Cutaneous Lymphoid Infiltrates Research Articles

Inflammatory dermatoses mimicking malignancy (pseudolymphoma)

Interpretation of cutaneous lymphoid infiltrates is one of the most troublesome areas of diagnostic dermatopathology. The term ‘pseudolymphoma’ has been used to classify cases of benign lymphoid infiltrates that mimic lymphoid malignancy. Pseudolymphomas can be categorized according to predominant cell type (B cell, T cell and mixed) and pattern of inflammation (including band-like and nodular). Examples of T-cell, B-cell and mixed pattern pseudolymphomas are illustrated, including solitary pseudolymphomatoid lichenoid lesion, pseudolymphomatoid drug reaction, immunosuppression-associated lymphoproliferative disorder and lymphocytoma cutis. The majority of cases can be diagnosed and managed on the basis of clinical history, light microscopic findings and follow-up. In difficult cases, the usefulness and limitations of immunohistochemistry and molecular studies are discussed. The light microscopic, immunohistochemical and molecular features should be interpreted in the context of the clinical information, with direct discussion between dermatologist and histopathologist in difficult cases.

Inflammatory Dermatopathology

CD30 is a marker of lymphoid activation that is characteristically expressed in lymphoproliferative disorders such as anaplastic large cell lymphoma (ALCL), lymphomatoid papulosis (LyP) and Hodgkin lymphoma, but also in other T- and B-cell lymphomas, and in cutaneous lymphoid hyperplasia. However, CD30 expression can also be found in a wide variety of inflammatory and infectious skin conditions including immune-mediated disorders (eg, atopic dermatitis, pityriasis lichenoides, scleroderma, graft versus host disease), drug reactions (eg, antibiotics, chemotherapeutic agents), viral infections (eg, molluscum contagiosum, parapoxvirus, herpes simplex virus, human immunodeficiency virus), bacterial and fungal infections (eg, abscesses, cellulitis, chromomycosis), environmental conditions (eg, scabies, insect and spider bites), peritumoral host responses (eg, basal cell carcinoma, cutaneous lymphadenoma) and in other miscellaneous disorders (eg, hidradenitis suppurativa, ruptured cysts, pressure ulcers, granulation tissue). Moreover, CD30 expression can also be found in nonhematolymphoid cells such as germ cells and mesothelial cells. In inflammatory skin conditions, atypical CD30+ lymphoid cells may cause differential diagnostic problems with CD30+ lymphoproliferative disorders. It is obvious that the sole presence of CD30+ atypical cells in the skin can not in itself support a malignant diagnosis. The differentiation between benign and malignant cutaneous lymphoid infiltrates is only possible through the combined use of multiple clinical, histologic, immunophenotypic and molecular genetic analyses, as there is no single reliable criterion that would allow this distinction. Large atypical CD30+ lymphoid cells are a part of cutaneous reactive infiltrates and do not qualify alone for the diagnosis of malignancy.

Contribution of Flow Cytometry in the Diagnosis of Cutaneous Lymphoid Lesions

The histologic diagnosis of cutaneous lymphoid lesions remains one of the most challenging areas of dermatopathology and is augmented by incorporation of immunophenotypic and genotypic data. To improve the analysis of surface Ig light chain expression and to increase the yield of immunophenotypic data obtained from skin biopsies, we evaluated the utility of flow cytometry in cutaneous lymphoid infiltrates. Flow cytometric immunophenotypic analyses were performed on skin specimens of 19 patients as a part of diagnostic procedures. We found that skin biopsy specimens, including a routine punch biopsy, yield sufficient material for diagnostic flow cytometry. One reactive lymphoid hyperplasia showed polyclonal B cells and no aberrant T cell populations. Ig light chain restriction was detected by flow cytometry and contributed to the diagnosis in 88% (15 of 17) of cutaneous primary or secondary B cell lymphomas, compared to 37% (three of eight) by immunohistochemistry. Nearly one-third of these cases were histologically suspicious but difficult lesions due to processing artifact, mixed cellular infiltrate, or paucity of abnormal cells. Additional markers (3-23) were analyzed by flow cytometry on 15 specimens, and contributed to subclassification of the lymphomas. Our experience demonstrates that flow cytometry can be successfully applied to routine skin biopsies and contributes to the diagnosis and subclassification of cutaneous lymphoid lesions.

Automated kappa and lambda light chain mRNA expression for the assessment of B-cell clonality in cutaneous B-cell infiltrates: its utility and diagnostic application.

Primary cutaneous B-cell lymphoma (1 degrees CBCL) accounts for 25% of all lymphomas. The difficulty in distinction of reactive from neoplastic B-cell infiltrates prompts the use of molecular diagnostic adjuncts. While T-cell clonality can be seen in various reactive states, clonal B-cell infiltrates are often neoplastic; standard assays employed include polymerase chain reaction (PCR) or Southern blot analysis to assess heavy chain rearrangement. We sought to assess the utility of kappa (kappa) and lambda (lambda) mRNA expression using the Ventana automated assay (Ventana Medical Systems, Tucson, AZ, USA) in the analysis of atypical cutaneous B-cell lymphoid infiltrates. Multiple 4 micro m sections of paraffin-embedded, formalin-fixed skin biopsies from 31 patients with CBCL were placed on silane-coated slides, deparaffinized, then digested in pepsin (5 mg/ml) for 30 min at 37 degrees C. Fluorescein-tagged oligoprobes and tissue mRNA were denatured at 80 degrees C for 5 min, hybridized for 2 h at 37 degrees C, and incubated with antifluorescein alkaline phosphatase conjugates. Detection of the probe target complex employed nitroblue tetrazolium and bromochloroindolyl phosphate conjugates with a nuclear fast red counterstain. A kappa : lambda ratio > 3 : 1 was held to represent kappa light chain restriction and a kappa : lambda ratio </= 1 : 1 to indicate lambda light chain restriction. The diagnosis in each case was determined by careful integration of clinical, histologic, and phenotypic data. The diagnoses included: pseudolymphoma (PL), marginal zone lymphoma (MZL), 1 degrees CBCL of the trunk, scalp or leg, 2 degrees lymphoma, and plasma cell dyscrasia. All but one case of lymphoma were light chain restricted. All cases of PL were proven to be polyclonal by this methodology. In non-plasmacytic small cell lymphomas, only 5-10% of the infiltrate expressed kappa or lambda, with clonality established through the abnormal kappa : lambda ratio. Interpretations were most difficult in the 2 degrees small cell-dominant follicular center cell lymphomas and easiest in cases with significant plasmacytic differentiation (i.e. MZL, immunocytomas, or plasma cell dyscrasias). The Ventana kappa/lambda assay is a reliable, quick, and inexpensive way to determine B-cell clonality in cutaneous lymphoid infiltrates in paraffin-embedded formalin-fixed tissue.

CD30 antigen expression in cutaneous inflammatory infiltrates of scabies: a dynamic immunophenotypic pattern that should be distinguished from lymphomatoid papulosis.

Expression of CD30 antigen is a distinct marker of lymphocyte activation that was originally described in the Reed-Sternberg cells of Hodgkin's disease. The observation of CD30+ cells has been considered a diagnostic feature of cutaneous CD30 lymphoid proliferations. However, CD30 expression has also been reported in some cutaneous benign inflammatory infiltrates. Eleven skin biopsies from patients with scabies were double-blindly and retrospectively analysed. A panel of histopathological parameters and immunophenotypic expression of CD4, CD8, CD30 and S-100 antigens was studied. CD30 and S-100 antigens expression were related to clinical features. Large CD30+ cells were demonstrated in eight (8/11) biopsies, corresponding to patients with long-standing lesions (3 months or longer). However, no expression of the CD30 antigen was observed in all biopsy specimens (3/11) corresponding to early lesions (2 months or less). The presence of S-100 positive cells in the papillary dermis was an almost constant feature. CD30+ large cells seem to be a common feature in long-standing infiltrates of scabies. CD30 expression in scattered cells of a cutaneous lymphoid infiltrate cannot be assessed as a strong diagnostic argument of neoplastic cutaneous CD30+ lymphoid proliferation (lymphomatoid papulosis/cutaneous CD30+ lymphoma). Therefore, the possibility that large atypical CD30+ cells may be also present in several benign inflammatory diseases should be always considered.

Heavy multinodular cutaneous lymphoid infiltrates: clinicopathologic features and B-cell clonality.

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. 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. 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. 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.

Impact of molecular analysis in the diagnosis of cutaneous lymphoid infiltrates.

The diagnosis and classification of cutaneous lymphomas is a challenge for the dermatopathologist. This is particularly true for determining the distinction between a malignant lymphoma and a benign reactive infiltrate (pseudolymphoma). Recent advances in molecular genetics, as the determination of clonality of lymphoid infiltrates, have emerged as an important tool to overcome these diagnostic dilemmas. In our experience, more than 90% of cutaneous T-cell lymphomas have a rearrangement of the T-cell receptor gamma chain gene, whereas clonal rearrangements in cutaneous T-cell pseudolymphomas could not be found. However, the demonstration of clonality does not necessarily indicate malignancy. There have been several reports that have identified clonal lymphoid proliferations in pityriasis lichenoides et varioliformis acuta, pseudolymphomas, and lichen planus. For this reason one must carefully evaluate the information that is provided by these techniques. The results should always correlate with clinical, histologic, and immunophenotypic data to achieve the correct diagnosis.

Cutaneous lymphoid hyperplasias.

Benign hyperplastic lymphoid infiltrates of the skin (pseudolymphoma, older term) simulate lymphoma clinically and histologically. They can be divided into B-cell predominant (typical cutaneous lymphoid hyperplasia (CLH), angiolymphoid hyperplasia, Kimura's disease, and Castleman's disease) and T-cell predominant (T-cell CLH, lymphomatoid contact dermatitis, and lymphomatoid drug eruption). Both types may represent exaggerated reactions to diverse external antigens (insect bite, tattoo, zoster, trauma, among others). A composite assessment of clinical presentation and behavior, routine histology, immunophenotyping, and molecular studies is essential for the diagnosis of benign cutaneous lymphoid infiltrates. Treatment includes antibiotics, intralesional and systemic corticosteroids, excision, radiotherapy, and immunosuppressants. Treatment depends on the assessment and biologic behavior, which is usually benign. Molecular biologic analysis has shown that a significant proportion of cases harbor occult B- or T-cell clones (clonal CLH). Progression to overt cutaneous lymphoma has been observed in a minority of cases. Patients with clonal populations of B or T cells and persistent lesions should be closely observed for emergence of a lymphoma.

Impact of Molecular Analysis in the Diagnosis of Cutaneous Lymphoid Infiltrates

Impact of Molecular Analysis in the Diagnosis of Cutaneous Lymphoid Infiltrates

Detection of Clonally Restricted Immunoglobulin Heavy Chain Gene Rearrangements in Normal and Lesional Skin: Analysis of the B Cell Component of the Skin-Associated Lymphoid Tissue and Implications for the Molecular Diagnosis of Cutaneous B Cell Lymphomas

A monoclonal B cell population is the hallmark of B cell neoplasms including cutaneous B cell lymphomas (CBCLs). We modified and tested several polymerase chain reaction (PCR)-based assays involving amplification of immunoglobulin heavy chain (IgH) gene rearrangements to optimize assays specifically for cutaneous lymphoid infiltrates. We achieved greatest sensitivity with an assay employing IgH consensus primers complementary to the framework 3 portion of the upstream variable region and the downstream joining region. We studied 12 CBCLs, 6 nodal lymphomas and 7 cell lines. In 17/25 of these B cell neoplasms (84%), we detected one or two dominant bands, consistent with one or both IgH alleles being rearranged in the neoplastic B cell clone. As expected, IgH PCR assays produced diffuse smears in agarose gels or complex ladders in polyacrylamide gels when polyclonal B cell controls (blood and tonsil) were analyzed. However, in normal skin and non-CBCL skin lesions, one or a small number of discrete bands were sometimes detected. In certain cases, this made it difficult to distinguish true positives (monoclonal CBCL) from false positives (clonally restricted benign B cells). Correlation with immunophenotyping confirmed that false positive results were confined to samples with sparse or immunohistologically undetectable B cell infiltrates. Pseudoclonal bands showed variable sizes in repeat PCR reactions and could be distinguished from monoclonal bands by polyacrylamide gel electrophoresis of pooled triplicate PCR products. These findings suggest that molecular diagnosis using IgH PCR assays is best suited for B-cell-rich infiltrates, and can be problematic when applied to suspected T-cell-rich CBCLs, cutaneous T cell lymphomas, or other lesions containing only few B cells unless one is cognizant of the potential pitfalls. Furthermore, these results demonstrate the presence of rare B cells in normal skin and immunohistologically defined cutaneous T cell infiltrates. This correlates with recent reports of sparse B cells within the lymph draining from normal skin and may represent molecular evidence for a trafficking B cell component of the skin-associated lymphoid tissue (SALT). It also suggests a candidate B cell subset for the pathogenesis of cutaneous lymphoid hyperplasia and CBCLs.

Analysis of clonality of atypical cutaneous lymphoid infiltrates associated with drug therapy by PCR/DGGE

Atypical lymphocytic infiltrates that mimic cutaneous lymphoma (ie, pseudolymphoma) are often observed in skin biopsy specimens from patients with altered immune function. The latter may reflect systemic immune dysregulatory states such as collagen vascular disease or human immunodeficiency virus infection. Among the iatrogenic causes are drug therapy with agents that abrogate lymphocyte function. These drugs encompass the anticonvulsants, antidepressants, phenothiazines, calcium channel blockers, and angiotensin-converting enzyme inhibitors. The appellation of lymphomatoid hypersensitivity reaction has been applied to cases of drug-associated pseudolymphoma. Pathologically and clinically, the distinction of such cases from cutaneous lymphoma is difficult. We employed the polymerase chain reaction (PCR) on archival material of proven drug-associated lymphomatoid hypersensitivity reactions both to explore its utility as an adjunct in diagnosis and to investigate the genotypic aberrations induced by drug therapy. Formalun-fixed, paraffin-embedded biopsy specimens from seven cutaneous T-cell lymphomas (CTCL), one noda T-cell lymphoma, two cutaneous B-cell lymphomas, three typical hypersensitivity reactions, one tonsil, and 14 lymphomatoid hypersensitivity reactions were studied. Control cases for which DNA derived from fresh tissue was used include the Jurkat T-cell tumor line, placenta, one noda B-cell lymphoma, and one case of reactive lymph node hyperplasia. DNA was obtained and purified by standard methods, then amplified with oligonucleotide primers specific for the T-cell receptor gamma locus and the immunoglobulin heavy chain genes. T-cell amplicons were analyzed by denaturing gradient gel electrophoresis (DGGE) and B-cell amplicons by either nondenaturing polyacrylamide or agarose gel electrophoresis. The nodal and Jurkat T-cell lymphomas, six of seven CTCL, one cutaneous B-cell lymphoma, and 2 of 14 lymphomatoid hypersensitivity reactions showed dominant (“monoclonal”) T-cell gene rearrangement patterns, and the remainder of cases were polyclonal. A causal relationship between drug therapy and skin eruption was ascertained in the two patients showing T-cell rearrangements, and both experienced complete and sustained lesional resolution on discontinuation of the implicated drug. The only immunoglobulin heavy chain gene rearrangements detected by PCR were in two of the three B-cell lymphomas. We conclude that PCR/DGGE is a powerful method for assaying T-cell clonality in archival tissue and can aid in the discrimination of reactive from malignant cutaneous infiltrates with appropriate clinicopathologic correlation. Recognition that a monoclonal TCRγ rearrangement can be observed in cases of drug-associated lymphomatoid hypersensitivity may help in avoiding a misdiagnosis of malignant lymphoma.

Follicular mucinosis presenting as an acneiform eruption: Report of four cases

Follicular mucinosis can be a primary idiopathic disease or a secondary disease associated with lymphoma. When it appears in childhood or adolescence, it is usually primary and self-limited. We describe four cases of follicular mucinosis occurring in early adulthood that have had protracted courses. Each presented as an unusual acneiform eruption. Two of the cases demonstrated a clonal genetic rearrangement of the T-cell receptor within the cutaneous lymphoid infiltrate, a finding not previously reported. Although its significance is not clear, the clonal lymphocytic expansion indicates a need for continued surveillance of these patients. (J Am Acad Dermatol 1998;38:849-51.)

Spontaneous regression of granulomatous mycosis fungoides in an HIV positive patient

The development of mycosis fungoides in HIV-positive patients is uncommon. We describe the granulomatous type of mycosis fungoides in an HIV-positive patient whose cutaneous lesions regressed without treatment. In addition to HIV seropositivity and mycosis fungoides, he had a long history of pulmonary sarcoidosis. Immunophenotyping of the cutaneous lymphoid infiltrates revealed a predominance of CD4 + T cells, and monoclonality was demonstrated by T-cell gene rearrangement studies. The regression of mycosis fungoides in this patient was associated with a falling peripheral blood CD4 T-cell count. (J Am Acad Dermatol 1997:37:876-80.)

Losartan-associated atypical cutaneous lymphoid hyperplasia

Drug hypersensitivity reactions can induce an atypical lymphoid infiltrate ranging from a benign condition to a malignant lymphoma. Here we describe two patients in whom atypical cutaneous lymphoid infiltrates developed while they were receiving losartan, an angiotensin II inhibitor. Drug hypersensitivity reactions can induce an atypical lymphoid infiltrate ranging from a benign condition to a malignant lymphoma. Here we describe two patients in whom atypical cutaneous lymphoid infiltrates developed while they were receiving losartan, an angiotensin II inhibitor.

T-cell receptor gene rearrangement analysis in the primary cutaneous T-cell lymphoma

Object: The present paper is to evaluate the significance of T-cell receptor (TCR) gene rearrangements in primary cutaneous T-cell lymphomas (PCTCL) as detected by analysis of Southern Blot (SBA) and polymerase chain reaction (PCR). Patients and Methods: Skin specimens and peripheral blood samples were taken from 44 patients with PCTCL, including 30 patients with mycosis fungoides (MF), 2 patients with Sezary's syndrome (SS), and 12 patients with PCTCL other than MF and SS (PNCTCL). 11 patients with a presumptive diagnosis of MF, 23 patients with lymphoproliferative dermatoses including lymphomatoid papulosis (LyP) and 8 patients with benign cutaneous lymphoid infiltrates were simultaneously studied by the ampfification of junctional V (variable)-J (joining) sequences of the rearranged TCR T genes by PCR(TCRγPCR) and the analysis of TCRβ-chain genes by SBA(TCRβSBA) for detection of clonal gene rearrangements (GR). One lymph node specimen of a case with MF IIA was also detected by TCRγPCR and TCRβSBA. Results: In MF, GR were detected by TCRγPCR and TCRβSBA[3 in 83.3- 85.7% and 66.7%-71.4% of skin specimens of cases IIAliB and in 57.1%-70.0% and 14.3%-10.0% of those of cases IA-IB, respectively. GR were seen in 66.7%- 71.4% and 33.3%-43.0.% of blood samples of cases IIAliB, and 42.9%-40.0% and 0-10.0% of those of cases IAIB, respectively. GR was confirmed by TCRγPCR and TCRβSBA in one lymph node showing dermatopathic lymphadenopathy of a case with MF IIA. In 11 patients of clinically suspected MF, GR were present in skin specimens of 5 cases (45.4%) and in blood samples of 3 cases (27.3%) by TCRγPCR. In PNCTCL, GR were found in 9 skin specimens (90.0%) from 10 patients detected by TCRγPCR and in 6 skin specimens (75.0%) from 8 patients detected by TCRβSBA. GR were also seen in 6 blood samples (72.8%) from 11 patients detected by TCRγPCR, and in 7 blood samples (70.0%) from 10 patients by TCRβSBA. In SS and LyP, GR were detected by TCRγPCR and TCRβSBA in each of the two skin specimens of two cases with LyP and in each of the two blood samples of two cases with SS. GR were seen in one skin specimen of one case with SS and one blood sample of one case with LyP detected by TCRγPCR. Conclusions: This study demonstrated that TCRγPCR is a rapid, more sensitive tool than TCRβSBA, can be used in the analysis of T-cell clonality in skin, lymph node and blood samples of patients with PCTCL and indicated that this method forms a useful supplement to other methods for diagnosis of early and suspected MF, confirmation of PNCTCL and determination of extracutaneous involvement of lymph node and blood.

Assessment of Clonality in Cutaneous Lymphoid Infiltrates by Polymerase Chain Reaction Analysis of Immunoglobulin Heavy Chain Gene Rearrangement

Determination of the biologic potential of cutaneous lymphoid infiltrates may be difficult by standard histologic or immunohistologic examination. The polymerase chain reaction (PCR) has been used to document clonal rearrangements of the immunoglobulin heavy chain gene in paraffin-embedded fixed tissues. To explore the value of PCR in evaluation of cutaneous lymphoid infiltrates, 93 archival nonmycotic lymphoid lesions (28 small or mixed lymphocytic lymphomas, 15 large cell lymphomas, 40 benign infiltrates, and 10 with atypical features) were analyzed. These cases had been previously immunophenotyped on paraffin sections, and clinical follow-up from 7 to 20 years was gathered. DNA products were generated using a seminested PCR technique, separated by 5% polyacrylamide gel electrophoresis, stained with ethidium bromide, and visualized under UV light. Cases with a 100- to 120-base pair band were scored as positive. Of the 28 small or mixed cell lymphomas, 23 had a B-cell immunophenotype or consisted of a mixture of B and T cells; of these, seven (30%) demonstrated a monoclonal pattern, and three (13%) were indeterminate. Twelve large cell cases were B-cell or mixed; five (42%) of these were positive for a monoclonal band, while four (33%) were indeterminate. None of five T-cell small cell or three T-cell large cell lymphomas demonstrated a monoclonal band. In contrast, 39 of the 40 benign cases were T-cell predominant or mixed lesions. Nevertheless, 18 of these 40 cases on initial testing suggested possible monoclonality. Six were indeterminate, and 12 demonstrated apparent monoclonal bands, of which four were reproducible on repeat testing. No histologic or clinical features of lymphoma were present in 17 of these 18 cases, suggesting that they represent false-positive results. Most of the latter lesions showed sparse perivascular infiltrates, with very few B cells. This suggests that amplification of the immunoglobulin heavy chain gene from a small number of lymphocytes may produce a monoclonal band. In summary, PCR may provide adjunct information about clonality in selected lymphoid skin lesions, but is rather insensitive in this setting. Such data must be carefully considered in the context of the histologic, immunohistologic, and clinical findings, particularly when assessing sparse infiltrates, because of the potential for false-positive results.

Laser beam microdissection in the diagnosis of cutaneous B-cell lymphoma

Interpretation of molecular analyses of cutaneous lymphoid infiltrates may be difficult because a heterogeneous group of cells in usually present within the neoplasms. Extraction of DNA from tissue sections does not provide exact information about which cell population has been analysed. We present a laser microscope system that allows selective molecular analysis of single cells or small groups of cells in cases of cutaneous lymphoma. An ultraviolet (UV)-laser microscope system (PALM, Wolfratshausen, Germany) was used to isolate particular populations of cells from a routinely processed specimen of a cutaneous follicular lymphoid proliferation. Using the UV-laser beam, a circle was cut around a target germinal centre in order to separate it from neighbouring tissues and to isolate a pure population of germinal centre cells. Isolated cells were scraped off with a micromanipulator and placed in a proteinase-K solution. DNA was extracted and amplified by the polymerase chain reaction (PCR) technique. Analysis of immunoglobulin JH gene rearrangement showed a distinct monoclonal band. In a second phase, using the same procedure in the same specimen, mantle zone cells around a germinal centre and single interfollicular B lymphocytes were isolated for PCR analysis of immunoglobulin JH gene rearrangement. In this population of cells, no clonality could be detected. This new technique allows the selective elimination of undesired cells and tissue from cutaneous neoplasms. By destruction of unwanted tissues with laser-beam energy a contamination-free sample is obtained. Analysis of isolated cells in our case demonstrated a clonal rearrangement derived from germinal centre cells and not from other B lymphocytes in the specimen, confirming the diagnosis of cutaneous follicle centre lymphoma. The method described has exciting implications for dermatology and dermatopathology, allowing precise correlation of morphological features with findings by molecular genetics.

Immunoperoxidase techniques in the evaluation of cutaneous lymphocytic infiltrates.

The widespread availability of immunoperoxidase technology and antibody probes over the past 15 years has changed the discipline of dermatopathology. In no aspect is this more evident than in the microscopic study of cutaneous lymphoid infiltrates. In the following review, the discussion focuses on some of the ways in which immunophenotyping is used to enhance the diagnosis of cutaneous lymphoproliferative disorders. A strategy for the use of immunophenotyping in some common clinical situations is forwarded. The immunopathologic findings can be helpful in resolving problems in the differential diagnosis of lymphoma and mimics of lymphoma.

Interleukin-7 receptor expression in cutaneous T-cell lymphomas

Keratinocyte-derived interleukin-7 (IL-) is a potent growth factor for some cutaneous T-cell lymphomas (CTCL). We investigated the expression of IL-7 receptor (IL-7R) in several types of cutaneous and nodal lymphomas. We studied 44 CTCL (13 mycosis fungoides, six Sézary syndromes, eight pleomorphic small cell, and 17 pleomorphic medium and large cell), 10 lymphomatoid papulosis (LP), five cutaneous B-cell lymphomas, and five reactive lymphocytic infiltrates. Twenty nodal T-cell lymphomas, and three reactive lymph nodes were also analysed. Frozen sections were stained with monoclonal antibodies directed against IL-7R, CD25, CD30 and T antigens (CD3, CD2, CD5, CD7, CD4, CD8), using the alkaline phosphatase-antialkaline phosphatase technique. No expression of IL-7R was observed in cutaneous B-cell lymphomas, benign cutaneous lymphoid infiltrates, and reactive lymph nodes. IL-7R was expressed by more than 20% of lymphoid cells in 50-75% of all histological subtypes of CTCL, and by more than 50% of cells in 15-50%. IL-7R was expressed by more than 20% and 50% of cells in 40% and 10% of nodal large T-cell lymphomas, respectively. Eighty-nine per cent of CTCL and LP expressing IL7-R also expressed CD25+, compared with 58% of IL-7R--CTCL and LP (P < 0.05). No association of IL7-R and CD30 expression was found. In conclusion, CTCL frequently express IL-7R. This expression is not related to the epidermotropic characteristic of the infiltrate. In CTCL and LP, IL-7R expression is associated to CD25 expression, but not to CD30 expression.

Drug-induced immune dysregulation as a cause of atypical cutaneous lymphoid infiltrates: A hypothesis

The authors encountered 22 patients in whom a skin biopsy showed atypical lymphoid hyperplasia and in whom a subsequent drug history showed ingestion of one or more agents before lesional onset. In 13 patients, the biopsy had been performed to rule out a diagnosis of malignant lymphoma, whereas in the other nine the clinical impression was that of a drug eruption. Among the more frequently prescribed agents were calcium-channel blockers, angiotensin-converting enzyme (ACE) inhibitors, antidepressants, antihistamines, β-blockers, benzodiazepines and lipid-lowering agents, all of which are either known to perturb lymphocyte function or have been implicated as a cause of pseudolymphomata. Twelve of the patients were on two or more of these drugs. The effect of drug modulation on the clinical course was assessed. The clinical presentations were as one or more erythematous plaques or multiple infiltrative papules, or as solitary nodules. The patients had been on one or more of the aforementioned drugs from 2 weeks to 5 years before developing the lesions. Resolution of the eruptions occurred in 17 patients within 1 to 32 weeks (mean, 7 weeks) of discontinuing the medication. Five additional patients had complete excision of solitary lesions without recurrence. A history of atopy, autoimmune disease, or previous carcinoma was elicited in five patients. All biopsy specimens showed atypical lymphoid infiltrates, which assumed one or more of the following patterns: mycosis fungoides (MF)—like, a lymphomatoid vascular reaction, lymphocytoma cutis, and follicular mucinosis. Based on the histopathology of the biopsied lesions and the clinical course being one of lesional resolution after cessation of drug therapy or excision of a solitary lesion without subsequent recurrence, a diagnosis of drug-associated lymphomatoid hypersensitivity was established in all specimens. A diagnosis of drug-associated pseudolymphoma should be excluded before a diagnosis of cutaneous lymphoma is rendered, and should be considered if the patient is on a drug known to alter lymphocyte function, particularly in the setting of systemic immune dysregulation or multidrug therapy where agents may act synergistically or cumulatively to alter lymphoid function. The authors postulate that the drug may promote an aberrant immune response to an antigen that may be the drug itself or some other stimulus. A skin biopsy may be particularly helpful, as the lesions of drug-associated pseudolymphoma have a morphology distinctive from malignant lymphoma.