Cutaneous Lymphoid Infiltrates Research Articles

Assessing T-cell receptor clonality by next-generation sequencing in atypical cutaneous lymphoid infiltrates and cutaneous T-cell lymphoma: A scoping review.

The diagnosis of cutaneous T-cell lymphoma (CTCL) remains challenging. Demonstration of a clonal T-cell population using T-cell receptor (TCR) gene rearrangement studies by next-generation sequencing (NGS) has been explored in several studies. This review summarizes the current literature on NGS-based sequencing methods for the assessment of TCR clonality in the evaluation of atypical cutaneous lymphoid infiltrates and CTCL on behalf of the American Society of Dermatopathology Appropriate Use Criteria Committee (lymphoproliferative subgroup). PubMed was searched for relevant articles, including CTCL and NGS, for clonality from 1967 to 2022. Thirteen studies were included in the analysis. The skin was the most commonly assayed compartment with TCR NGS. Sensitivity for TCR NGS in the skin ranged between 69% and 100%, compared to 44%-72% for polymerase chain reaction (PCR)-capillary electrophoresis. Specificity for TCR NGS in the skin ranged from 86% to 100%, compared to 77%-88% for PCR capillary electrophoresis. TCR NGS was also reported to have potential prognostic value in CTCL and can also be used to detect relapse and/or minimal residual disease after treatment.

Primary Cutaneous CD4 Small/Medium T-Cell Lymphoproliferative Disorder Following COVID-19 Vaccination-What Do We Know about Lymphoproliferative Disorders and Cutaneous Lymphomas after COVID-19 Vaccination? A Report of an Atypical Case and a Review of the Literature.

The association between Primary cutaneous CD4 small/medium T-cell lymphoproliferative disorder (PCSM-TCLPD) and COVID-19 immunization has been sparsely documented in the medical literature. Reviewing the literature, albeit infrequently, we can find cases of the recurrence and new onset of lymphoproliferative processes and cutaneous lymphomas following the COVID-19 vaccine. Many of the entities we encounter are classified as cutaneous lymphoproliferative disorders. The prevailing hypothesis suggests that the predominant cutaneous reactions to SARS-CoV-2 vaccines may stem from T-cell-mediated immune activation responses to vaccine components, notably messenger RNA (mRNA). Specifically, it is posited that the presence of cutaneous lymphoid infiltrates may be linked to immune system stimulation, supported by the absence, to date, of instances of primary cutaneous B-cell lymphoma following mRNA vaccination. Within this context, it is imperative to underscore that the etiological association between PCSM-TCLPD and COVID-19 vaccination should not discourage vaccination efforts. Instead, it underscores the necessity for continuous surveillance, in-depth investigation, and comprehensive follow-up studies to delineate the specific attributes and underlying mechanisms of such cutaneous manifestations post vaccination.

Primary cutaneous lymphomas in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A series of 12 cases

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is associated with an increased risk of a second malignancy. We conducted a retrospective clinicopathologic review of 12 patients with CLL/SLL who developed a second lymphoma in the skin. Demographic data, clinical information, and histopathology from 31 biopsies were recorded. Cases of secondary cutaneous involvement by CLL/SLL (leukemia cutis) and non-primary cutaneous lymphomas were excluded. A wide variety of primary cutaneous lymphomas was identified, including classic mycosis fungoides (3), cutaneous marginal zone lymphoma (2), primary cutaneous peripheral T-cell lymphoma unspecified (2), folliculotropic mycosis fungoides (1), Sézary syndrome (1), cutaneous gamma-delta T-cell lymphoma (1), cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (1), and cutaneous anaplastic large cell lymphoma (1). A male predominance was observed, and the average age was 74.1 years. In all patients, CLL/SLL predated the development of the second lymphoma, which was aggressive in the majority of cases (58%). Aggressive cytotoxic T-cell lymphomas, generally rare neoplasms, were relatively common (30%). CLL/SLL patients may develop a second lymphoma in the skin, which may be aggressive. Atypical cutaneous lymphoid infiltrates in this patient population should not be assumed to represent secondary CLL/SLL involvement and require thorough immunohistochemical analysis.

T-cell receptor antibodies expression in benign and malignant cutaneous lymphoid infiltrates in comparison with T-cell receptor gene rearrangement and its diagnostic utility in borderline cases

IntroductionCutaneous T-cell lymphoid infiltrate can represent reactive lesion or a malignant T-cell lymphoma. However, clinical and histopathological appearance can overlap in both groups with a risk of misdiagnosis. Aberrant expression of T-cell markers is not always applicable and T-cell receptor (TCR) gene rearrangement is not always accessible and diagnosis in borderline cases can be challenging. AimsSeveral types of TCR antibodies are currently available with limited knowledge of their expression in different cutaneous lymphoid infiltrates. Aim of the study is a comparison of expression of TCR antibodies in benign and malignant lymphoid infiltrates and their utility in borderline cases. MethodsRepresentative cases of reactive and malignant lymphoproliferations were collected. Separate group of lesions with borderline morphology was selected for comparison. Immunohistochemical expression of TCR-V-betaF1 (TCRBF1), TCR-C-beta1 (TCRJOVI.1), TCR gamma/delta (TCRGD) and TCR delta (TCRD) was performed in all cases. TCR gene rearrangement evaluation was performed in all cases using PCR BIOMED-2 assay. ResultsBenign lymphoid infiltrates were all negative in TCRD and TCRGD. Expression of TCRJOVI.1 was seen in 3/10 cases and TCRBF1 in one. T-cell lymphomas were positive for TCRBF1 and TCRGD in 60% and 30% of cases respectively. TCR gene rearrangement was confirmed in 90% of lymphoma cases. All benign lesions were polyclonal. Morphologically borderline lesions showed expression of TCRBF1 in 6/10 cases and TCR gene rearrangement in 4/10 cases. Re-evaluation of the cases and clinical correlation led to the change of the diagnosis and confirmation of T-cell lymphoma in 4/10 cases. ConclusionsExpression of TCRBF1 and TCR-gene rearrangement was significantly associated with malignant infiltrates. TCRBF1 positivity in borderline cutaneous lymphoproliferations can raise the suspicion of malignancy but confirmation by TCR gene rearrangement and careful clinical correlation is still advisable.

Kappa and lambda immunohistochemistry and in situ hybridization in the evaluation of atypical cutaneous lymphoid infiltrates.

Atypical cutaneous lymphoid infiltrates are challenging lesions in dermatopathology. We present a summary of the literature regarding kappa and lambda immunohistochemistry (IHC) and in situ hybridization (ISH) in the evaluation of atypical cutaneous or mucosal lymphoid infiltrates. Relevant articles from 1967 to 2018 in the English language were identified and summarized. In the absence of larger studies, case series of n ≥ 3 were included. Sixty-three articles assessing kappa and lambda IHC and/or ISH were identified. Most focused on marginal zone lymphomas. Other lymphomas included follicle center lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma, plasmablastic lymphoma, multiple myeloma, monoclonal gammopathy of undetermined significance, and polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS). Non-neoplastic lesions included reactive lymphoid hyperplasia, cutaneous plasmacytosis, connective tissue disease, IgG4-related disease, acrodermatitis chronic atrophicans, Zoon balanitis, dermatitides, and infiltrates around epithelial dysplasias/neoplasias. Kappa and lambda IHC and ISH are useful tools in the evaluation of cutaneous B-cell lymphomas and plasma cell neoplasms. The literature supports that the detection of light-chain restriction by IHC and ISH is one of the most useful findings in the differential diagnosis of reactive lymphoid hyperplasia vs B-cell lymphoma with plasmacytic differentiation.

A Systematic Approach to the Cutaneous Lymphoid Infiltrates: A Clinical, Morphologic, and Immunophenotypic Evaluation.

The evaluation of cutaneous lymphoid infiltrates, both neoplastic and inflammatory, occurs very frequently in routine dermatopathologic examination and consultation practices. The "tough" cutaneous lymphoid infiltrate is feared by many pathologists; skin biopsies are relatively small, whereas diagnostic possibilities are relatively broad. It is true that cutaneous lymphomas can be difficult to diagnose and that in many circumstances multiple biopsies are required to establish a correct diagnostic interpretation. As a reminder, one should understand that low-grade cutaneous lymphomas are indolent disorders that usually linger for decades and that therapy does not result in disease cure. It is also important to remember that in most circumstances, those patients will die from another process that is completely unrelated to a diagnosis of skin lymphoma (even in the absence of specific therapy). To use a clinicopathologic, immunophenotypic, and molecular approach in the evaluation of common lymphocytic infiltrates. An in-depth analysis of updated literature in the field of cutaneous lymphomas was done, with particular emphasis on updated terminology from the most recent World Health Organization classification of skin and hematologic tumors. A diagnosis of cutaneous lymphoid infiltrates can be adequately approached using a systematic scheme following the proposed ABCDE system. Overall, cutaneous T- and B-cell lymphomas are rare and "reactive" infiltrates are more common. Evaluation of lymphoid proliferations should start with a good sense of knowledge of the clinical presentation of the lesions, the clinical differential considerations, and a conscientious and appropriate use of immunohistochemistry and molecular tools.

The role and contribution of clonality studies in the diagnosis of lymphoproliferative disorders.

To explore the frequency, context and diagnostic impact of B- and T-lymphocyte clonality assay use in the assessment of possible lymphoproliferative disorders at a central haematopathology diagnostics hub. All cases reported by haematopathologists over a sixteen-month period were identified, n=4462, and those which had clonality studies undertaken analysed further. Clonality studies were requested in 9% of cases, directly contributing to a diagnosis being made in 79%. They were most frequently used to help distinguish reactive lymphoid infiltrates from low-grade B-cell lymphomas and in cases of possible T-cell lymphoma, facilitating a diagnosis being made in over 90% of these. In contrast when clonality assays were requested as a diagnostic adjunct in cases with an atypical cutaneous lymphoid infiltrate, and in occasional cases of lymphoid proliferations with Hodgkin-like cells or EBV-driven proliferations, a definitive final diagnosis was possible in less than 60% of cases. Clonality studies were used in 9% of cases assessed for a possible lymphoproliferative disorder and had a differing impact depending on the differential diagnoses being considered. These findings can be used to guide access to clonality assays by highlighting the likelihood of an informative result in different diagnostic settings.

Histopathological approach to cutaneous lymphoid infiltrate

Cutaneous lymphoid infiltration is common histology seen in the day-to-day practice of dermatopathology. The reasons for this infiltration can range from a spontaneously remitting pseudolymphoma such as Jessner's infiltration to a sinister and aggressive cytotoxic T-cell lymphoma. Before analyzing the slide, the clinical perspective needs to be borne in mind as a diagnosis can never be made in isolation, especially in dermatopathology. In this article, we discuss in brief the various common cutaneous lymphoid infiltrative entities encountered in routine practice, discuss the differentiating features, and suggest an algorithmic approach to arrive at the possible diagnosis.

Drug induced pseudolymphoma.

Atypical lymphocytic infiltrates of the skin comprise a broad spectrum of entities ranging from benign infiltrates to those that are malignant. Many of these infiltrates are in fact reactive lymphomatoid ones related to drug therapy falling under the general category of drug associated pseudolymphoma. Within this nosologic umbrella are nodular and diffuse infiltrates resembling low grade T and B cell lymphoma consistent with lymphocytoma cutis, drug associated reversible T cell dyscrasiaswhich draw astrong morphologic and phenotypic parallel with mycosis fungoides and the various pre-lymphomatous T cell dyscrasias,and angiocentric CD30 positive infiltrates mirroring lymphomatoid papulosis. The implicated drug classes are quite varied and include antidepressants, antihistamines, calcium channel blockers, statins, anticonvulsants, and various biologic drugs. The drugs from these various drug classes exert certain effects on lymphoid function including evoking overzealous responses to other antigenic stimuli.As the adverse effect on lymphocyte function may be cumulative over years and or reflect the interplay ofother drugs, a temporal association may not exist between the onset of the rash/lesion and the initiation of the drug. In certain lymphomatoid reactions however such asDRESS syndrome the drug may function asboth an antigen as well as an immune dysregulating agent.It is critical that the pathologist works carefully with the clinician inthe evaluation of all atypical cutaneous lymphoid infiltrates where the distinction between pseudolymphoma versus lymphomacannot be reliably made based on pathologic analysis alone.

Approach to Cutaneous Lymphoid Infiltrates: When to Consider Lymphoma?

Cutaneous lymphoid infiltrates (CLIs) are common in routine dermatopathology. However, differentiating a reactive CLI from a malignant lymphocytic infiltrate is often a significant challenge since many inflammatory dermatoses can clinically and/or histopathologically mimic cutaneous lymphomas, coined pseudolymphomas. We conducted a literature review from 1966 to July 1, 2015, at PubMed.gov using the search terms: Cutaneous lymphoma, cutaneous pseudolymphoma, cutaneous lymphoid hyperplasia, simulants/mimics/imitators of cutaneous lymphomas, and cutaneous lymphoid infiltrates. The diagnostic approach to CLIs and the most common differential imitators of lymphoma is discussed herein based on six predominant morphologic and immunophenotypic, histopathologic patterns: (1) Superficial dermal T-cell infiltrates (2) superficial and deep dermal perivascular and/or nodular natural killer/T-cell infiltrates (3) pan-dermal diffuse T-cell infiltrates (4) panniculitic T-cell infiltrates (5) small cell predominant B-cell infiltrates, and (6) large-cell predominant B-cell infiltrates. Since no single histopathological feature is sufficient to discern between a benign and a malignant CLI, the overall balance of clinical, histopathological, immunophenotypic, and molecular features should be considered carefully to establish a diagnosis. Despite advances in ancillary studies such as immunohistochemistry and molecular clonality, these studies often display specificity and sensitivity limitations. Therefore, proper clinicopathological correlation still remains the gold standard for the precise diagnosis of CLIs.

Clonality Assessment of Cutaneous B-Cell Lymphoid Proliferations

Cutaneous lymphoid infiltrates are diagnostically challenging. Although ancillary techniques to assess clonality can help distinguish between reactive lymphoid hyperplasia and lymphoma, one of the most widely used techniques in hematopathology, flow cytometry immunophenotyping (FCI), has not been routinely applied to skin specimens. We performed FCI on 73 skin specimens from 67 patients clinically suspected of having a cutaneous B-cell lymphoma (CBCL) and compared the results with those obtained from immunoglobulin heavy chain (IGH) gene molecular studies (58 cases, primarily by polymerase chain reaction) and either immunohistochemistry (IHC) or in situ hybridization to evaluate for light chain restriction (22 and 2 cases, respectively). Sufficient quantity of CD45 (leukocyte common antigen)-positive cells and staining quality were achieved in 88% of cases by FCI, and clonality was detected in 68% of CBCLs versus molecular studies showing sufficient DNA quality in 74% and only 39% clonality detection, and interpretable/contributory IHC results in 84% of cases with 55% clonality detection. Clonality was documented more frequently in secondary rather than primary CBCLs by all 3 techniques. Therefore, FCI is feasible and appears to be more reliable than molecular studies or IHC/in situ hybridization for detecting clonality in CBCLs and can provide additional prognostically and therapeutically relevant information. The exception is cases with plasmacytic differentiation such as marginal zone lymphoma for which IHC might be a superior tool. We have also shown that a large subset of primary cutaneous follicle center lymphomas express CD10 and/or BCL2 by FCI. Recent advances in FCI beg the question of applicability to cutaneous T-cell and NK-cell lymphomas.

Primary cutaneous NK/T cell lymphoma-nasal type with cutaneous aspergillosis. A case report and literature review

We report a 66-year-old male who presented with a blackish discolored ulcerated nodule over the right flank of 2 months duration. Biopsy of the lesion revealed ulcerated epidermis with fungal hyphae of Aspergillus overlying dense, angiocentric atypical lymphoid infiltrate involving the dermis, and extending into sub cutis with geographic areas of necrosis. The patient had three episodes of cutaneous recurrence over a three year period. The cutaneous lymphoid infiltrates showed similar immunohistochemical profiles: LCA+, CD3€+, CD20- and CD56-. CD30 was positive in a small percentage of cells. P53 proliferation marker was strongly positive.There was no evidence of systemic involvement by the neoplastic lymphoid and fungal infiltrates. This is one amongst the rare reports of cutaneous aspergillosis with primary cutaneous NK/T cell lymphoma nasal-type.

Clonality testing of cutaneous lymphoid infiltrates: practicalities, pitfalls and potential uses

PCR is the method of choice for assessing antigen receptor gene rearrangement in suspect cutaneous infiltrates. It is a powerful and robust technique, but not without certain limitations and pitfalls. Of particular importance in the analysis of lymphoproliferations in the skin are the quality of DNA obtainable, an understanding of how primer choice may influence sensitivity and issues surrounding pseudoclonality. When interpreting results, cognisance must also be taken of the well-documented fact that monoclonal T-cell receptor and immunoglobulin gene rearrangements are not infrequently encountered in benign reactive cutaneous disorders. We discuss these issues in detail herein, and outline the situations in which we believe clonality testing may add value to assessing the biological nature of a cutaneous lymphoid infiltrate. Lastly, we emphasize the importance of interpreting any results derived from PCR assays in the context of the clinical, histological and immunophenotypic findings.

Cutaneous Papules, Hypercalcemia, and Osteolytic Bone Lesions

A 61-year-old Japanese American woman was hospitalized with recalcitrant hypercalcemia of 3 months’ duration. Physical examination showed generalized cutaneous papules. The patient also had osteolytic bone lesions that caused fractures. On admission, the calcium level was 17.5 mg/dL (to convert to mmol/L, multiply by 0.25), and the parathyroid hormone level was suppressed. Peripheral blood smear showed a slight absolute lymphocytosis with occasional atypical lymphocytes. A skin biopsy specimen revealed a dense dermal infiltrate of atypical T lymphocytes with strong CD25 expression, characteristic of human T-cell lymphotropic virus type 1 (HTLV-1)–associated adult T-cell leukemia/lymphoma (ATCLL). Serologic testing for HTLV-1 was subsequently shown to be positive. The HTLV-1 is endemic in Japan, the Caribbean, Central Africa, and the southeastern United States. Infection is transmitted by sexual contact, blood transfusion, or mother-to-child vertical transmission. The HTLV-1 genome is clonally integrated into the DNA of the lymphoma cells. The clinical differential diagnosis of the skin findings in this patient included generalized histiocytic disorders, leukemia cutis, and other types of lymphoma. The diagnosis is established through identification of the leukemia/lymphoma cells within the peripheral blood, skin, or other affected organs. The strong expression of CD25 by the lymphoma cells is a characteristic immunophenotypic finding. With conventional systemic chemotherapy regimens, the prognosis for patients with ATCLL is poor. Recent studies have examined other potentially more promising treatments, such as allogeneic stem cell transplant, alemtuzumab, denileukin diftitox, or antiviral agents. Although rare in the United States, ATCLL should be considered in patients from endemic areas who present with cutaneous lymphoid infiltrates, hypercalcemia, and osteolytic bone lesions.

Cutaneous lymphoid proliferations: a clinicopathological continuum?

The distinction of cutaneous lymphomas from inflammatory dermatoses is considered to be one of the most vexing problems in diagnostic dermatopathology. Identification of “clonal dermatoses” which, in some instances, evolve into overt lymphomas, has prompted the suggestion that cutaneous lymphoid hyperplasia may represent a continuum with lymphomatous potential. Some of the difficulties that we encounter in the diagnosis of cutaneous lymphomas are, however, conceptual. That is because diagnostic criteria for the earliest stages of malignant tumours impinge on the “grey zone” between what is clearly benign and what is obviously malignant. On the other hand, a pragmatic approach to the management of patients with “borderline” lymphoproliferative disorders seems to be the most appropriate. Dermatologists and dermatopathologists should be mindful of patients’ best interests, avoiding unnecessarily aggressive treatment of cutaneous lymphoid infiltrates. That approach is valid regardless of personal opinion over whether such lesions are “premalignant” or “early malignant”.

Immunocytochemistry and the diagnosis of cutaneous lymphoma

Cutaneous lymphoid infiltrates may pose some of the most difficult diagnostic problems in dermatopathology. Immunocytochemistry is often employed in an effort to determine whether an infiltrate is neoplastic or, in the case of clearly malignant infiltrates, to provide a specific diagnosis. The rarity of these disorders and the variant immunocytochemical profiles they may present further thwart understanding and sometimes prevent an accurate diagnosis. In this review the common immunocytochemical profiles of various cutaneous lymphomas are presented and potential pitfalls and problems considered. Immunocytochemistry is not a diagnostic test but, as in other areas of histopathology, is a highly valuable tool that requires critical interpretation within a context: so applied, it is an indispensable part of the pathologist's arsenal in evaluating lymphoid infiltrates and defining different lymphomas.

Cutaneous lymphocyte antigen expression in benign and neoplastic cutaneous B‐ and T‐cell lymphoid infiltrates

Cutaneous lymphocyte-associated antigen (CLA) is expressed in resident cutaneous T lymphocytes, high endothelial venules, peripheral monocytes, granulocytes and a small percentage of memory B cells. It has been postulated to be an important factor in homing of lymphocytes to the skin because of its function as a ligand for E-selectin expressed on cutaneous endothelial cells. We investigated the expression of CLA using the HECA-452 antibody on paraffin-embedded, formalin-fixed tissue in a variety of reactive, neoplastic and preneoplastic cutaneous lymphoid infiltrates of T- and B-cell derivation. CLA was expressed at high levels in various types of inflammatory dermatoses with the exception of lupus erythematosus. High levels of CLA expression were seen in epidermotropic T-cell dyscrasias and epidermotropic T-cell lymphomas including mycosis fungoides (MF) and adult T-cell leukemia/lymphoma (ATCLL). A loss of CLA in tumors normally positive for CLA was a feature of disease progression best exemplified by tumor-stage MF and acute ATCLL. There was a lack of CLA expression in those lymphocytic infiltrates manifesting subcutaneous localization including lupus profundus, panniculitis-like T-cell lymphoma and atypical lymphocytic lobular panniculitis. CLA expression was not only observed in primary cutaneous anaplastic large cell lymphoma but also seen in cases of nodal anaplastic large cell lymphoma secondarily involving the skin and was negative in cases of nodal anaplastic large cell lymphoma without any established skin involvement. An oligodot pattern defined a novel reaction pattern in those aggressive systemic dyscrasias with a proclivity to involve the skin. CLA was negative in the majority of B-cell lymphomas. CLA plays a role in the pattern of T-cell lymphocyte migration in the skin and subcutis in both reactive and neoplastic states. An alteration in the expression of this marker, whether it is in the context of the acquisition of expression in a cell that is normally CLA negative or its loss of expression, may define a key event in determining cutaneous and extracutaneous hematopoietic cell distribution.

Cutaneous lymphoid infiltrates

Cutaneous lymphoid infiltrates

Primary cutaneous B-cell lymphoma (marginal zone) with prominent T-cell component and aberrant dual (T and B) genotype; diagnostic usefulness of laser-capture microdissection

The presence of a dominant B- or T-cell clone is an important diagnostic criterion for distinguishing cutaneous lymphomas from lymphoid reactive infiltrates. Rarely, a combined B- and T-cell rearrangement can be detected from a single sample. In such instances, genotypic analysis does not permit differentiation of the coexistence of a T- and B-cell lymphoma from a single clone harbouring a monoclonal rearrangement for both immunoglobulin heavy chain and T-cell receptor genes. We herein report a case of a skin tumour consistent with a dense cutaneous lymphoid infiltrate showing a double prominent B- and T-cell component. A dual B- and T-cell clonality was detected by polymerase chain reaction from whole-tissue DNA sample. Genotypic analysis with DNA, obtained after laser-assisted microdissection from the B-cell population, again showed both T- and B-cell monoclonal rearrangements. Conversely, the microdissected T-cell population did not reveal a clonal pattern. The diagnosis of cutaneous B-cell lymphoma with a dual B- and T-cell genotype was established. This description illustrates the diagnostic usefulness of laser-capture microdissection in cutaneous lymphomas presenting dual genotype.

Cutaneous Lymphoid Hyperplasia and Other Lymphoid Infiltrates of the Breast Nipple

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.