An update on viral-induced cutaneous lymphoproliferative disorders. CME Part I.

Viral-induced cutaneous T-cell lymphomas are an uncommon group of lymphoproliferative disorders characterized by a viral infection of T and natural killer (NK) cells. This group of cutaneous T-cell lymphomas is more commonly encountered in Asians and Native Americans from Central and South America compared with Western populations. Viral-associated lymphoproliferative disorders include a spectrum of entities that range from nonneoplastic lesions, such as chronic active Epstein-Barr virus infection and infective dermatitis to malignant diseases, such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and adult T-cell leukemia/lymphoma. This review article will focus on hydroa vacciniforme-like lymphoproliferative disorder, extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid granulomatosis, and Epstein-Barr virus-positive mucocutaneous ulcers. We will review the pathogenesis of these conditions and the challenges of making a timely diagnosis in early-stage disease and discuss the common clinicopathologic manifestations, mutational landscape, and approaches to treat these highly aggressive and frequently lethal types of lymphoma.

A Rare Case of Epstein-Barr Virus-Positive T-Cell Lymphoma in the Skin of an Immunocompromised Patient.

ABSTRACT: Immunodeficiency-associated lymphoproliferative disorders are associated with latent infection by Epstein-Barr virus (EBV). Most cases of EBV-positive immunodeficiency-associated lymphoproliferative disorders arise from B cells, although some are of T-cell or natural killer origin. Cutaneous involvement is unusual and sporadically reported in the literature. We describe a rare case of an EBV-positive T-cell lymphoma presenting in the skin of a 32-year-old woman using adalimumab for neurosarcoidosis.

Lack of detection of Cutavirus DNA using PCR real time in cutaneous T-cell lymphomas.

BACKGROUND: A novel human protoparvovirus named Cutavirus has been discovered. We investigated the presence of Cutavirus in a sample of Cutaneous T-cell lymphomas by using PCR real time TaqMan® (Thermo Fisher Scientific, Waltham, MA, USA). METHODS: In total, 55 CTCL samples were analyzed using a TaqMan® Real time PCR on a 7500 ABI instrument. All of these shown internal control amplification. RESULTS: The presence of Cutavirus DNA corresponding was examined. CuV DNA sequences were not detected in any skin specimen. CONCLUSIONS: The role of Cutaviruses in cutaneous cancers remains to be investigated.

Structural variation of centromeric endogenous retroviruses in human populations and their impact on cutaneous T-cell lymphoma, Sézary syndrome, and HIV infection.

BACKGROUND: Human Endogenous Retroviruses type K HML-2 (HK2) are integrated into 117 or more areas of human chromosomal arms while two newly discovered HK2 proviruses, K111 and K222, spread extensively in pericentromeric regions, are the first retroviruses discovered in these areas of our genome. METHODS: We use PCR and sequencing analysis to characterize pericentromeric K111 proviruses in DNA from individuals of diverse ethnicities and patients with different diseases. RESULTS: We found that the 5' LTR-gag region of K111 proviruses is missing in certain individuals, creating pericentromeric instability. K111 deletion (-/- K111) is seen in about 15% of Caucasian, Asian, and Middle Eastern populations; it is missing in 2.36% of African individuals, suggesting that the -/- K111 genotype originated out of Africa. As we identified the -/-K111 genotype in Cutaneous T-cell lymphoma (CTCL) cell lines, we studied whether the -/-K111 genotype is associated with CTCL. We found a significant increase in the frequency of detection of the -/-K111 genotype in Caucasian patients with severe CTCL and/or Sézary syndrome (n = 35, 37.14%), compared to healthy controls (n = 160, 15.6%) [p = 0.011]. The -/-K111 genotype was also found to vary in HIV-1 infection. Although Caucasian healthy individuals have a similar frequency of detection of the -/- K111 genotype, Caucasian HIV Long-Term Non-Progressors (LTNPs) and/or elite controllers, have significantly higher detection of the -/-K111 genotype (30.55%; n = 36) than patients who rapidly progress to AIDS (8.5%; n = 47) [p = 0.0097]. CONCLUSION: Our data indicate that pericentromeric instability is associated with more severe CTCL and/or Sézary syndrome in Caucasians, and appears to allow T-cells to survive lysis by HIV infection. These findings also provide new understanding of human evolution, as the -/-K111 genotype appears to have arisen out of Africa and is distributed unevenly throughout the world, possibly affecting the severity of HIV in different geographic areas.

Cutaneous lesions of angioimmunoblastic T-cell lymphoma: Clinical, pathological, and immunophenotypic features.

BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) is a systemic peripheral T-cell lymphoma with a follicular helper T-cell (TFH ) immunophenotype that frequently involves the skin. However, the histopathology of cutaneous involvement by AITL has not been fully established. METHODS: We reviewed the clinicopathological features of 19 patients seen at our institution with AITL involving the skin. Pan-T-cell and TFH marker expression was evaluated by immunohistochemistry. Epstein-Barr virus (EBV) was detected using in situ hybridization (ISH) for Epstein-Barr virus-encoded small RNA (EBER). T-cell receptor (TCR) gene rearrangement was evaluated by PCR. RESULTS: AITL affected both trunk and extremities in 15/19 cases (79%). Perivascular infiltration by small and/or medium-sized lymphocytes was seen in 18/19 (95%). Granulomatous inflammation was identified in 4/19 (21%). Aberrant loss of CD2, CD5, or CD7 was identified in 1/18 (6%), 2/18 (11%), or 7/19 (37%) cases, respectively. Seventeen of eighteen evaluable cases (95%) expressed 2 to 3 TFH markers: PD-1 in 19/19 (100%), BCL6 in 94% (17/18), and CD10 in 37% (7/19). EBV-positive cells were detected in 3/18 (17%) with varying density. Clonal TCR gene rearrangement was identified in 9/11 (82%). CONCLUSIONS: Cutaneous involvement by AITL shows relatively non-specific histopathological features. However, an immunohistochemical panel including TFH markers and EBER ISH is useful in differential diagnosis.

Cutavirus DNA in Malignant and Nonmalignant Skin of Cutaneous T-Cell Lymphoma and Organ Transplant Patients but Not of Healthy Adults.

BACKGROUND: Three new parvoviruses of Protoparvovirus genus, bufavirus (BuV), tusavirus (TuV), and cutavirus (CuV), have recently been discovered in diarrheal stools. CuV was further detected in a proportion of cutaneous T-cell lymphoma (CTCL)/mycosis fungoides skin samples and in one melanoma. PATIENTS AND METHODS: With novel multiplex quantitative polymerase chain reaction and antibody assays, we studied 3 patient groups for BuV, TuV, and CuV DNA and immunoglobulin G (IgG): CTCL patients, immunosuppressed solid-organ transplant recipients, and immunocompetent healthy adults. RESULTS: CuV DNA was detected in skin biopsies of 4/25 (16.0%) CTCL and 4/136 (2.9%) transplant patients but not in any of 159 skin samples of 98 healthy adults. The dermal CuV-DNA prevalence was significantly higher in CTCL patients than in the other subjects. CuV DNA was further detected in healthy skin of 4 organ transplant recipients, 2 of whom also had CuV-positive skin carcinomas. One CTCL patient harbored CuV DNA in both malignant (CTCL, melanoma) and nonmalignant skin and sentinel lymph nodes but not in his prostate. The CuV IgG seroprevalences were among CTCL patients 9.5% (4/42), transplant recipients 6.5% (8/124), and healthy adults 3.8% (3/78). BuV and TuV DNAs were absent and antibodies infrequent in all cohorts. Parvoviral antibodies were shown to persist for ≥20 years and dermal CuV DNA for 4 years. All 3 CuV-DNA-positive patients, with both biopsies and sera available, were CuV-IgG positive. CONCLUSION: Our results suggest that dermal CuV DNA carriage is associated with CTCL. Any putative roles of CuV in the carcinogenesis must be determined in forthcoming studies.

Cutaneous angioimmunoblastic T-cell lymphoma: Epstein-Barr virus positivity and its effects on clinicopathologic features.

BACKGROUND: Epstein-Barr virus (EBV) positivity frequently presents in patients with nodal angioimmunoblastic T-cell lymphoma (AITL). However, the presence of EBV in skin lesions and its clinicopathologic significance have not been evaluated. OBJECTIVE: To analyze the clinical and histopathologic features of cutaneous AITL and evaluate EBV positivity in skin tissue and its effects on clinicopathologic features of AITL. METHODS: Clinicopathologic variables in patients with cutaneous AITL were analyzed and compared depending on EBV in situ hybridization status in skin lesions by using patients' medical records. RESULTS: Of the 86 patients with AITL, 42 had a cutaneous presentation. In situ hybridizations positive for EBV were noted in 19 of 42 patients with cutaneous AITL. EBV positivity was more common in papular and nodular skin lesions than other cutaneous morphologies, such as nonspecific rash or purpuric patches. An EBV-positive in situ hybridization was associated with a pattern of dense, superficial and deep infiltrates of pleomorphic, large-sized, atypical lymphocytes. EBV positivity in skin lesions was an independent negative prognostic factor in patients with AITL. LIMITATIONS: Retrospective study at a single institution. CONCLUSION: EBV-positive cutaneous AITL is associated with distinctive clinicopathologic features.

DNA from Human Polyomaviruses, MWPyV, HPyV6, HPyV7, HPyV9 and HPyV12 in Cutaneous T-cell Lymphomas.

BACKGROUND/AIM: The etiopathogenesis of mycosis fungoides and Sézary syndrome remains obscure. Different viruses have been proposed to have a role in the etiopathogenesis of cutaneous T-cell lymphomas (CTCL). In the present study, the presence of five recently discovered human polyomaviruses 6 (HPyV6), human polyomaviruses 7 (HPyV7), human polyomaviruses 9 (HPyV9), human polyomaviruses 12 (HPyV12), and Malawi polyomavirus (MWPyV), have been analyzed in 55 CTCL in order to confirm the skin tropism and the possible pathological association of these new polyomaviruses. MATERIALS AND METHODS: Human polyomaviruses DNA were amplified from skin lesions were recovered from a total of 55 patients (32 males and 23 females, average age 63±15 years) affected by CTCL. RESULTS: When assayed for the presence of 5 different HPyVs, (HPyV6, HPyV7, HPyV9, MWPyV, and HPyV12) HPyV9, HPyV10 and HPyV12 DNA sequences were not found in any skin specimens. HPyV6 and 7 DNA was detected in 1/55 (1.8%) of skin specimens. CONCLUSION: The low-level presence of HPyV6 and HPyV7 DNA, and lack of detection of polyomaviruses HPyV9, MWPyV and HPyV12 in our series do not support a significant role of these HPyVs subtypes in the etiopathogenesis of skin cancers.

Human Protoparvoviruses.

Next-generation sequencing and metagenomics have revolutionized the discovery of novel viruses. In recent years, three novel protoparvoviruses have been discovered in fecal samples of humans: bufavirus (BuV) in 2012, tusavirus (TuV) in 2014, and cutavirus (CuV) in 2016. BuV has since been studied the most, disclosing three genotypes that also represent serotypes. Besides one nasal sample, BuV DNA has been found exclusively in diarrheal feces, but not in non-diarrheal feces, suggesting a causal relationship. According to both geno- and seroprevalences, BuV appears to be the most common of the three novel protoparvoviruses, whereas TuV DNA has been found in only a single fecal sample, with antibody detection being equally rare. Moreover, the TuV sequence is closer to those of non-human protoparvoviruses, and so the evidence of TuV being a human virus is thus far insufficient. Interestingly, besides in feces, CuV has also been detected in skin biopsies of patients with cutaneous T-cell lymphoma and a patient with melanoma, while all other skin samples have tested PCR negative. Even if preliminary disease associations exist, the full etiological roles of these viruses in human disease are yet to be resolved.

Primary cutaneous NK/T-cell lymphoma of nasal type: an age-related lymphoproliferative disease?

Among extranodal NK/T-cell lymphoma of nasal type (NKTL), the extranasal variant (ENKTL) is known to have a worse prognosis with advanced clinical stage than the nasal variant of NKTL. However, detailed clinicopathological features of the localized extranasal disease have not been well documented in English literature. Here, we described the clinicopathological profiles of 14 patients with stage I ENKTL, including 7 in the skin, 5 in the gastrointestinal tract, and 2 in the central nervous system, highlighting the distinctiveness of the first. The 7 primary cutaneous (PCNKTL) cases were characterized by an older onset age (median, 76 versus 53 years, P=.012) and a more favorable clinical course (P=.041) compared with 17 patients with stages II-IV ENKTL that showed cutaneous involvement. The skin lesions in the PCNKTL group were distributed in the face or neck (n=4) and limbs (n=3) but not the trunk, which was most frequently affected (60%, P=.017) in the latter group. Furthermore, the stage I cutaneous disease showed a female predominance (male-female, 2:5 versus 7:0; P=.021) and a significantly more favorable survival compared with the noncutaneous stage I ENKTL (P=.037). These results suggest that PCNKTL constitute a distinct subgroup in the nasal-type lymphoma spectrum.

Hepatitis E virus-induced primary cutaneous CD30(+) T cell lymphoproliferative disorder.

BACKGROUND & AIM: Several types of unexplained extra-hepatic manifestations, including haematological disorders, have been reported in the context of hepatitis E virus (HEV) infection. However, the underlying mechanism(s) of these manifestations are unknown. We provide evidence that HEV has an extra-hepatic endothelial tropism that can engage cutaneous T cells towards clonality. METHODS: A patient with a CD30(+) cutaneous T cell lymphoproliferative disorder (T-LPD) and biopsy-proven chronic HEV infection received three rounds of oral ribavirin treatment, administered either without or with interferon, and eventually achieved a sustained virologic response (SVR). Pathologic, virologic and immunologic investigations were carried out on biopsied skin lesion, and peripheral blood mononuclear cells between the 2nd and 3rd round of antiviral treatment and biopsied liver. RESULTS: Remission of T-LPD was observed upon antiviral treatment, and the patient remained in complete remission after achieving SVR. The T cell analysis showed large CD30(+) lymphocytes surrounding the blood vessels within the CD8(+) T cell infiltrate. HEV was detected within dermal microvascular endothelial cells using immunofluorescence staining, in situ hybridisation and electron microscopy. Infiltrating T cells mostly comprised memory CD8(+) T cells with a tissue-resident memory T cell phenotype. Overall, 98% of extracted T cells were CD8(+) T cells with aVß signature skewed towards Vß4 and with an oligoclonal profile. T cell clones from T-LPD were more like T cells in the liver than T cells in the blood [odds ratio=4.55, (3.70-5.60), p<0.0001]. No somatic mutations were found in the T-LPD exomes. CONCLUSION: HEV has an extra-hepatic tissue tropism in humans, including dermal endothelium, and can induce CD30(+) T-LPD that is sensitive to antivirals. LAY SUMMARY: Hepatitis E virus (HEV) has an extra-hepatic tissue tropism and should be added to the list of viruses associated with lymphoproliferative disorders. As such, HEV should be part of the laboratory workup of any lymphoproliferation, particularly those of the T cell phenotype that involve the skin. In the context of HEV-associated cutaneous T cell lymphoproliferative disorders, antiviral treatment could be considered a first-line treatment instead of chemotherapy.

Cutaneous intravascular natural killer/T cell lymphoma with peculiar immunophenotype.

Intravascular lymphoma (IVL) is a rare entity. Most cases are a variant of extranodal diffuse large B cell lymphoma, and fewer than 10% of the published cases are of T cell origin. Only intravascular B cell lymphoma is recognized as a distinct entity in the most recent World Health Organization (WHO) classification of lymphoproliferative disorders. We describe a case of cutaneous natural killer (NK)/T IVL, with a cytotoxic immunophenotype and Epstein-Barr virus (EBV) positivity. However, our case was immunohistochemically negative not only for T cell receptor (TCR)-ßF1 and TCR-γ (TCR-silent), but also for CD56, making it the first triple-negative NK/T IVL case to be described. We urge recognition of this NK/T cell lineage intravascular lymphoma due to its particular immunophenotypical profile and its unvarying relationship with EBV. Its occurrence should not be considered a coincidence, but rather a key aspect of the pathogenic background of this haematological neoplasm.

Current Status of Dedicator of Cytokinesis-Associated Immunodeficiency: DOCK8 and DOCK2.

DOCK8 deficiency is an autosomal recessive combined immunodeficiency disease associated with elevated IgE, atopy, recurrent sinopulmonary and cutaneous viral infections, and malignancy. The DOCK8 protein is critical for cytoskeletal organization, and deficiency impairs dendritic cell transmigration, T-cell survival, and NK cell cytotoxicity. Early hematopoietic stem cell transplantation is gaining prominence as a definitive treatment given the potential for severe complications and mortality in this disease. Recently, DOCK2 deficiency has been identified in several patients with early-onset invasive bacterial and viral infections.

Hydroa Vacciniforme-Like EBV-Positive Cutaneous T-Cell Lymphoma, First Report of 2 Cases in Ecuador.

Hydroa vacciniforme-like cutaneous lymphoma is a very rare Epstein-Barr virus positive peripheral T-cell lymphoma affecting Asian and Hispanic children and young adults with a defective cytotoxic immune response to EBV predisposing to the development of the disease. We report on 2 Ecuadorian patients with papulovesicular and ulcerated crusted lesions on the face, upper and lower extremities and abdomen, with aggressive clinical course and, in one case, a fatal outcome. The histological and molecular profiles (immunohistochemistry and in situ hybridization) established a diagnosis of hydroa vacciniforme-like Epstein-Barr virus-encoded small RNAs + cutaneous T-cell lymphoma in both cases.

Clinicopathologic Features of Hydroa Vacciniforme-Like Lymphoma: A Series of 9 Patients.

Hydroa vacciniforme-like lymphoma is a recently recognized cutaneous T-cell lymphoma associated with Epstein-Barr virus. The disease is observed in children of Latin American or Asian ethnicity. The authors report the clinical, histopathological, and immunophenotypical features of 9 new Mexican patients (M:F = 2:1; mean age, 14.5 years; median age, 13.3 years; age range, 4-27 years), expanding on previous observations of this elusive disease. The most common clinical aspects were persistent facial edema with necroses and pitted scars. Histopathological analyses revealed variably dense lymphoid infiltrates with common angiodestructive features. Neoplastic cells expressed CD3 and cytotoxic markers in all cases and were constantly positive for Epstein-Barr virus (EBER-1). Expression of other markers was variable. Follow-up data revealed that all patients died within 6 months or less, thus showing a very aggressive course with poor prognosis.

Human Endogenous Retrovirus Expression in Primary Cutaneous T-Cell Lymphomas.

BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most frequent cutaneous T-cell lymphomas (CTCL). Human endogenous retroviruses (HERVs) were reverse transcribed and integrated into primate chromosomal DNA, becoming noninfectious, although various stimuli may reactivate them. HERV expression seems to be impaired in several human diseases but limited data regarding CTCL are available. OBJECTIVE: To evaluate the endogenous retroviral transcription profile in CTCL and their expression among disease clinical stages. METHODS: Peripheral blood mononuclear cells from 42 MF/SS patients were analyzed. Total RNA was extracted and amplified with reverse transcription polymerase chain reaction. Results were compared with those obtained in a cohort of 20 healthy donors. RESULTS: HERVs were significantly overexpressed in MF/SS patients compared with healthy donors. No differences were found between early and advanced CTCL stages. CONCLUSION: HERVs can act as promoters in MF/SS pathogenesis. It remains to link HERV hyperexpression to the outcome in CTCL patients.