Classifications of cutaneous lymphomas and lymphoproliferative disorders: An update from the EORTC cutaneous lymphoma histopathology group.

The classification of primary cutaneous lymphomas and lymphoproliferative disorders (LPD) is continuously evolving by integrating novel clinical, pathological and molecular data. Recently two new classifications for haematological malignancies including entities of cutaneous lymphomas were proposed: the 5th edition of the WHO classification of haematolymphoid tumours and the International Consensus Classification (ICC) of mature lymphoid neoplasms. This article provides an overview of the changes introduced in these two classifications compared to the previous WHO classification. The main changes shared by both classifications include the downgrading of CD8+ acral T-cell lymphoma to CD8+ acral T-cell LPD, and the recognition of entities that were previously categorized as provisional and have now been designated as definite types including primary cutaneous small or medium CD4+ T-cell LPD, primary cutaneous gamma/delta T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, Epstein-Barr virus-positive mucocutaneous ulcer. Both classifications consider primary cutaneous marginal zone B-cell clonal neoplasm as an indolent disease but use a different terminology: primary cutaneous marginal zone lymphoma (WHO) and primary cutaneous marginal zone LPD (ICC). The 5th WHO classification further introduces and provides essential and desirable diagnostic criteria for each disease type and includes chapters on reactive B- or T-cell rich lymphoid proliferations formerly referred as cutaneous pseudolymphomas, as well as histiocyte and CD8 T-cell rich LPD in patients with inborn error of immunity. As already emphasized in previous lymphoma classifications, the importance of integrating clinical, histological, phenotypic and molecular features remains the crucial conceptual base for defining cutaneous (and extracutaneous) lymphomas.

Different mutational profiles of subcutaneous panniculitis-like T-cell lymphoma and lupus panniculitis: an additional case series.

BACKGROUND AND OBJECTIVE: subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma with indolent behavior, mostly present in women and associated with immunological diseases whose pathogenic background is still poorly understood. SPTCL is associated with lupus erythematosus panniculitis (LEP) and histologically misdiagnosed. OBJECTIVES: the aim of our study was to identify mutations affecting the pathogenesis of both SPTCL and LEP. MATERIALS AND METHODS: we studied a total of 10 SPTCL and 10 LEP patients using targeted Next Generation Sequencing and pyrosequencing. Differences in gene expression between molecular subgroups were investigated using NanoString technology. Clinical data were collected, and correlations sought with the molecular data obtained. RESULTS: the mutational profile of SPTCL and LEP is different. We identified fewer pathogenic mutations than previously reported in SPTCL, noting a single HAVCR2-mutated SPTCL case. Interestingly, 40% of our SPTCL cases showed the pathogenic TP53 (p.Pro72Arg) (P72R) variant. Although cases showing HAVCR2 mutations or the TP53 (P72R) variant had more severe symptomatic disease, none developed hemophagocytic syndrome (HPS). Furthermore, TP53 (P72R)-positive cases were characterized by a lower metabolic signaling pathway and higher levels of CD28 expression and Treg signaling genes. In addition, 30% of our cases featured the same mutation (T735C) of the epigenetic modificatory gene DNMT3A. None of the LEP cases showed mutations in any of the studied genes. CONCLUSIONS: the mutational landscape of SPTCL is broader than previously anticipated. We describe, for the first time, the involvement of the TP53 (P72R) pathogenic variant in this subgroup of tumors, consider the possible role of different genetic backgrounds in the development of SPTCL, and conclude that LEP does not follow the same pathogenic pathway as SPTCL.

Single-cell RNA sequencing profiling in a patient with discordant primary cutaneous B-cell and T-cell lymphoma reveals micromilieu-driven immune skewing.

BACKGROUND: Primary cutaneous lymphomas comprise a heterogeneous group of B-cell and T-cell malignancies which often show an indolent course, but can progress to aggressive disease in a subset of patients. Diagnosis is often delayed owing to clinical and histopathological similarities with benign inflammatory conditions. Especially during early disease, cancer cells are present at relatively low percentages compared with the inflammatory infiltrate, an interplay that is currently only insufficiently understood. OBJECTIVES: To improve diagnostics and perform molecular characterization of a complex type of primary cutaneous lymphoma. METHODS: Single-cell RNA sequencing (scRNA-seq) was performed and combined with T-cell and B-cell receptor sequencing. RESULTS: We were able to diagnose a patient with concurrent mycosis fungoides (MF) and primary cutaneous follicle centre lymphoma (PCFCL), appearing in mutually exclusive skin lesions. Profiling of tumour cells and the tissue microenvironment revealed a type-2 immune skewing in MF, most likely guided by the expanded clone that also harboured upregulation of numerous pro-oncogenic genes. By contrast, PCFCL lesions exhibited a more type-1 immune phenotype, consistent with its indolent behaviour. CONCLUSIONS: These data not only illustrate the diagnostic potential of scRNA-seq, but also allow the characterization of specific clonal populations that shape the unique tissue microenvironment in clinically distinct types of lymphoma skin lesions.

Should we be imaging lymph nodes at initial diagnosis of early-stage mycosis fungoides? Results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) international study.

BACKGROUND: Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs. OBJECTIVES: To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging. METHODS: A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data. RESULTS: PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six. CONCLUSIONS: Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2.

Primary cutaneous peripheral T-cell lymphoma, not otherwise specified: results of a multicentre European Organization for Research and Treatment of Cancer (EORTC) cutaneous lymphoma taskforce study on the clinico-pathological and prognostic features.

BACKGROUND: Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm. OBJECTIVES: The European Organization for Research and Treatment of Cancer cutaneous lymphoma taskforce (EORTC CLTF) investigated 33 biopsies of 30 patients with primary cutaneous PTL NOS to analyse their clinical, histological, immunophenotypic features and outcome. METHODS: Retrospective analysis of clinical data and histopathological features by an expert panel. RESULTS: Cutaneous PTL NOS manifested clinically either with solitary or disseminated rapidly grown ulcerated tumours or disseminated papulo-nodular lesions. Histologically, a mostly diffuse or nodular infiltrate in the dermis and often extending into the subcutis was found. Epidermotropism was rarely present and only mild and focal. Unusual phenotypes were frequent, e.g. CD3+ /CD4- /CD8- and CD3+ /CD4+ /CD8+ . Moreover, 18% of the cases exhibited an aberrant expression of the B-cell marker CD20 by the tumour cells. All solitary tumours were located on the limbs and presented a high expression of GATA-3 but this did not correlate with outcome and therefore could not serve as a prognostic factor. The prognosis was shown to be generally poor with 10 of 30 patients (33%) dying of lymphoma within the follow-up of 36 months (mean value; range 3-144). The survival rates were 61% after 3 years (CI, 43-85%) and 54% after 5 years (CI, 36-81%). Small to medium-sized morphology of tumour cells was associated with a better outcome than medium to large or large tumour cells. Age, gender, clinical stage, CD4/CD8 phenotype and GATA-3 expression were not associated with prognosis. Chemotherapy was the most common treatment modality, but surgical excision and/or radiotherapy may represent an appropriate first-line treatment for solitary lesions. CONCLUSIONS: Cutaneous PTL NOS shows an aggressive course in most patients independent of initial presentation, age and phenotype. Cytomorphology was identified as a prognostic factor. The data indicate a need for more effective treatment modalities in PTL NOS.

Risk of mycosis fungoides in psoriatic patients: a critical review.

Psoriasis has been controversially associated with risk of non-Hodgkin lymphoma (NHL) and mycosis fungoides (MF). Also patients who developed MF after systemic treatment for psoriasis have been reported, and some authors suggested that the association between MF and psoriasis is not infrequent. We performed an extensive literature review in order to examine the risk of developing MF in psoriatic patients with a systematic search of the English-language databases. An increased risk for lymphoma overall in psoriatic patients has been found only by three out of seven studies. The risk of developing MF in psoriatic patients has been investigated by different studies in different populations and with different methodologies presenting bias and limitations, and it seems reasonable that misclassification between psoriasis and MF may explain the association reported. In contrast to the large number of psoriatic patients treated with biologicals, only 27 case reports of MF after biological therapy for psoriasis have been reported, and in 10 cases, the initial psoriasis diagnoses were then revised as MF. A true association between MF and psoriasis is possible, but the real incidence and prevalence are still unknown. The reported higher risk of developing MF in psoriatic patients should be reconsidered in the light of the bias of misclassification and the low magnitude reported in previous studies. There is not enough evidence to support a causal relation among biological therapies and MF in psoriatic patients.

CD30-positive primary cutaneous anaplastic large cell lymphoma with coexistent pseudocarcinomatous hyperplasia.

CD30-positive primary cutaneous anaplastic large cell lymphoma (C-ALCL) is an indolent type of cutaneous lymphoma with favourable clinical prognosis. Pseudocarcinomatous hyperplasia (PCH) is a rare benign epithelial condition that can resemble invasive squamous cell carcinoma both clinically and histopathologically. PCH predominantly occurs in CD30-positive lymphoproliferative disorders. We report a 75-year-old woman with PCH in a multifocal C-ALCL located on the scalp and right retroauricular area, which rapidly responded to treatment with psoralen ultraviolet A photochemotherapy. Comprehensive virological analyses for potential oncogenic viruses, including Epstein-Barr virus, human herpesvirus-8, human papillomaviruses, the recently discovered cutavirus and nine different human polyomaviruses, were negative.

Dermatomyositis panniculitis: a clinicopathological and immunohistochemical study of 18 cases.

BACKGROUND: Panniculitis occurring in dermatomyositis is uncommon, with only a few cases described in the literature, most of them as case reports. OBJECTIVE: This report describes the clinicopathological and immunohistochemical findings in a series of 18 patients with panniculitis associated with dermatomyositis. METHODS: In each patient, we collected the clinical data of the cutaneous lesions as well as the characteristic clinical and laboratory findings. A series of histopathologic findings was recorded in the biopsy of each patient. A panel of antibodies was used in some cases to investigate the immunophenotype of the infiltrate. Data of treatment and follow-up were also collected. RESULTS: Of the 18 patients, 13 were female and 5 were male, ranging in age from 13 to 74 years (median, 46.4 years). In addition to panniculitis, all patients presented pathognomonic cutaneous findings of DM and reported proximal muscle weakness prior to the diagnosis of panniculitis. Muscle biopsy was performed in 17 patients and MRI in one, all with the diagnosis of inflammatory myopathy. None of the patients presented any associated neoplasia. Panniculitis lesions were located in the upper or lower limbs. Histopathology showed a mostly lobular panniculitis with lymphocytes as the main component of the infiltrate. Most cases showed also numerous plasma cells and lymphocytes surrounding necrotic adipocytes (rimming) were frequently seen. Lymphocytic vasculitis and abundant mucin interstitially deposited between collagen bundles of the dermis were also frequent findings. Late-stage lesions showed hyaline necrosis of the fat lobule and calcification. Immunohistochemistry demonstrated that most lymphocytes of the infiltrate were T-helper lymphocytes, with some B lymphocytes in the lymphoid aggregates and small clusters of CD-123-positive plasmacytoid dendritic cells in the involved fat lobule. CONCLUSION: Panniculitis in dermatomyositis is rare. Histopathologic findings of panniculitis dermatomyositis are identical to those of lupus panniculitis. Therefore, the final diagnosis requires clinic-pathologic correlation.

Taxanes-induced cutaneous eruption: another histopathologic mimicker of malignancy.

BACKGROUND: Paclitaxel and docetaxel are antineoplastic drugs that bind the microtubules, producing the arrest of mitoses, which may be seen histopathologically. These histopathologic changes may simulate an intraepidermal keratinocytic malignant neoplasm, and an accurate diagnosis may be only established by clinicopathological correlation. OBJECTIVES: We report six cases of cutaneous eruptions by taxanes in which a striking cytotoxic effect was evident histopathologically. METHODS: Cutaneous biopsies were obtained in each patient. RESULTS: Atypical starburst-like or ring-like mitoses and dyskeratosis on basal and suprabasal layers of the epidermis. Areas of squamous syringometaplasia were also seen in one case. DISCUSSION: These findings were interpreted as expression of mitotic arrest due to taxanes. Similar changes have been described in association with other chemotherapeutic drugs such as vincristine, podophyllin and its derivative etoposide; colchicine, busulfan and maytansine, but cases like ours due to taxanes are exceptional or under-reported. CONCLUSION: Dermatopathologists should be aware of these effects in order to interpret carefully cutaneous biopsy specimens of patients receiving taxanes.

Degos disease: report of a case and review of the literature.

We report the case of a 20-year-old woman with one-year history of asymptomatic pink papules on the abdomen, with central atrophy. Fever and symptoms suggesting involvement of other organs were absent. Histological examination revealed wedge-shaped area of cutaneous ischemia extending into the deep dermis with superficial and deep perivascular lymphocytic infiltrate. On this basis, we diagnosed malignant atrophic papulosis. Laboratory tests and instrumental investigation did not reveal any systemic involvement. The rarity of this disease makes early diagnosis challenging, even if clinical and histological patterns of the skin lesions are peculiar.

[Merkel cell carcinoma]. / Merkel-Zell-Karzinom.

Merkel cell carcinoma (MCC, cutaneous neuroendocrine carcinoma) is a rare form of tumor of unclear histogenesis which predominantly occurs in elderly patients on areas exposed to the sun. A higher incidence and occurrence in younger people is predominantly found in immunosuppressed persons which is why a pathogenetic role is also attributed to immunosuppression in addition to ultraviolet (UV) radiation. Additionally, in 80% of cases clonally integrated polyomavirus (Merkel cell polyomavirus, MCPyV) could be detected. Clinically MCC represents an uncharacteristic tumor. Histopathologically, monomorphic dermal and/or subcutaneous nodes are found consisting of round or oval medium sized cells with a vesicular nucleus and sparse cytoplasm. The neoplastic cells of MCC express cytokeratin (CK) 20 with a dot-like perinuclear accentuation. In addition, pan-CK, neuroendocrine markers (e.g. chromogranin A and synaptophysin), neurofilament proteins, CD56, CD57, Bcl-2, TdT and PAX-5 are immunohistochemically positive. In most cases CM2B4, an antibody against MCPyV is also positive. Expression of p63 has been observed in some of the cases and in some studies was associated with a favorable prognosis. The markers thyroid transcription factor 1, mammalian achaete scute complex like 1, vimentin, S-100 and CK7 are not normally expressed by MCC. The prognosis is primarily dependent on tumor size and the lymph node status. The presence of intralymphatic tumor complexes is associated with a higher rate of local recurrence and lymph node metastasis. A larger number of intratumoral cytotoxic T-lymphocytes is accompanied by a favorable prognosis and the presence of > 50% of K-67+ neoplastic cells with an unfavorable prognosis. Further morphological, phenotypical and genetic factors have not yet been validated in larger cohorts with respect to the prognostic relevance.

Periodontal bacteria in the genital tract: are they related to adverse pregnancy outcome?

One of the most important factors implicated in preterm birth (PTB) is acute genitourinary tract infection. The bacteria causing chronic periodontal inflammation include Gram-negative rods and anaerobes similar to those found in women with bacterial vaginosis. The aim of this prospective study is to investigate the relationship between oral and vaginal microflora and preterm low birth weight. Real-time polymerase chain reaction was used to detect both the presence and level of six periodontitis-related species: Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), Treponema denticola (Td), Fusobacterium nucleatum ssp(Fn), and Prevotella intermedia (Pi) for both oral samples of subgingival plaque and cervical samples, obtained from 80 patients, during gynaecological examinations. The more representative oral pathogen (less than 60 percent) species in oral samples of preterm and term group were Tf, Td, and Fn. 24.4 percent of pregnant women presented periodontal pathogens in vaginal swab; the most representative species with a percentage over 0.1 percent of total bacteria in genital tract of preterm group were Tf, Td, and Piwith a positive correlation (less than 0.5). The presence of the bacterium T. denticolain the vagina, regardless of the amount, adversely affects preterm delivery.

A case of lymphomatoid papulosis limited to Becker's melanosis.

Regional lymphomatoid papulosis (LyP) accounts for 2-27% of all LyP cases. Several localized dermatoses have been reported in association with Becker's melanosis (BM), e.g. acneiform lesions or lichen planus. Here, we report on regional LyP confined to the area of BM. A 56-year-old man presented with a 1-year history of a steadily increasing number of multiple pruritic red papules developing on the area of BM, which had occurred on his left shoulder during puberty. Histopathological analysis was consistent with regional LyP. Potent topical steroids followed by oral doxycycline did not achieve improvement, while long-term oral bexarotene treatment ameliorated the skin condition. Recently, the proposed entity of 'persistent agmination of LyP' (PALP) has extended the clinicopathological observations of regional LyP. Since PALP remains controversial, a unifying concept of localized LyP and PALP will be discussed.

Recent advances in cutaneous lymphoma-implications for current and future classifications.

The Revised European-American Classification of mature lymphoid neoplasms published in 1994 and the 2001, 2008 and 2016 WHO classifications that followed, were the product of international collaboration and consensus amongst haematopathologists, geneticists, molecular scientists and clinicians. Primary cutaneous lymphomas were fully incorporated into this process following the publication of the WHO-EORTC classification of cutaneous lymphomas in 2005. The definition, diagnostic criteria and recommended studies for primary cutaneous lymphoma continue to be refined. The 2022 International Consensus Classification represents the most recent update and an overview of all the main entities presenting primarily in the skin, together with the major changes in classification, are summarized herein. Primary cutaneous marginal zone lymphoma is segregated from other extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma) and downgraded to a lymphoproliferative disorder in line with its markedly indolent behaviour. In addition, two subtypes are recognised, based largely but not exclusively on whether they are heavy chain class-switched or IgM positive. Similarly, in keeping with a trend to greater conservatism, primary cutaneous acral CD8 positive T cell lymphoma is now also classified as a lymphoproliferative disorder. In addition, significant new insights into the biology of primary cutaneous lymphoma have also recently been forthcoming and will be presented. These studies have enhanced our knowledge of genetic, epigenetic and transcriptional changes in this group of diseases. They not only identify potential targets for novel therapies, but also raise as yet unanswered questions as to how we categorise cutaneous lymphomas, particularly with respect to relationships with similar lymphomas at extracutaneous sites.

Excised melanocytic lesions in children and adolescents - a 10-year survey.

BACKGROUND: Early recognition and prompt excision is to date the only available strategy for reducing mortality from melanoma. Little is known about the accuracy of melanoma detection in children and adolescents. OBJECTIVES: To assess the accuracy of melanoma detection in a paediatric population. METHODS: From the Department of Dermatology, Medical University of Graz, Austria, we reviewed the dermatopathology reports of naevi and melanomas excised in patients younger than 20 years over a 10-year period (1998-2007). Patients were subdivided into four age groups: 0-4, 5-9, 10-14 and 15-19 years. RESULTS: Accuracy in melanoma detection was tested using the number needed to excise (NNE) value that is obtained by dividing the total number of excised lesions by the number of melanomas. A total of 22564 lesions were reviewed, disclosing 22526 naevi and 38 melanomas, for an overall NNE value of 593.8. Five melanomas were excised in children aged 10-14 years (NNE 1141) and 33 in children aged 15-19 years (NNE 479.8), whereas no melanomas were found among 1026 lesions excised in children younger than 10 years. In children aged 0-4 years, congenital and Spitz/Reed naevi accounted for 34.5% and 20% of lesions, respectively. These percentages decreased progressively when moving to older age groups (P<0.0001). In contrast, the percentage of dermal and compound naevi rose in direct proportion with age, being 3.4% and 20.7%, respectively, in the youngest age group, and 36.7% and 31.9%, respectively, among the oldest patients (P<0.0001). CONCLUSIONS: The overall NNE value in paediatric patients over the 10-year study period was 593.8, meaning that about 594 lesions were excised to find one melanoma. This value is 20 times higher than the rates found in adult patients.