Pseudolymphomas of the skin mimic lymphomas both clinically and histologically. B-cell pseudolymphomas are recognized as a specific entity while T-cell pseudolymphomas are heterogeneous. Disorders as varied as Jessner's lymphocytic infiltrate, lymphomatoid drug eruptions, lymphomatoid contact dermatitis, lymphomatoid photoallergic reactions including actinic reticuloid, and pseudolymphomatous angiokeratoma (also known as acral pseudolymphomatous angiokeratoma of children or APACHE) have been lumped into this latter T-cell category.
- Acral pseudolymphomatous angiokeratoma of children (APACHE)
- Actinic reticuloid
- Contact dermatitis
- Drug eruptions
- Jessner's lymphocytic infiltrate
- Photoallergic dermatitis
B-cell pseudolymphomas (also known as lymphocytoma cutis, lymphadenosis benigna cutis, cutaneous lymphoplasia, cutaneous lymphoid hyperplasia, and Speigler-Fendt sarcoid) usually present as solitary or grouped nodules, on the head, trunk, and extremities, ranging in size from a few millimeters to 5 cm or more. These lesions may resolve spontaneously after a few months but can recur. The disheartening fact is 25% of these "benign" tumors progress on to lymphomas. The reason may be misdiagnosis of the original lesion or development of lymphoma occurring within this lymphocytic proliferation. Sophisticated studies such as polymerase chain reaction have found monoclonal gene rearrangements in up to 14% of cases. However, monoclonality does not guarantee malignant transformation. Nontheless, distinction from a true lymphoma is the most important task for the pathologist.
Pseudolymphomas have been associated with arthropod bites, drug eruptions, chronic contact dermatitis, tattoos, and injections. Lyme disease in Europe has been associated with these lesions occurring on the ears, areola of nipples, and axillary folds. Other benign conditions that should be excluded include secondary syphilis, lupus profundus, and angiolymphoid hyperplasia with eosinophilia.
The histology is composed of nodular collections of B lymphocytes associated with T lymphocytes, plasma cells, histiocytes, and occasional eosinophils. Unlike malignant lymphomas, the infiltrate usually does not destroy the hair follicles and accompanying structures. There is usually no cytologic atypia or necrosis and a grenz zone is usually present.
Disease Associations Clinical Variants Histopathological Features and Variants Prognosis Treatment Commonly Used Terms Internet Links
DISEASE ASSOCIATIONS CHARACTERIZATION MOLLUSCUM CONTAGIOSUM
Cutaneous pseudolymphoma in association with molluscum contagiosum in an elderly patient.
Moreno-Ramirez D, Garcia-Escudero A, Rios-Martin JJ, Herrera-Saval A, Camacho F.
Department of Dermatology, and Department of Pathology, Universitary Hospital Virgen Macarena, Seville, Spain.
J Cutan Pathol. 2003 Aug;30(7):473-5. Abstract quote
BACKGROUND: Molluscum contagiosum (MC) is a common cutaneous infection, which has been reported in association with cutaneous pseudolymphoma in few cases.
METHODS: A 72-year-old woman with a nodule arising on the external canthus was reviewed. The lesion was surgically removed, and the histopathological study demonstrated an epidermal invagination filled by molluscum bodies and a diffuse infiltrate comprising atypical lymphocytes.
RESULTS: Immunohistochemical stains disclosed predominance of T cells with positive CD30 labeling. Polymerase chain reaction failed to demonstrate clonal rearrangement of the T-cell receptor.
CONCLUSION: After ruling out systemic involvement, the patient was followed up for 2 years with no evidence of recurrence. We report this case to the best of our knowledge and discuss the literature about atypical clinical and histological presentations of MC.
- Am J Dermatopathol. 2006 Oct;28(5):438-41 Abstract quote
Lymphomatoid contact dermatitis is a form of pseudolymphoma that was first described in 1976 by Orbaneja et al. Since that initial report, a number of allergens have been reported to cause this type of pseudolymphoma. Most cases involve hyperplasia of T cells.
We describe a case of cutaneous B-cell pseudolymphoma due to paraphenylenediamine. This report underscores the importance of thorough history and observation when assessing patients with suspected lymphoproliferative processes.
- Vaccination-induced cutaneous pseudolymphoma.
Maubec E, Pinquier L, Viguier M, Caux F, Amsler E, Aractingi S, Chafi H, Janin A, Cayuela JM, Dubertret L, Authier FJ, Bachelez H.
Institut de Recherche sur la Peau, Universite Paris 7, Paris, France.
J Am Acad Dermatol. 2005 Apr;52(4):623-9. Abstract quote
BACKGROUND: Although mild early cutaneous transient reactions to vaccinations are common, late-onset chronic lesions have been scarcely reported. We report herein a series of 9 patients presenting with cutaneous and subcutaneous pseudolymphoma.
OBSERVATIONS: Nine patients presenting with late-onset, chronic skin lesions occurring at the site of antihepatitis B (8 cases) and antihepatitis A (one case) vaccination were reported. Histopathologic and immunohistochemic studies, and molecular analysis of clonality of skin biopsy specimens, were performed. Furthermore, the presence of vaccine products was investigated in skin lesions by using histochemical, microanalytic, and electronic microscopy techniques.
RESULTS: Histopathologic studies showed dermal and hypodermal lymphocytic follicular infiltrates with germinal center formation. The center of follicles was mostly composed of B cells without atypia, whereas CD4+ T cells were predominant at the periphery. Molecular analysis of clonality revealed a polyclonal pattern of B-cell and T-cell subsets. Aluminium deposits were evidenced in all cases by using histochemical staining in all cases, and by microanalysis and ultrastructural studies in one case. Associated manifestations were vitiligo (one case) and chronic fatigue with myalgia (two cases).
CONCLUSION: Cutaneous lymphoid hyperplasia is a potential adverse effect of vaccinations including aluminium hydroxide as an adjuvant. Further prospective studies are warranted to evaluate the incidence of this complication in the immunized population.
Am J Dermatopathol. 2005 Oct;27(5):411-7. Abstract quote
Post herpes zoster (HZ) reactions have been associated with panoply of neoplastic, inflammatory, and fibro-inflammatory cutaneous disorders. Varicella zoster virus (VZV) DNA has not been identified in most of these reports.
After an episode of HZ, a healthy, active 90-year-old female developed ulcerative nodules in the affected trigeminal V1 dermatome and the contra-lateral trigeminal region over a 1-year period. Excision and/or biopsy of all these lesions showed similar pathologic changes that consisted of herpetic folliculitis, adjacent dense mixed nodular lymphocytic infiltrates with germinal centers (cutaneous lymphoid hyperplasia (CLH)), and in the deeper excision specimens, an obliterative vasculitis of a vessel with smooth muscle in its wall. Immunophenotype analysis revealed a mixed, predominate T- and B-cell population without loss of pan-T cell antigens or aberrant expression by B cells of T-cell antigens. Polymerase chain reaction for herpetic DNA was positive for VZV DNA. Lymphocyte gene rearrangement analysis revealed 2 distinct, anatomically and chronologically, monoclonal B-cell populations and a monoclonal T-cell population in one nodule. Treatment with valacyclovir has lead to almost complete resolution of her cutaneous nodules after 6 months of therapy.
In this case, it can be surmised that persistence of VZV infection and lack of effective cell-mediated immunity lead to development of both immunopathology (vasculitis) and excessive lymphoid cell proliferation (CLH).
CLINICAL VARIANTS CHARACTERIZATION NIPPLE
- Cutaneous lymphoid hyperplasia and other lymphoid infiltrates of the breast nipple: a retrospective clinicopathologic study of fifty-six patients.
Boudova L, Kazakov DV, Sima R, Vanecek T, Torlakovic E, Lamovec J, Kutzner H, Szepe P, Plank L, Bouda J, Hes O, Mukensnabl P, Michal M.
Department of Pathology, Medical Faculty Hospital, Charles University, Pilsen, Czech Republic.
Am J Dermatopathol. 2005 Oct;27(5):375-86. Abstract quote
This study characterizes the clinicopathological spectrum of lymphoproliferations involving the breast nipple and/or areola.
Morphologic, immunohistochemical, molecular-genetic, and clinical features of 58 specimens from 56 patients were analyzed. They were re-diagnosed as cutaneous lymphoid hyperplasia (CLH, n = 44); other benign lymphoid infiltrates (OBLI, n = 8); peripheral T-cell lymphoma, not otherwise specified (n = 1); cases with overlapping features of CLH and B-cell lymphoma (n = 3), one of them composed of spindle cells.
Cutaneous lymphoid hyperplasia infiltrates were dense, composed mainly of B cells forming follicles with germinal centers (GC). Cutaneous lymphoid hyperplasia frequently showed features suggesting a malignancy as coalescing follicles with non-polarized germinal centers lacking mantle zones, and smudged infiltrates of lymphoid cells spreading into collagen (often as "Indian files"), smooth muscle, vessel walls, and nerve sheaths. Only two cutaneous lymphoid hyperplasias recurred; otherwise all patients are without disease (mean follow-up 62 months). Monoclonal rearrangement of immunoglobulin heavy chain gene was detected in five, and of T-cell receptor gamma gene in two cutaneous lymphoid hyperplasias using polymerase chain reaction (PCR), but the patients fared well too. In 47% of cases Borrelia burgdorferi was detected by polymerase chain reaction and/or serology, of which one was monoclonal.
We conclude that cutaneous lymphoid hyperplasia is the most common lymphoproliferation of the breast nipple, rarely recognized clinically, and often overdiagnosed histologically as lymphoma.
HISTOPATHOLOGY CHARACTERIZATION GENERAL
- A review of 55 cases of cutaneous lymphoid hyperplasia: Reassessment of the histopathologic findings leading to reclassification of 4 lesions as cutaneous marginal zone lymphoma and 19 as pseudolymphomatous folliculitis.
Arai E, Shimizu M, Hirose T.
Hum Pathol. 2005 May;36(5):505-11. Abstract quote
Summary To clarify the confusion surrounding the diagnosis of cutaneous lymphoid hyperplasia (CLH) that was formerly described as lymphadenosis benigna cutis, lymphocytoma cutis, or lymphocytic infiltration of Jessner and to assess whether newly recognized diagnoses, such as cutaneous marginal zone lymphoma and pseudolymphomatous folliculitis (PLF), may have been overlooked, we reexamined 55 Japanese cases of nonepidermotropic lymphoproliferative disorder that had previously been diagnosed as "cutaneous pseudolymphoma."
In all these cases, the immunohistochemical expressions of CD1a, CD3, CD4, CD8, CD20, CD21, CD30, CD43, CD56, CD68, CD79a, kappa and lambda chains, S-100 protein, and latent membrane protein were assessed. In addition, in 13 cases the gene rearrangement of the immunoglobulin heavy chain was investigated using a polymerase chain reaction method.
As a result of these investigations, we have identified 4 cases of cutaneous marginal zone lymphoma, 19 cases of PLF, 1 case of diffuse large B-cell lymphoma, and 2 cases of solitary nonepidermotropic pseudo-T-cell lymphoma, with the remaining 29 cases being CLH. Cutaneous marginal zone lymphoma, which represented 7.3% of the total, was distinguished from CLH by the presence of patchy or diffuse proliferation of centrocyte-like cells, plasma cells at the periphery of the lymphocytic infiltration, monotypic restriction of the light chains, and gene rearrangement of the immunoglobulin heavy chain.
Pseudolymphomatous folliculitis was identified by the presence of activated pilosebaceous units with abundant CD1a-and S-100 protein-positive T-cell-activated dendritic cells. Of the cases that were reassessed, 34.5% were PLF.
VARIANTS CUTANEOUS LYMPHOID HYPERPLASIA
Cutaneous lymphoid hyperplasia: A lymphoproliferative continuum with lymphomatous potential.
Nihal M, Mikkola D, Horvath N, Gilliam AC, Stevens SR, Spiro TP, Cooper KD, Wood GS.
Hum Pathol. 2003 Jun;34(6):617-22. Abstract quote
Cutaneous lymphoid hyperplasia (CLH) has been proposed to be the benign end of a continuum of lymphoproliferative disorders with cutaneous lymphoma at its malignant extreme. An intermediate condition, known as "clonal CLH," was first recognized by us and shown to be a transitional state capable of eventuating in overt lymphoma.
To better determine the prevalence of dominant clonality and risk of lymphoma among CLH cases, we studied the immunohistology and clonality of fresh-frozen samples from 44 CLH patients referred to a multidisciplinary cutaneous lymphoproliferative disorders program. Using a large panel of lymphoid markers, the cases were divided into 38 typical mixed B-cell/T-cell type CLH and 6 T-cell-rich type (T-CLH), the latter containing > 90% T cells. Of the 44 patients, 38 had solitary or localized lesions (4 cases of T-CLH), and 6 had regional/generalized lesions (2 cases of T-CLH). Forty cases were of idiopathic etiology.
Suspected etiologies among 4 other cases included mercuric tattoo pigment, doxepin, clozapine, and bacterial infection. Immunoglobulin heavy chain (IgH) and T-cell receptor (TCR)-gamma gene rearrangements (GR) were studied using polymerase chain reaction assays, which are approximately 80% sensitive. Overall, 27 cases (61%) showed clonal CLH: 12 IgH+ (27%; 3 cases of T-CLH); 13 TCR+ (30%; 1 case of T-CLH); and 2 IgH+/TCR+ (4%; neither case was T-CLH). Two cases (4%; 1 case of T-CLH) progressed to cutaneous B-cell lymphoma. Both of these patients presented with regional lesions.
Our findings indicate that clonal overgrowth is common in CLH, links CLH to lymphoma, and probably involves both B- and T-cell lineages (although TCR GR by B cells and vice versa could not be ruled out). The high prevalence of dominant clonality in our series may have resulted from the sensitivity of our PCR assays as well as patient selection.
- Lymphomatoid keratosis: an epidermotropic type of cutaneous lymphoid hyperplasia: clinicopathological, immunohistochemical, and molecular biological study of 6 cases.
Author Affiliations: Departments of Pathology and Dermatology, and Department of Dermatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
- Arch Dermatol. 2007 Jan;143(1):53-9. Abstract quote
OBJECTIVE: To provide evidence that lymphomatoid keratosis should be categorized as an epidermotropic subtype of cutaneous lymphoid hyperplasia.
DESIGN: Clinicopathological, immunohistochemical, and molecular biological studies of epidermotropic and dermal bandlike infiltrates of lymphocytes without necrotic keratinocytes, Civatte bodies, or Max-Joseph spaces and solar lentigo or seborrheic keratosis adjacent to the lesion, but with epidermal hyperplastic change (clinically scaly plaque) in cases of lymphomatoid keratosis. Conventional histopathologic study as well as immunohistochemical examinations for CD1a, CD3, CD4, CD8, CD20, and CD79a and S100 protein and genotypic examinations were performed.
SETTING: University departments comprising 2 sections of dermatology and 1 section of pathology.
MAIN OUTCOME MEASURES: Ratio of T to B cells and of CD4(+) to CD8(+) cells, and the phenotype of epidermotropic cells were evaluated. Gene rearrangement of the immunoglobulin heavy chain gene and T-cell receptor (TCR)-beta and TCRgamma genes was also investigated by the polymerase chain reaction method.
RESULTS: Immunohistochemically, epidermotropic CD20(+) and/or CD79a(+) cells were present. In the upper dermal lymphocytic infiltrates, the CD3(+)/CD79a(+) cell ratio ranged from 5:5 to 8:2. The CD4(+)/CD8(+) cell ratio was within normal limits. Rearrangements of the TCRgamma gene were demonstrated in 2 cases and of the TCRbeta gene in 1 case.
CONCLUSIONS: Our results indicate that lymphomatoid keratosis is a clinically benign keratotic lesion but histologically malignant, simulating mycosis fungoides. Immunohistochemical findings showed a reaction pattern in all cases, but genotypical examination showed some clonal dermatoses. Therefore, "lymphomatoid" keratosis should be classed as a pseudolymphoma, namely, a subtype of cutaneous lymphoid hyperplasia with epidermotropism.
PALPABLE ARCIFORM MIGRATORY ERYTHEMA
Palpable arciform migratory erythema in an HIV patient, a CD8 pseudolymphoma.
Muche JM, Toppe E, Sterry W, Haas N.
Department of Dermatology and Allergy, Charite, Humboldt-University Berlin, Berlin, Germany.
J Cutan Pathol. 2004 May;31(5):379-82. Abstract quote
Background: Palpable arciform migratory erythema (PAME) is characterized by large, elevated, reddish annular lesions localized on the upper trunk. As its infiltrate consists predominantly of dense infiltrates of CD4(+) lymphocytes with polyclonal T-cell receptor (TCR) gene rearrangement, it has been grouped as a rare member of the T-cell pseudolymphomas.
Methods: We performed histology, immunophenotyping, and TCR-gamma gene rearrangement studies in an human immunodeficiency virus (HIV)-positive patient, CDC stage IIIB, who showed a clinically typical PAME.
Results: While TCR-gamma gene rearrangement studies showed a polyclonal infiltrate confirming a pseudolymphoma, 85% of skin-infiltrating lymphocytes were CD8(+) T cells.
Conclusion: PAME may also occur in HIV-positive patients with CD4(+) deficiency. Our case demonstrates that regular CD4 counts and immunocompetence are not necessary for its pathogenesis.
TREATMENT AND PROGNOSIS CHARACTERIZATION PROGNOSIS CLONALITY
Heavy multinodular cutaneous lymphoid infiltrates: clinicopathologic features and B-cell clonality.
Ceballos KM, Gascoyne RD, Martinka M, Trotter MJ.
Department of Pathology, Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia, Canada, Department of Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada, and Department of Pathology, Calgary Laboratory Services, University of Calgary, Calgary, Alberta, Canada.
J Cutan Pathol 2002 Mar;29(3):159-167 Abstract quote
BACKGROUND: Criteria for distinguishing between cutaneous lymphoid hyperplasia (CLH) and low-grade B-cell lymphoma are not well defined. We examined the hypothesis that the presence of a clonal B-cell population in heavy multinodular lymphoid infiltrates correlates with clinical presentation and outcome.
METHODS: We identified 29 patients with skin lesions characterized histologically by a heavy dermal lymphocytic infiltrate with a multinodular architecture and extension into deep dermis and subcutaneous fat. Clonality was assessed immunophenotypically by light-chain restriction and also by analysis for IgH-gene rearrangement using PCR on DNA extracted from paraffin blocks.
RESULTS: Follow-up (mean 80 months; median 45 months) was obtained in all patients. Twenty-four patients (83%) presented with a solitary lesion: only four had solitary recurrences, and none developed multiple synchronous lesions or systemic B-cell lymphoma. However, 9/24 of these solitary lesions (38%) were clonal by light-chain restriction or IgH PCR; 5/29 patients (17%) presented with multiple recurrent lesions and continued to develop lesions during the period of follow-up; 3/5 patients (60%) with multiple lesions demonstrated a B-cell clone. No patient developed systemic B-cell lymphoma.
CONCLUSIONS: Heavy, multinodular cutaneous lymphoid infiltrates have an excellent prognosis. Multiple lesions at presentation are the best predictor of recurrent multiple lesions confined to the skin. The presence of a clonal B-cell population does not correlate with clinical presentation or histology, nor does it predict development of further lesions or systemic lymphoma.
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