Diagnosis of T-cell lymphoid proliferations of the skin: putting all the pieces together.

The spectrum of T-cell lymphoid proliferations of the skin varies from indolent to highly aggressive diseases and therefore an accurate pathological diagnosis is paramount. Integration of clinical, histopathological, immunohistochemical, and molecular findings is of crucial importance in the evaluation of these processes. In this article, we discuss selected situations where difficulty may arise for the pathologist evaluating this type of skin biopsies, such as: the diagnosis of early (patch stage) mycosis fungoides, the distinction of mycosis fungoides with large cell transformation from primary cutaneous anaplastic large cell lymphoma, the recognition of new histopathological patterns of lymphomatoid papulosis and the entities they mimic, the evaluation of primary cutaneous anaplastic large cell lymphoma with expression of markers suggestive of systemic origin (such as ALK), the awareness of the wide range of clinical and pathological presentations of hydroa vacciniforme-like EBV-positive T-cell lymphoproliferative disorders, the evaluation of cases of primary cutaneous γδ T-cell lymphoma showing predominantly epidermotropic pattern of growth, and the correct interpretation of findings seen in indolent proliferations such as primary cutaneous acral CD8-positive T-cell lymphoma and primary cutaneous small/medium size CD4 + T-cell lymphoproliferative disorder.

Lymphomatoid papulosis type E with a CD56+ immunophenotype presenting with purpura-like lesions.

Lymphomatoid papulosis (LyP) type E is a recently described variant characterized by the occurrence of large necrotic eschar-like lesions displaying microscopically angioinvasive and angiodestructive infiltrates of CD30+ lymphocytes, frequently coexpressing CD8. Rare cases of LyP type E with a CD56+ immunophenotype have been described. Herein, we describe a 36-year-old woman with LyP type E, characterized by purpura-like lesions on her left ankle. Initially, she presented with left ankle swelling, petechiae and ecchymosis, and rapidly developing necrotic papules, all of which resolved spontaneously over a period of a few months without intentional therapy. Biopsy revealed CD30 and CD56 positive atypical cell infiltrates with marked angiocentricity and angiodestruction. Awareness of this rare LyP variant and its correct recognition, even if the clinical presentation is unusual, is important to avoid aggressive treatment.

CD30+ lymphoproliferative disorder with spindle-cell morphology.

Lymphomatoid papulosis (LyP) is classified as a CD30+ primary cutaneous lymphoproliferative disease. The phenotypic variability along the spectrum of CD30+ lymphoproliferative diseases is highlighted by the distinct histologic subtypes of LyP types A, B, C, and the more recently described types D, E, and F. We report the case of an elderly woman with a clinical presentation and histopathologic findings consistent with LyP, whose atypical CD30+ infiltrate uniquely demonstrated a spindle-cell morphology. To our knowledge, this is the first reported case of LyP characterized by CD30+ spindle-shaped cells, and may represent a new and distinct histologic variant of LyP.

Histopathological aspects and differential diagnosis of CD8 positive lymphomatoid papulosis.

Lymphomatoid papulosis (LyP) belongs to CD30+ lymphoproliferative disorders with indolent clinical course. Classic histological subtypes, A, B and C are characterized by the CD4+ phenotype, while CD8+ variants, most commonly classified as type D, were reported in recent years. We present 14 cases of CD8+ LyP. In all patients, self-resolving or treatment-sensitive papules were observed. Of 14 cases 7 produced results with typical microscopic features of LyP type D mimicking primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. The infiltration pattern in 4 of 14 cases were consistent with classic LyP type B, without CD30 expression in two cases, resembling mycosis fungoides (MF). The morphology of 2 of 14 cases shared a certain consistency with classic type A and C, lacking eosinophils and neutrophils. Extensive folliculotropism characteristic to type F was observed in 1 of 14 case. Significant MUM1 and PD1 expression were detected in 2 of 14 and 3 of 14 cases, respectively. We concluded that CD8+ LyP may present with different histopathological features compared with type D, similar to CD4+ LyP variants. Differential diagnoses include CD8+ papular MF, folliculotropic MF and anaplastic large cell lymphoma in addition to primary cutaneous aggressive epidermotropic T-cell lymphoma. We emphasise that rare CD8+ LyP cases may exist with CD30-negativity.

A Primary Cutaneous CD30-Positive T-Cell Lymphoproliferative Disorder Arising in a Patient With Multiple Myeloma and Cutaneous Amyloidosis.

CD30-positive cutaneous lymphoproliferative disorders, a group of T-cell neoplasms, including lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma, require careful clinicopathologic correlation for diagnosis. An association between LyP and the development of a second hematolymphoid malignancy has been established in the literature. LyP has also been reported with systemic amyloidosis, but no such reports have documented coexisting cutaneous amyloid deposition with LyP to our knowledge. A 66-year-old woman with cutaneous amyloidosis, secondary to multiple myeloma, in remission, presented with erythematous and dark-brown papules involving the right arm, scalp, and torso. Punch biopsy of the arm showed a dermal infiltrate of intermediate-sized lymphocytes, some of which displayed a plasmacytoid morphology and prominent nodular subepidermal amyloid deposition. Punch biopsy of the scalp similarly showed a nonepidermotropic dense dermal infiltrate of intermediate-sized plasmacytoid lymphocytes and multifocal amyloid deposition. Both infiltrates were immunophenotypically CD30-positive, anaplastic lymphoma kinase-negative T-cell lymphoproliferative processes. Subsequent studies showed no systemic involvement, and clinical correlation suggested a final diagnosis of LyP. We present this case of LyP, which histologically mimics a B-cell proliferation with a plasmacytoid morphology arising in association with cutaneous amyloidosis to highlight the importance of clinicopathologic correlation, a thorough battery of immunohistochemical studies, and consideration for a second hematologic malignancy arising in the setting of LyP.

Exacerbation of lymphomatoid papulosis during rituximab therapy.

We report two cases of lymphomatoid papulosis (LyP) occurring in conjunction with B-cell lymphoproliferative malignancies where the LyP was exacerbated during rituximab (anti-CD20 antibody)-based therapy. We postulate that the altered B-cell cytokine milieu acted to allow an exacerbation of the patient's concomitant T-cell disease and discuss the possible mechanisms by which this may have occurred.

Lymphomatoid papulosis and recurrent transitional cell carcinoma of the bladder: a paraneoplastic association.

Lymphomatoid papulosis is a rare, papulonodular skin eruption with histologic features of a CD30+ T cell lymphoma. We present a 79-year-old man with lymphomatoid papulosis and transitional cell carcinoma of the bladder.

In search of prognostic indicators for lymphomatoid papulosis: a retrospective study of 123 patients.

BACKGROUND: Lymphomatoid papulosis (LyP) is a benign recurrent papulonodular skin eruption with histologically malignant features that sometimes (10%-20%) progresses to lymphoma. OBJECTIVE: We retrospectively evaluated the clinical course of patients with LyP and identify prognostic factors possibly indicating a malignant course. METHODS: Clinical, histopathologic, and immunologic features and molecular genetics were examined and correlated with clinical course and outcomes. Immunophenotyping and chemokine profiling were performed in select skin biopsy samples. A follow-up questionnaire was sent to patients. Clinical course and association with neoplastic disorders were correlated with LyP subtypes, molecular genetics, and immunophenotyping studies. RESULTS: Of 123 patients with LyP (1991-2008) followed up a mean of 4 years (range, 2 months to 14 years), 17 (14%) had an associated hematologic malignancy, 8 of which were mycosis fungoides. Histopathologic analyses demonstrated classic LyP type A (n = 69), B (n = 13), or C (n = 6), and a slight predominance of T-cell CD8 marker expression for type A. More than one type of lesion was present in 9 patients with a higher incidence of hematologic malignancies. T-cell receptor gene rearrangement positivity was about two times higher, with LyP associated with hematologic malignancy (82% vs 44%; odds ratio 5.7; P = .02). Chemokine studies in a subset of 25 patients showed chemokine receptor (CCR) CCR4(+) and thymus and activation-related chemokine (TARC(+)) in all LyP types and CCR3(+) and chemokine-related receptor (CXCR) CXCR3(+) in types B and C. LIMITATIONS: Retrospective study design is a limitation. CONCLUSIONS: Positive T-cell receptor gene rearrangement or diagnosis of mixed-type LyP may be a prognostic indicator of disease more prone to progress to lymphoma.

Persistent agmination of lymphomatoid papulosis: an ongoing debate.

BACKGROUND: Persistent agmination of lymphomatoid papulosis (PALP) has been a matter of controversy in the literature, some authors suggesting that it represents composite lymphoma, others localized lymphomatoid papulosis (LyP). PATIENT AND METHODS: A 64-year-old man was referred to our outpatient center complaining of papular eruptions lasting 3 years. At physical examination, he showed papulonodular lesions on the trunk and extremities. Some patches on the trunk and upper arms were also observed. Both types of lesion were biopsied and studied on histological, immunohistochemical and molecular grounds. RESULTS: The nodular lesion revealed the classical features of LyP type A, while the patch was characterized by the presence of a superficial and deep infiltrate with perivascular and interstitial location, consisting of mature lymphocytes admixed with plasma cells and large atypical cells that became more numerous beneath the epidermis. On immunohistochemistry the two lesions presented the same profile. CONCLUSION: Our case suggests that PALP does not correspond to localized LyP, as it can involve different skin areas since its presentation. Furthermore it rules out the possibility that PALP is a composite lymphoma. In fact, the same cytological and phenotypic characteristics were detected in all samples, including those taken from patchy areas.

Lymphomatoid papulosis type D: a newly described variant easily confused with cutaneous aggressive CD8-positive cytotoxic T-cell lymphoma.

Lymphomatoid papulosis (LyP) is defined as a chronic recurrent skin disease characterized by waxing and waning papules and nodules with histologic features of a CD30-positive T-cell lymphoma. Three histological subtypes (A, B, and C) were already recognized, and only more recently, a further variant simulating histologically an aggressive epidermotropic CD8-positive T-cell lymphoma was described, which was named LyP type D by the authors. We report the case of a 38-year-old woman presenting with a 1-year history of recurrent self-healing papules and nodules, predominantly affecting her upper and lower limbs but also the face, including the lower lip, with no associated systemic symptoms. A biopsy from 1 lesion revealed an infiltrate of atypical lymphoid cells extending throughout the dermis with massive epidermotropism displaying a pagetoid reticulosis-like pattern and a CD8(+)CD30(+) cytotoxic T-cell phenotype. The clinicopathologic features conformed to the newly described type D variant of LyP. Diagnostic studies did not reveal any systemic involvement, and the patient remains otherwise well with no active treatment. In the present report, we discuss the need for clinicopathologic correlation to establish an accurate diagnosis and its importance for an adequate management of these patients.

[Lymphomatoid papulosis: clinical and pathological findings in 18 patients]. / Papulosis linfomatoide: hallazgos clínico-patológicos en 18 pacientes.

BACKGROUND: Lymphomatoid papulosis (LyP) is a CD30(+) lymphoproliferative skin disease that has been described in association with Hodgkin lymphoma. It has also been reported to progress to mycosis fungoides or cutaneous anaplastic large-cell lymphoma. OBJECTIVE: To study the clinical and histologic features of LyP and response to treatment in a patient series. MATERIALS AND METHODS: For this retrospective, descriptive, observational study of patients with histologically confirmed LyP and sufficient follow-up data on record, we extracted histologic findings on skin biopsy, clinical presentation, clinical course, and response to treatments. RESULTS: Eighteen patients (10 male, 8 female) were identified. Most biopsies (14/18, 78%) showed a wedge-shaped lymphocytic infiltrate with CD30(+), CD3(+), and CD56(-) cells. A type A histologic pattern was present in the biopsies of 83% of the patients. The most common presentation (83%) consisted of papules on the trunk; for 62% LyP resolved after a single episode. Twelve percent of the patients developed mycosis fungoides (mean follow-up, 7 years); no other associations were noted. DISCUSSION: Although few series of patients with LyP have been published in recent years, the findings reported generally coincide with our observations. CONCLUSION: LyP is typically a CD30(+) lymphoproliferative disorder that usually runs a benign course and responds well to treatment.

Lymphomatoid papulosis followed by pityriasis lichenoides: a common pathogenesis?

Pityriasis lichenoides (PL) and lymphomatoid papulosis (LyP) are uncommon idiopathic eruptions with overlapping clinical and histological features. Although current opinion indicates that PL and LyP are distinct and separate entities, molecular genetic evidence of T-cell clonality in both conditions suggests that an etiopathogenic relationship may exist. We report a patient who was diagnosed with LyP type B in 1985 followed by PL after 11 years. We hypothesize that LyP followed by PL in the same patient reflects differences in the host immune response to a common antigenic stimulus.

Is immunohistochemical expression of GATA3 helpful in the differential diagnosis of transformed mycosis fungoides and primary cutaneous CD30-positive T cell lymphoproliferative disorders?

Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.

Lymphomatoid papulosis.

Lymphomatoid papulosis (LyP) is a non-aggressive skin disorder characterized by papulonodular injuries, sometimes necrotic, often scattered, relapsing, which frequently regress spontaneously. LyP represents about 12% of cutaneous lymphomas. The etiology of LyP is unknown. Based on its histopathology, in 2018, the World Health Organization (WHO) classified LyP into six types with similar prognosis (A,B,C,D,E and DUSP22). Once the diagnosis of LyP has been made, having an excellent prognosis, this pathology must be managed mainly with a "watch and wait" strategy. Treatment should be given only in the presence of diffuse, symptomatic lesions with disfiguring evolution, with the aim of reducing time of resolution and preventing recurrences or the formation of new lesions.

Evidence linking atopy and staphylococcal superantigens to the pathogenesis of lymphomatoid papulosis, a recurrent CD30+ cutaneous lymphoproliferative disorder.

BACKGROUND: Primary cutaneous CD30+ lymphoproliferative disorders (CD30CLPD) are the second most common type of cutaneous T cell lymphoma (CTCL) and include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL). Case reports and small patient series suggest an association of CD30CLPD with atopic disorders. However, the prevalence of atopy in patients with CD30CLPD in retrospective studies depends on patients' recall which is not always reliable. More objective criteria of atopy include evidence of skin reactivity to allergens (positive prick test) and evidence of allergen-specific IgE in serum. This study was undertaken to test the hypothesis that atopy is prevalent in patients with CD30CLPD using serologic criteria of allergen-specific IgE antibodies to aeroallergens and Staphylococcal aureus enterotoxin superantigens (SSAgs). METHODS: We tested serum samples of CD30CLPD for common IgE-specific airborne allergens with the Phadiatop test, which if positive, is regarded as serologic evidence of atopy in adults. Sera were also tested for IgE antibodies reactive to three Staphylococcal enterotoxins with superantigenic properties (SSAg-IgE). Control sera were obtained from adult subjects evaluated for rhino-sinusitis and a negative Phadiatop test. Patients' history of an atopic disorder was obtained by retrospective chart review. FINDINGS: Nearly 50% of patients with the most common LyP types (A and C) had a positive Phadiatop test for allergic sensitization to common airborne allergens, and total serum IgE (IgE-t) was increased compared to non-atopic controls. At the IgE antibody concentration generally used to define serologic atopy (≥ 0.35 kUA/L), 8/31 (26%) samples of CD30CLPD and 7/28 (25%) samples of LyP were reactive to at least one SSAg-IgE compared to 3/52 (6%) control specimens (P = 0.016 and P = 0.028, respectively). TSST1-IgE was detected in 7 (23%) specimens of CD30CLPD, often together with SEB-IgE; SEA-IgE ≥ 0.35 kUA/L was not detected. For control specimens, TSST1-IgE exceeded the 0.35 kUA/L threshold in 3 (6%) specimens. CONCLUSIONS: Patients with LyP types A and C have serologic evidence of atopy against common airborne antigens and SSAgs when compared to control adult subjects who had rhino-sinusitis and a negative Phadiatop test for aero-IgEs. Serologic evidence of atopy exceeded that determined by LyP patients' personal history. The findings support our hypothesis that an atopic diathesis may contribute to the pathogenesis of the most common types of LyP (A and C).

Primary Cutaneous CD30+ Lymphoproliferative Disorders: a Comprehensive Review.

PURPOSE OF REVIEW: Primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPDs) are the second most common cutaneous lymphomas after mycosis fungoides and Sezary syndrome. They include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP), and borderline lesions. The purpose of this literature review is to consolidate the available evidence on the primary cutaneous CD30+ LPD in order to define the tools for correct diagnosis and appropriate treatment. RECENT FINDINGS: The current body of knowledge regarding the clinical features, histopathologic changes, recently described genetic alterations, and therapeutic options will be covered in this comprehensive review. Primary cutaneous CD30+ LPD represent rare cutaneous lymphomas that have significant histologic overlap within the defined group as well as with other neoplastic and reactive entities. The importance of differentiating these entities is crucial, as each one has a different clinical course and prognosis.