cm. Larger lesions are occasionally seen and are clinically indistinguishable from those of primary or secondary anaplastic large cell lymphoma (ALCL (picture 4A-C)) [54]. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'Primary cutaneous ALCL'.)

A type E variant with clinical and histologic manifestations simulating highly aggressive angiocentric and angiodestructive T cell lymphoma has been described [46,55]. Patients present with a few papulonodular lesions that rapidly evolve to large ulcerations covered by a hemorrhagic and necrotic crust (picture 5). (See 'Histologic features' above.)

There is no preferential site of involvement. Lesions typically occur on the extremities and may involve the hands, face, and genitalia. Mucous membranes (eg, oral or vaginal mucosa), are rarely involved [56-58]. Localized or regional forms have been reported in a few patients [59-62]. Localized, circumscribed lesions can resemble limited plaque mycosis fungoides and have been reported to progress similarly to untreated mycosis fungoides [59]. Follicular and pustular variants have also been described [63-66].

The evolution of an individual lesion generally occurs over three to eight weeks; larger nodules may take months to heal. As lesions resolve, they may take on a brownish-red color and disappear, leaving an area of increased pigmentation or scarring (picture 3B). Ulcerated and necrotic lesions may leave hypo- or hyperpigmented, depressed, varioliform scars.

The duration of the disease is highly variable. Crops of lesions may recur and regress for months, years, or even decades.

ASSOCIATED HEMATOLOGIC MALIGNANCIES — Patients with lymphomatoid papulosis (LyP) have a lifelong increased risk of hematologic malignancies, most frequently mycosis fungoides (MF) and cutaneous or systemic anaplastic large cell lymphoma (ALCL) and, less commonly, B cell or Hodgkin lymphoma [4,6,67,68]. LyP-associated hematologic malignancies may occur before, concurrent with, or after the onset of LyP [4,6,23,28,53,67,69]. In the largest cohort study that included 504 patients with LyP, 78 patients (15.5 percent) developed a hematologic malignancy after a median follow-up of 120 months [68]. Of these 78 patients, 31 had MF, 29 had ALCL, and 19 had other hematologic malignancies, mainly of B cell or myeloid origin. Some cases originally believed to be Hodgkin lymphoma may actually represent T cell lymphomas with Reed-Sternberg-like cells expressing CD30 and CD15 [70]. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides" and "Hodgkin lymphoma: Epidemiology and risk factors".)

A clonal relationship between LyP and the associated lymphomas has been established in most of the cases analyzed [24-32]. The finding of identical TCR gene rearrangements in LyP and LyP-associated lymphomas [25] suggests that both disorders arise from a common lymphoid progenitor [71]. However, the molecular mechanisms underlying the progression of LyP to malignant lymphoma are unknown. The progression of LyP to ALCL appears to be mediated by the loss of cell growth regulation induced by inactivating mutations of cell surface receptors for transforming growth factor (TGF)-beta [33,34,72].

In a study of 106 French patients with LyP, the mean age of patients who developed lymphoma was 12 years older than patients without lymphoma [73]. There are no other clinical or histopathologic criteria to predict the progression of LyP to a malignant lymphoma [4]. Observational studies have identified several potential markers of increased risk, including monoclonal TCR gene rearrangement [73,74]; coexistence of different histologic types of LyP in an individual patient; B and C histologic subtypes [69]; fascin expression [75]; or high blood levels of soluble CD30, CD25, interleukin (IL) 6, and IL-8. [76]. However, their role in disease progression has not been established.

DIAGNOSIS

Clinical suspicion — The diagnosis of lymphomatoid papulosis (LyP) is clinically suspected in a patient presenting with:

●History of a recurrent eruption of papules and nodules that evolve and regress spontaneously in the absence of systemic B symptoms. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'B symptoms'.)

●Grouped or generalized papules and nodules in different stages of evolution, some with central ulceration, crusting, or eschar (picture 3A-E) (see 'Clinical features' above)

Biopsy — A skin biopsy for histopathologic, immunohistochemical, and molecular genetic evaluation is necessary to confirm the diagnosis. The complete excision of two or more inflammatory lesions without signs of necrosis or involution provides the optimal specimens for the pathologist.

The definitive diagnosis is based upon the correlation of the clinical appearance and course of the skin lesions with the following histologic, immunophenotypic, and cytogenetic features [77]:

●A wedge-shaped infiltrate of large atypical T cells, intermingled with numerous inflammatory cells, including small lymphocytes, neutrophils, eosinophils, and histiocytes (type A LyP) (picture 1A-B) (see 'Histologic features' above)

●Expression of CD30 on immunohistochemistry (picture 1B) (see 'Immunophenotype' above)

●Clonal rearrangement of the TCR genes (in 40 to 100 percent of cases) (see 'Genetic features' above)

Diagnostic pitfalls — The diagnosis of LyP may be difficult or delayed in some patients for several reasons:

●Histologic variability – The histology of LyP is highly variable. The histologic subtypes of LyP probably represent evolutionary stages of the skin lesions and may be seen in individual patients at presentation or at different times in the course of the disease. (See 'Histologic features' above.)

●Histologic overlap – There is considerable clinical, histologic, and immunophenotypic overlap between LyP and primary cutaneous anaplastic large cell lymphoma (PC-ALCL). As an example, the finding of scattered CD30⁺ blast cells in a background of mixed inflammatory infiltrate is highly suggestive of LyP, but may be also seen in PC-ALCL presenting with ulcerated lesions [2]. Conversely, dermal clusters or sheets of large atypical CD30⁺ cells with relatively few inflammatory cells are characteristic of PC-ALCL, but can also be found in patients with clinical presentation and course of LyP. (See 'CD30+ lymphoproliferative diseases' below.)

●Mimics of CD30⁺ lymphoproliferative diseases – CD30⁺ lymphoid cells can be seen in a wide range of inflammatory and infectious disorders and other lymphoid neoplasms that may be clinically and histologically indistinguishable from LyP. Appropriate clinicopathologic correlation is essential for accurate diagnosis. (See 'CD30+ inflammatory and infectious diseases' below.)

FURTHER DIAGNOSTIC EVALUATION — Following the diagnosis of lymphomatoid papulosis (LyP), additional evaluation may be needed in some patients to exclude a concurrent malignant lymphoma. Elements of history that increase the risk of malignant lymphoma include:

●Previous lymphoid neoplasm, particularly Hodgkin lymphoma, systemic anaplastic large cell lymphoma (ALCL), or mycosis fungoides (MF)

●Systemic symptoms, such as unexplained weight loss, fever, night sweats, shortness of breath, abdominal fullness

●HIV infection or immunosuppressive therapy

Examination findings that may suggest malignant lymphoma include:

●Morphology, size, and extent of skin lesions (isolated or few lesions that are larger than 2 cm are more suggestive of cutaneous ALCL than LyP (picture 4A-D))

●Erythematous, scaly patches and plaques (suggestive of mycosis fungoides (picture 6A-D))

●Lymph node enlargement

●Hepatic or splenic enlargement

Additional laboratory investigations that may be helpful to exclude a malignant lymphoma include:

●Complete blood cell count and differential

●Examination of a peripheral blood smear for the presence of atypical cells (absent in LyP)

●Routine biochemistry tests, including lactate dehydrogenase (LDH)

●Human T-lymphotropic virus I (HTLV-I) serology in endemic areas to exclude adult T cell leukemia-lymphoma (see "Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology", section on 'Epidemiology and transmission')

Imaging studies, including chest radiograph, ultrasonography of abdomen and pelvis, or computed tomography scan, are considered optional examinations in patients with typical LyP, normal laboratory tests, and absence of palpable enlarged lymph nodes, hepatosplenomegaly, and systemic symptoms [77].

However, a chest radiograph at presentation may be helpful to exclude a mediastinal mass from occult Hodgkin or non-Hodgkin lymphoma. A chest radiograph also may be warranted for patients who will be treated with methotrexate because pre-existing lung disease may be a risk factor for lung toxicity. (See "Major side effects of low-dose methotrexate" and "Methotrexate-induced lung injury".)

A liver biopsy should be considered in patients with abnormal liver function tests and/or history of excess alcohol use, hepatitis, or diabetes mellitus.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of lymphomatoid papulosis (LyP) includes other lymphoproliferative diseases expressing CD30 and several inflammatory and reactive disorders that contain CD30⁺ cells and mimic LyP clinically and histologically [54]. The clinicopathologic characteristics of the main disorders that should be differentiated from LyP are summarized in the table (table 1).

CD30+ lymphoproliferative diseases

●Primary cutaneous anaplastic large cell lymphoma – Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) usually manifests as a solitary, firm, large, and sometimes ulcerated nodule (picture 4C). Approximately 20 percent of patients have multifocal disease (picture 4A-B). CD30 is expressed by at least 75 percent of the large atypical T cells, and clonal TCR gene rearrangement is found in 90 percent of cases. Unlike systemic ALCL, primary cutaneous ALCL usually lacks expression of epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK). However, an ALK protein variant localized to the cytoplasm and distinct from the nuclear/cytoplasmic variant resulting from the nucleophosmin (NPM):ALK translocation has been detected in a few cases of primary cutaneous ALCL, some of which also expressed EMA [78-82].

When NPM-ALK is detected as a nuclear/cytoplasmic stain, a thorough investigation should be done to exclude nodal systemic ALCL [82,83]. ALK protein is essentially absent in LyP [84]. If an ALK gene rearrangement is detected, secondary skin lesions of systemic ALCL should be suspected. Cutaneous presentations of ALK-positive systemic ALCL associated with regional lymphadenopathy have been reported in children following insect bites [85,86]. (See "Primary cutaneous anaplastic large cell lymphoma".)

●Secondary skin lesions of systemic anaplastic large cell lymphoma – Most systemic anaplastic large cell lymphomas (ALCLs) carry the t(2;5)(p23;q35) translocation and express ALK, which is absent in LyP. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'Primary cutaneous ALCL'.)

●Transformed mycosis fungoides and Sézary syndrome – Approximately one-half of transformed mycosis fungoides (MF) and Sézary syndrome (SS) are CD30⁺. A previous history of patch or plaque MF or erythroderma clarifies the diagnosis, although LyP lesions may be coexistent with MF [25,87]. LyP type B is difficult to distinguish histologically from papular MF, in which lesions persist and may eventually become associated with typical patches and plaques [88,89]. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'Transformation to large-cell histology'.)

●Adult T cell leukemia-lymphoma – Adult T cell leukemia-lymphoma (ATLL) is a peripheral T cell leukemia-lymphoma caused by the human retrovirus HTLV-1. Most cases have an acute onset with generalized lymphadenopathy. All patients with ATLL have serologic antibodies to HTLV-1. Cutaneous involvement occurs in approximately 50 percent of cases. Large blast-like cells can be CD30⁺ but are ALK^-. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

●Hodgkin lymphoma – Skin involvement is rare in Hodgkin lymphoma, and primary cutaneous forms are even rarer (picture 4D). The Reed-Sternberg cells of Hodgkin lymphoma are CD30⁺ and CD15⁺. The latter is less frequently expressed in LyP. (See "Hodgkin lymphoma: Epidemiology and risk factors".)

Other lymphoid neoplasms that can have CD30-expressing neoplastic T cells may be confused with LyP in the absence of proper clinical context:

●Gamma/delta T cell lymphomas commonly present as ulcerating tumors in the extremities (usually legs) of adults. Lesions are larger than in LyP and ulcers often expose subcutaneous fat not seen in LyP [90]. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma", section on 'Primary cutaneous gamma/delta T cell lymphoma'.)

●Subcutaneous panniculitis-like T cell lymphoma (SPTCL) presents as palpable cutaneous nodules in children and adults but rarely ulcerates as in LyP [91]. Ringing of fat cells by tumor cells characteristic of SPTCL is infrequently seen in CD30⁺ cutaneous ALCL but rarely in LyP in which the CD30⁺ cells are usually confined to the dermis. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

●Hydroa vacciniforme-like lymphoma is an Epstein-Barr virus (EBV)-driven lymphoproliferative disease affecting children and adolescents from Asia, Central and South America, and Mexico [92,93]. Clinical features include facial edema and vesicles, small necrotic areas, crusts, and pitted scars involving the face and sun-exposed areas (picture 7). EBV is detected in CD30⁺ cells but is absent in LyP.

●Type E LyP can mimic angiocentric lesions of gamma-delta T cell lymphoma and NK/T cell lymphoma [94]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

●Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) infrequently presents as a primary skin tumor in absence of lymphadenopathy [95,96]. Lesions contain sheets of tumor cells of varied size without inflammatory cells, whereas inflammatory cells are characteristic of LyP. Whereas LyP and PC-ALCL typically show disturbed expression of the T cell receptor/CD3 complex (CD3-gamma, -delta, -epsilon, -zeta) and associated signaling molecules (Lck, ZAP-70, LAT, bcl-10, Carma1, NFATc1, c-Jun, c-Fos, Syk), the full expression program required for T cell receptor signaling is retained in PTCL, NOS, facilitating their differential diagnosis [97]. (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified".)

CD30+ inflammatory and infectious diseases — Several inflammatory and reactive disorders may contain a significant number of CD30⁺ cells and mimic LyP clinically or histologically [54,98]. However, the reactive or inflammatory disorders are less likely to have dominant T cell clones, especially identical clones in multiple biopsies. These disorders, sometimes referred to as CD30⁺ pseudolymphomas, include:

●Pityriasis lichenoides – Pityriasis lichenoides et varioliformis acuta (PLEVA) is a skin disease of unknown etiology clinically characterized by the eruption of crops of papules that evolve to necrotic lesions and eventually resolve leaving varioliform scars (picture 8A-B). LyP and PLEVA may have overlapping clinical, histopathologic, and molecular features [99]. With few exceptions [99], the lymphocytic infiltrate in PLEVA is predominantly CD8⁺ with few large atypical CD30⁺ cells. A dominant T cell clone was detected in 13 of 20 cases (65 percent) in one study [100].

Pityriasis lichenoides chronica (PLC) may be more difficult to distinguish from LyP because the predominant lymphoid infiltrate can be CD4⁺. In children, the two entities may coexist [23]. (See "Pityriasis lichenoides et varioliformis acuta (PLEVA)" and "Pityriasis lichenoides chronica".)

●Reactions to arthropod bites/nodular scabies – Chronic reactions to insect bites and nodular scabies may simulate LyP clinically and histologically (picture 9A-C). The dermis contains a dense inflammatory infiltrate of lymphoid cells and histiocytes, with an admixture of eosinophils and plasma cells and atypical mononuclear cells with hyperchromatic nuclei. A history of exposure and the presence of symptoms (eg, intense pruritus) may help in differentiating arthropod bites from LyP. (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Classic scabies'.)

●Lymphomatoid drug eruption – A lymphomatoid eruption is a rare type of drug reaction clinically characterized by indurated papules or plaques (picture 10). Cases associated with the presence of large atypical CD30⁺ T cells on histologic examination have been reported following the administration of antibiotics, antiepileptics, or biologics [98,101-104]. The temporal relationship between the drug administration and skin eruptions and the disappearance of the rash after the drug suspension clarifies the diagnosis. (See "Cutaneous T cell pseudolymphomas", section on 'Lymphomatoid drug reaction'.)

●Viral infection – Cutaneous viral infections (orf and milker's nodule viruses, herpes simplex, varicella-zoster, molluscum contagiosum) may show large atypical CD30⁺ cells on histologic examination [98,105]. In contrast to LyP, skin lesions caused by viruses do not have a waxing and waning clinical course and do not show T-cell-receptor (TCR) gene rearrangement on molecular genetic studies.

●Other – CD30⁺ T cells may also be found in skin lesions of atopic dermatitis [106-109], mycobacterial infection [110], syphilis, and leishmaniasis [98]. The history and clinical course are usually sufficient to differentiate these conditions from LyP.

INDICATIONS FOR REFERRAL — If physical examination, blood tests, or imaging studies suggest extracutaneous lymphoproliferative disease associated with LyP, the patient should be referred to a hematologist/oncologist for appropriate diagnostic evaluation, staging, and treatment of possible malignancy.

TREATMENT

General considerations — Lymphomatoid papulosis (LyP) has a chronic course of years to decades of recurrent papulonodular lesions that undergo spontaneous regression after weeks or months. Treatment may hasten lesion healing and reduce the severity or prevent the eruption of new crops of lesions. However, none of the available treatment modalities alters the natural history of LyP or reduces the risk of developing an associated lymphoma. Thus, the short-term benefits of treatment should be weighed against potentially harmful side effects in the individual patient [77,111].

Patients with limited or asymptomatic disease — For patients who have few asymptomatic lesions without scarring or other cosmetic concerns (eg, lesions not on the face or hands), a wait-and-see strategy is appropriate, depending upon patient preference [77]. If the patient desires treatment in an attempt to minimize the lesions or facilitate regression, super-high potency topical corticosteroids (group 1 (table 2)) are an option.

Skin lesions >2 cm that do not regress spontaneously in eight weeks should be biopsied and sent for pathology to exclude primary cutaneous anaplastic large cell lymphoma (PC-ALCL) [111]. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

Patients with extensive or symptomatic disease — Observation may be acceptable in patients who do not wish treatment. Some patients may use topical corticosteroids to alleviate symptoms alone or in conjunction with other treatment options listed below.

Methotrexate — We suggest low-dose methotrexate (5 to 35 mg per week by oral or subcutaneous administration) as the initial therapy for adult patients with symptomatic or extensive disease or disease involving cosmetically sensitive areas (eg, face or hands) [77]. Treatment is usually started at 5 to 10 mg per week and increased by 2.5 to 5 mg per week or as tolerated to a maximum of 25 to 35 mg per week if a clinical improvement is not observed in four to eight weeks. Patients receiving weekly methotrexate should also receive folic acid 1 mg per day orally.

A complete response is indicated by the clearance of all the active lesions without the development of new lesions. A partial response is defined as the regression of at least 50 percent of the active lesions and development of fewer new lesions [77]. Maintenance treatment is often required for long-term control of disease in a majority of patients. Maintenance therapy is usually initiated after complete response; the dose is gradually decreased by 2.5 or 5 mg per week to the lowest effective dose.

The duration of treatment and maintenance treatment is based upon clinical response, occurrence of side effects, and patient's preference. The time to relapse after discontinuation of methotrexate is variable and should be assessed in the individual patient.

Efficacy — The efficacy of methotrexate for LyP has not been evaluated in randomized trials. Its use is based upon evidence of efficacy from small observational studies and expert consensus [77,112]:

●In a retrospective study including 45 patients with LyP treated with methotrexate 15 to 25 mg weekly, 20 patients (44 percent) did not develop new lesions and 19 patients (42 percent) developed only a few lesions during the treatment [113]. After discontinuation of therapy, 10 of 40 patients did not relapse during a follow-up period of 24 to 227 months. Patients with relapsing disease required maintenance treatment for months or years. Side effects were reported in 77 percent of patients, including hepatic fibrosis in 5 of 10 patients treated with methotrexate for more than three years.

●In another study, 28 adult patients with extensive papulonecrotic and nodular skin lesions or cosmetically concerning lesions were treated with oral methotrexate 5 to 25 mg per week (median dose 10 mg per week) for 1 to 216 months (median 37 months) [114]. Excellent or good disease control was achieved in 24 patients in three to four weeks. Transient elevation of liver enzymes occurred in 10 patients during the first month of treatment; two patients discontinued treatment because of persistent elevated liver enzymes.

●In another study, 25 patients with LyP were treated with oral methotrexate 20 to 30 mg per week for a minimum of six months, followed by a two- to six-month weaning period [115]. Twenty-two patients had a partial or complete response, but only 6 were successfully weaned off the drug and maintained the response for six months or longer, whereas 16 remained methotrexate dependent.

Contraindications and adverse effects — Important contraindications to methotrexate therapy include liver disease, renal disease, and pregnancy or planned pregnancy (for both females and males) [116,117]. Before initiating long-term methotrexate therapy, screening for hepatitis B and hepatitis C virus infection is recommended. In patients with infection, this allows a decision whether to avoid the use of methotrexate, to try to eradicate the viral infection before initiating therapy, or to suppress viral replication during immunosuppressive therapy.

Minor adverse effects, including nausea, stomach upset, headache, and fatigue, occur in most patients treated with low-dose methotrexate. Hepatotoxicity, pulmonary fibrosis, and myelosuppression are serious adverse effects of methotrexate treatment and may infrequently occur with low-dose therapy. (See "Major side effects of low-dose methotrexate".)

Monitoring — Serum aminotransferases and peripheral blood cell count should be obtained twice monthly in the first month, then every 4 to 12 weeks, to detect hepatic and hematologic toxicity during long-term treatment with methotrexate. Blood should be drawn on the day before the once-weekly methotrexate dose is administered for accurate assessment.

Guidelines for dose adjustment for patients with abnormal liver function tests are presented separately. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)

Phototherapy — We suggest psoralen and ultraviolet A (PUVA) therapy for patients with LyP whose disease does not respond to methotrexate or patients for whom methotrexate is contraindicated. PUVA is administered twice weekly for six to eight weeks or until clearance [111]. Maintenance therapy with one treatment session per week may be needed to prevent relapses. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Treatment protocols'.)

The efficacy of PUVA for the treatment of LyP has not been evaluated in clinical trials. Its use is supported by a few case series and evidence of efficacy in other types of cutaneous lymphoproliferative disorders (eg, mycosis fungoides) [4,111]. In a review of 19 patients treated with PUVA, a complete response was reported in 5 and a partial response in 13 [77]. Bath PUVA has been used for treatment of LyP in children [118-120].

Narrowband ultraviolet B (NBUVB) phototherapy or, if available, ultraviolet A1 (UVA1; long-wave [340 to 400 nm] ultraviolet A [UVA]) phototherapy, which do not require the oral or topical administration of psoralens, may be alternatives to PUVA. In one study, UVA1 phototherapy induced a complete response in five of seven patients [121]. Three patients relapsed between 1 and 20 months after discontinuation but responded to a second treatment cycle.

Other therapies — Aggressive treatment of LyP with multiagent chemotherapy is inappropriate. In patients with associated lymphomas, treatment of lymphoma with multiagent chemotherapy does not alter the clinical course of LyP [122,123]. Therapies that seemed to be effective when used alone or in combination in small case series or in single patients include:

●Photodynamic therapy [124]

●Targeted phototherapy [125]

●Oral or topical retinoids (bexarotene) [126]

●Topical mechlorethamine and carmustine [127]

●Anti-CD30 monoclonal antibody-drug-conjugate (brentuximab vedotin) [128,129]

●Low-dose methotrexate plus interferon-alfa-2b in LyP with Th-17 phenotype [51]

Treatment in children — There is no consensus on treatment of LyP in children. In case series, no treatment or treatment with topical corticosteroids, oral antibiotics (macrolides or tetracyclines), ultraviolet B (UVB), or natural sunlight have been reported [23,53,130-132]. Low-dose methotrexate and bath PUVA are additional therapeutic options [118,119,133].

For children with limited disease (few or small lesions), treatment is usually not necessary. When children require treatment because of cosmetic concerns or peer group pressure, we suggest topical corticosteroids or NBUVB phototherapy. Narrowband phototherapy is administered two to three times per week for six to eight weeks.

Low-dose methotrexate (2.5 to 15 mg per week) may be an alternative for cases that do not respond to topical corticosteroids or NBUVB phototherapy.

PROGNOSIS — Despite the increased risk of developing a cutaneous or nodal malignant lymphoma, the prognosis of lymphomatoid papulosis (LyP) is excellent in the vast majority of cases [134]. Patients with LyP who do not develop malignancy have a normal life expectancy.

The reported mortality rates from associated lymphomas are low [4,69,74]. In two case series, each with approximately 120 patients, associated lymphoid malignancy was detected in 19 and 14 percent before, after (up to 19 years), or concurrently with the development of LyP [4,74]. The mortality rate from associated lymphoma was approximately 2 percent in both series. In another study of 180 patients with LyP, 93 (52 percent) developed 114 hematologic malignancies and six (6 percent) died of their disease [69]. Patients with LyP may have an increased risk of nonlymphoid malignancies [67].

LyP lesions may heal with scarring, especially in children. In small pediatric case series, varioliform scarring has been reported in approximately 80 percent of children [23,131].

FOLLOW-UP — Patients with lymphomatoid papulosis (LyP) require long-term follow-up to monitor the disease course and response to treatment and lifelong surveillance for cutaneous or systemic lymphoma. Frequency of follow-up for those on treatment will depend on the specific treatment. For monitoring of disease course and surveillance, patients should be seen at 6- to 12-month intervals for:

●Reassessment of clinical history

●Complete skin examination

●Physical examination focused on lymph node, hepatic, or splenic enlargement

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Lymphomatoid papulosis (LyP) is a rare, chronic recurrent, self-healing papulonodular skin eruption with histologic features of a CD30⁺ lymphoid proliferation of atypical T cells. The overexpression of CD30 on the large atypical T cell found in the skin lesions is the hallmark of LyP. Monoclonal rearrangement of the T cell receptor (TCR) genes has been detected in 40 to 100 percent of the LyP skin lesions. (See 'Introduction' above and 'Etiology and pathogenesis' above.)

●Clinical presentation – LyP manifests as a recurrent eruption of papules and nodules with central necrosis and crusting that spontaneously resolve in three to eight weeks, leaving hyperpigmentation or scarring (picture 3A-E). (See 'Clinical features' above.)

●Associated malignancies – Patients with LyP have an increased risk of associated lymphoid malignancy (mycosis fungoides, anaplastic large cell lymphoma, B cell or Hodgkin lymphoma) before, concurrent with, or after the onset of LyP. (See 'Associated hematologic malignancies' above.)

●Diagnosis – The diagnosis of LyP is based upon the clinical appearance and course of the skin lesions and the evaluation of an excisional biopsy of a full-developed skin lesion. Histologic characteristics include a wedge-shaped inflammatory infiltrate containing large atypical CD30⁺ cells (picture 1A-B). Clonal rearrangement of the TCR genes is found in 40 to 100 percent of cases. A careful clinicopathologic correlation is essential for a correct diagnosis. (See 'Pathology' above and 'Diagnosis' above.)

●Additional evaluation – At the time of diagnosis, patients with LyP should be further evaluated to exclude associated lymphoma. (See 'Further diagnostic evaluation' above.)

●Differential diagnosis – The differential diagnosis of LyP includes lymphoproliferative and inflammatory or reactive disorders that contain CD30⁺ cells and mimic LyP clinically and histologically (table 1). (See 'Differential diagnosis' above.)

●Treatment – None of the available treatment modalities alters the natural history of LyP or reduces the risk of developing an associated lymphoma. However, treatment may hasten lesion healing and reduce the severity or prevent the eruption of new crops of lesions (see 'General considerations' above):

•Limited disease – We suggest a wait-and-see strategy (observation) for patients who have limited or asymptomatic disease without scarring or other cosmetic concerns (eg, lesions not on the face or hands) (Grade 2C). (See 'Patients with limited or asymptomatic disease' above.)

•Extensive disease – For patients with extensive or symptomatic disease, scarring, or cosmetic concerns, we suggest low-dose methotrexate as the initial therapy (Grade 2C). The treatment is usually started at 5 to 10 mg per week orally or subcutaneously and increased by 2.5 mg per week or as tolerated to a maximum of 25 mg per week if clinical improvement is not observed.

For patients for whom methotrexate is contraindicated and for patients with LyP that does not respond to methotrexate, we suggest psoralen and ultraviolet A (PUVA) therapy (Grade 2C). PUVA is administered twice weekly for six to eight weeks or until clearance. (See 'Patients with extensive or symptomatic disease' above.)

•In children – For children with symptomatic lesions, scarring, or cosmetic concerns, we suggest topical corticosteroids or narrowband ultraviolet B (NBUVB) therapy (Grade 2C). Low-dose methotrexate (2.5 to 15 mg per week) may be an alternative for children who do not respond to topical steroids or ultraviolet B (UVB). (See 'Treatment in children' above.)

●Prognosis – The prognosis of LyP is excellent. However, because of the increased lifelong risk of developing a malignant lymphoma or other malignancy, patients with LyP require long-term follow-up. (See 'Prognosis' above and 'Follow-up' above.)