Primary CD30 Research Articles

Translated article] Primary Cutaneous Lymphoma Registry of the Spanish Academy of Dermatology and Venereology (AEDV): Data for the First 5 Years

Background and objectivePrimary cutaneous lymphomas (PCL) are uncommon. Observations based on the first year of data from the Spanish Registry of Primary Cutaneous Lymphomas (RELCP, in its Spanish abbreviation) of the Spanish Academy of Dermatology and Venereology (AEDV) were published in February 2018. This report covers RELCP data for the first 5 years. Patients and methodsRELCP data were collected prospectively and included diagnosis, treatments, tests, and the current status of patients. We compiled descriptive statistics of the data registered during the first 5 years. ResultsInformation on 2020 patients treated at 33 Spanish hospitals had been included in the RELCP by December 2021. Fifty-nine percent of the patients were men; the mean age was 62.2 years. The lymphomas were grouped into 4 large diagnostic categories: mycosis fungoides/Sézary syndrome, 1112 patients (55%); primary B-cell cutaneous lymphoma, 547 patients (27.1%); primary CD30+ lymphoproliferative disorders, 222 patients (11%), and other T-cell lymphomas, 116 patients (5.8%). Nearly 75% of the tumors were registered in stage I. After treatment, 43.5% achieved complete remission and 27% were stable at the time of writing. Treatments prescribed were topical corticosteroids (1369 [67.8%]), phototherapy (890 patients [44.1%]), surgery (412 patients [20.4%]), and radiotherapy (384 patients [19%]). ConclusionThe characteristics of cutaneous lymphomas in Spain are similar to those reported for other series. The large size of the RELCP registry at 5 years has allowed us to give more precise descriptive statistics than in the first year. This registry facilitates the clinical research of the AEDV's lymphoma interest group, which has already published articles based on the RELCP data.

Registro de linfomas cutáneos primarios (RELCP) de la AEDV: datos tras 5 años de funcionamiento

Background and objectivePrimary cutaneous lymphomas (PCL) are uncommon. Observations based on the first year of data from the Spanish Registry of Primary Cutaneous Lymphomas (RELCP, in its Spanish abbreviation) of the Spanish Academy of Dermatology and Venereology (AEDV) were published in February 2018. This report covers RELCP data for the first 5 years. Patients and methodsRELCP data were collected prospectively and included diagnosis, treatments, tests, and the current status of patients. We compiled descriptive statistics of the data registered during the first 5 years. ResultsInformation on 2020 patients treated at 33 Spanish hospitals had been included in the RELCP by December 2021. Fifty-nine percent of the patients were men; the mean age was 62.2 years. The lymphomas were grouped into 4 large diagnostic categories: mycosis fungoides/Sézary syndrome, 1112 patients (55%); primary B-cell cutaneous lymphoma, 547 patients (27.1%); primary CD30+lymphoproliferative disorders, 222 patients (11%), and other T-cell lymphomas, 116 patients (5.8%). Nearly 75% of the tumors were registered in stage I. After treatment, 43.5% achieved complete remission and 27% were stable at the time of writing. Treatments prescribed were topical corticosteroids (1369 [67.8%]), phototherapy (890 patients [44.1%]), surgery (412 patients [20.4%]), and radiotherapy (384 patients [19%]). ConclusionThe characteristics of cutaneous lymphomas in Spain are similar to those reported for other series. The large size of the RELCP registry at 5 years has allowed us to give more precise descriptive statistics than in the first year. This registry facilitates the clinical research of the AEDV's lymphoma interest group, which has already published articles based on the RELCP data.

Clinical Case of Lymphomatoid Papulosis

Lymphomatoid papulosis is a rare skin disease. The incidence averages 1.5 cases per 1 million population. It is the most common in adults around the age of 40. It was previously considered as paraneoplastic dermatosis, but recent studies have confirmed that lymphomatoid papulosis is a primary CD30 + T-lymphoma of the skin. Despite the aggressive morphological features, it is benign. The disease is characterized by a tendency to spontaneous regression. Typically, skin lesions last 3-12 weeks, although in some severe cases they may last longer. Skin lesions may disappear or recur over decades. Patients require observation because a second lymphoproliferative disease develops in 10-40% of patients.
 A case of lymphomatoid papulosis in a patient with diffuse astrocytoma is presented. The patient was treated with systemic retinoids. The results of differential diagnosis and additional research methods, including dermoscopy, are given. Although the use of dermoscopy was not crucial, the results of the research showed microscopic visual differences between the elements of the rash, depending on the stage of the disease. The picture was mostly typical, however, spots formed by the areas of central erythema on the background of light brown areas, with a predominance of the reticular vessels pattern were also noted in addition to the rash elements on the hairy skull. Clarification of this feature requires further study.
 The purpose of our report is to draw the attention of dermatologists and family doctors to cases of rare dermatoses. The rareness of the disease, lack of knowledge on the clinical findings lead to diagnostic errors, “inadequate treatment”.

Ulcerating mass on the upper eyelid as manifestation of a primary CD30+T-cell lymphoproliferative disease

Ulcerating mass on the upper eyelid as manifestation of a primary CD30+T-cell lymphoproliferative disease

Radiographic and High-Throughput Sequencing (HTS)-Based Response Assessment after Brentuximab Vedotin (BV) Plus Ifosfamide, Carboplatin, and Etoposide (ICE) for Relapsed/Refractory (Rel/Ref) Classical Hodgkin Lymphoma (cHL): Updated Results of a Phase I/II Trial

BACKGROUNDThe likelihood of long-term remission following autologous stem cell transplant (ASCT) for rel/ref cHL is predicted by response to pre-ASCT salvage therapy (Blood 2012;119:1665-70). Salvage regimens incorporating the anti-CD30 antibody-drug conjugate BV, administered sequentially and concurrently with chemotherapy, show promise in improving positron emission tomography (PET)-negative complete remission (CR) rates, transplant eligibility, and outcomes (Lancet Oncol 2015;16:284-92; ASH 2015, #293; ASH 2016, #1109; ASH 2016, #1834). While pre-ASCT PET is a strong predictor of outcome, novel HTS-based assays in development imply greater sensitivity than imaging and a potential role in management and surveillance of lymphomas. Here, we report updated clinical results from our ongoing phase I/II trial (#NCT02227199) in the context of HTS-based detection of HL pre- and post-therapy, as well as circulating cytokine and tumor microenvironment markers. METHODSPatients (pts) ≥ 18 years old with first relapse or primary refractory CD30+ cHL were eligible for this IRB-approved prospective clinical trial. Treatment included BV on Days 1 and 8 at either 1.2 or 1.5 mg/kg (based on 3+3 dose-escalation schema; capped at 150 mg), ifosfamide and mesna 5 g/m2 each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m2 daily on Days 1-3. 2 21-day cycles were given with G-CSF support. BV 1.5 mg/kg was selected as the phase II dose based on reported dose escalation data (ASH 2016, #1834). PET was performed after Cycle 2, with response assigned per Cheson 2007. Peripheral blood (PB) pre- and post-treatment, stem cell (PBSC) product, and (when available) archived formalin-fixed paraffin-embedded tissue (FFPET) from presentation and relapse were collected for correlative studies. DNA for HTS was extracted and analyzed by Adaptive Biotechnologies similar to that described previously (Clin Cancer Res 2014;20:4540-8). Pre-treatment PB cytokine levels were measured by Luminex. Immunohistochemistry (IHC) on FFPET identified components of inflammatory microenvironment. RESULTSTo date, 24 pts have enrolled and 23 are evaluable (1 withdrew consent after 1 cycle). 15 (65%) pts are female. Median age at enrollment was 30 (range, 20-60), with 7 (30%) age ≥ 45. 9 (39%) had advanced-stage disease at initial diagnosis. 14 (61%) did not obtain CR with first-line therapy, all but 1 of which was ABVD-based (the exception received Stanford V). 6 (26%) received prior radiation.Of 23 evaluable pts, 20 (87%) achieved a PET CR by investigator review, while 16 (70%) were in PET CR by central independent review. Of the 4 with discrepant results between investigator and central review, 2 were adjudicated as CR by a 3rd independent reviewer, and 2 were sent for biopsy of residual lesion: 1 biopsy was negative, and 1 noted resolution by imaging guidance so biopsy was aborted. 19 of 22 pts (86%) with adequate follow-up have undergone ASCT. 1 pt in CR after BV-ICE has since relapsed (5%), and no deaths have occurred. The toxicity profile remains similar to that reported previously: 11 (48%) pts experienced Grade 3-4 non-heme toxicity, with sepsis/neutropenic fever (4), hyperglycemia (2), and elevated ALT (2) being the most common; 7 pts (30%) developed neuropathy: 4 Grade 1, 2 Grade 2, and 1 Grade 3; only 1 pt (4%) discontinued study therapy due to toxicity (Grade 3 neuropathy).21 patients had samples tested for disease-specific clonal sequence by HTS. A clone was detectable in PB pre-treatment in only 1 (5%). Post-treatment, none of the PB or PBSC had a detectable clone. Proportions of CD68+ macrophages, granzyme+ cytotoxic cells, and CD20+ B cells by IHC of FFPET from either initial diagnosis or at relapse/enrollment were similar between those who achieved CR and those who did not, as were circulating levels of MIG, HGF, IL2Ra, IL6, and PDL1. CONCLUSIONSBV at a dose of 1.5 mg/kg on Days 1 and 8 per cycle of ICE results in high CR rates, is generally well tolerated, and warrants further investigation in pts with rel/ref cHL. Contrary to previous data (Br J Haematol, 2015;169:689-93), HTS was not able to reliably identify disease-specific clone in PB and thus may not be a useful tool in cHL at present. Inflammatory cell composition and selected serum cytokine levels were not predictive of response to BV-ICE. Enrollment is ongoing, and updated clinical and correlative data will be presented at the meeting. DisclosuresSmith:Dohme Corp: Research Funding; Acerta: Research Funding; Sharp: Research Funding; Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Merck: Research Funding; Genentech: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Gopal:Seattle Genetics: Consultancy, Research Funding.

Self-regressing oral CD30-positive, EBV-negative, T-cell lymphoproliferative lesions. A poorly understood process highlighted by ominous clinicopathologic features and indolent behavior

Intraoral, primary, CD30-positive (CD30+) T-cell lymphoproliferative disorders (TLPDs) are uncommon, and their clinicopathologic presentation and management can vary and may be challenging. Herein, we present a retrospective study of 4 examples of self-regressing primary CD30+ TLPD affecting the gingiva. Archived files were retrospectively reviewed for oral CD30+ TLPDs featuring (1) proper immunohistochemical documentation, (2) Epstein-Barr virus negativity, (3) adequate follow-up information corroborating regression, and (4) no history of hematopoietic malignancy or related-mucocutaneous disease. Three women and 1 man (age range, 55-82 years; mean, 68.3 years) presented with rapidly growing gingival ulcers. Microscopic evaluation revealed diffuse infiltration by sheets of large, atypical cells admixed with lymphocytes and eosinophils, showing angiocentric distribution, focal neurotropism, and muscle infiltration. The lesional cells consistently stained for CD3 and CD30 and were variably immunoreactive against CD2, CD4, CD5, CD7, and CD8, but were negative for ALK1 and EBV-encoded small RNA. TCR-γ gene rearrangement studies revealed a monoclonal T-cell population in 1 case. All lesions showed complete regression 2 to 8 weeks postoperatively (mean follow-up, 4.5 weeks). Notwithstanding their alarming clinicopathologic appearance, there are CD30+ TLPDs confined to the oral cavity that have an indolent course. However, clinical staging is essential to exclude aggressive systemic malignancy.

Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia

BCL-6 mutations are accumulated during B-cell transit through the germinal center (GC) and provide a histogenetic marker for B-cell tumors. On the basis of a comprehensive analysis of 308 B-cell neoplasms, we (1) expand the spectrum of tumors associated with BCL-6 mutations; (2) corroborate the notion that mutations cluster with GC and post-GC B-cell neoplasms; and (3) identify heterogeneous mutation frequency among B-lineage diffuse large cell lymphoma (B-DLCL) subsets. Mutations are virtually absent in acute lymphoblastic leukemia (P <.001) and mantle cell lymphoma (P <.05), whereas they occur frequently in GC or post-GC neoplasms, including lymphoplasmacytoid lymphoma, follicular lymphoma, MALT lymphomas, B-DLCL and Burkitt lymphoma. Among B-DLCL, mutations occur frequently in systemic nodal B-DLCL, primary extranodal B-DLCL, CD5(+) B-DLCL, CD30(+) B-DLCL, and primary splenic B-DLCL, suggesting a similar histogenesis of these B-DLCL subsets. Conversely, mutations are rare in primary mediastinal B-DLCL with sclerosis (10.0%; P <.01), supporting a distinct histogenesis for this lymphoma. Longitudinal follow-up of B-DLCL transformed from follicular lymphoma shows that they BCL-6 mutations may accumulate during histologic progression. Mutations also occur in some B-cell chronic lymphocytic leukemias, small lymphocytic lymphomas, and hairy cell leukemias, consistent with the hypothesis that a fraction of these lymphoproliferations are related to GC-like cells. Finally, the molecular pattern of 193 mutational events reinforces the hypothesis that mutations of BCL-6 and immunoglobulin genes are caused by similar mechanisms. (Blood. 2000;95:651-659)

Dose-Dense Brentuximab Vedotin Plus Ifosfamide, Carboplatin, and Etoposide (ICE) Is Highly Active for Second Line Treatment in Relapsed/Refractory Classical Hodgkin Lymphoma: Final Results of a Phase I/II Study

Dose-Dense Brentuximab Vedotin Plus Ifosfamide, Carboplatin, and Etoposide (ICE) Is Highly Active for Second Line Treatment in Relapsed/Refractory Classical Hodgkin Lymphoma: Final Results of a Phase I/II Study

Abstract 1789: CD30+T regulatory cells, but not CD30+CD8 T cells, are impaired following brentuximab vedotin treatment in vitro and in vivo

Abstract Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) directed against CD30, a TNF receptor superfamily (TNFRSF) member highly expressed on Reed Sternberg cells in Hodgkin lymphoma (HL) and also commonly expressed in a number of other lymphoid malignancies such as ALCL and CTCL. BV consists of a monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. MMAE-based ADC antitumor activity primarily results from intracellular payload release, leading to mitotic arrest and apoptotic cell death, although secondary MOAs may exist. CD30 is mostly absent on resting peripheral lymphocytes, but is known to be transiently upregulated on both CD4+ and CD8+ T cells following activation. Recently, CD30 was identified, by separate research groups, as a marker differentially upregulated by human intratumoral T regulatory cells (Tregs). This recent observation raises the possibility that BV could target and eliminate intratumoral CD30+ Tregs. Abundant evidence shows that tumor-specific CD8+ T cells are paramount to antitumor immunity. In contrast, tumor-resident T regulatory cells have been shown to counteract immunosurveillance and promote tumor escape. Given that CD30 may be expressed on both activated CD8+ T cells and intratumoral Tregs, we explored the outcome of BV treatment on each cell type. In this work, we show that BV directly depleted inducible and primary CD30+ Tregs in vitro, in a dose-dependent manner, while CD30+ CD8+ T cells were unaffected. Moreover, BV selectively depleted Tregs in a Treg:CD8 T cell co-culture suppression assay, resulting in expansion of proliferating CD8+ T cells. In vivo, using a humanized mouse model of graft-versus-host disease (xeno-GVHD), treatment of mice with BV significantly reduced splenic Treg numbers, while amplifying total xeno-reactive CD8+ cytotoxic T cells. In an effort to understand BV's selective impairment of Tregs, we evaluated CD30 expression following in vitro activation with CD3/CD28. Freshly isolated Tregs showed notably accelerated CD30 expression kinetics along with significantly higher peak receptor number compared to CD8+ T cells. Furthermore, assays confirmed that the heightened receptor expression on Tregs translated into increased BV internalization and drug-linker cleavage. Finally, CD8+ T cells were much more efficient at effluxing rhodamine than Tregs, suggesting lowered drug accumulation and exposure over time. Together, these data raise the novel possibility that brentuximab vedotin may be able to positively impact the Treg:CD8 T cell balance in the tumor microenvironment through selective depletion of CD30+ Tregs, but not activated CD8+ T cells. Citation Format: Ryan A. Heiser, Bryan M. Grogan, Luke S. Manlove, Shyra J. Gardai. CD30+T regulatory cells, but not CD30+CD8 T cells, are impaired following brentuximab vedotin treatment in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1789.

Upregulation of inhibitory signaling receptor programmed death marker-1 (PD-1) in disease evolution from cutaneous lymphoid dyscrasias to mycosis fungoides and Sezary's syndrome.

Negative immunoregulatory checkpoints impede effective immune responses to tumor and reduce the action of anticancer agents. One such example is programmed death marker-1 (PD-1), an inhibitory signaling receptor expressed on activated and regulatory T-cells. PD-1 expression was reported in a few reports, but the expression profile of PD-1 and mycosis fungoides (MF) remains largely to be characterized. In this study, skin biopsies from 42 prelymphomatous T-cell dyscrasias (CLD), 9 Sezary's syndrome (SS), 103 MF, and 20 CD30+ lymphoproliferative diseases (LPD) were examined for PD-1 expression using immunohistochemistry. PD-1 staining was observed amidst many neoplastic T-cells in 6/9(66.7%) and 62/103 (60.2%) cases of SS and MF respectively, while only 6/42 (14.3%) cases of CLD and 0/20 (0%) cases of CD30+ LPD (P<0.001). Three cases are from same patients representing different stages of disease evolution from CLD to MF and SS with a corresponding enrichment of PD-1 positivity. In all cases there was variable staining of PD-1 amidst macrophages. There was no correlation with disease progression among MF cases. Twenty cases of CD30+ LPD did not show any PD-1 positivity. PD-1 seems to correlate with disease progression in epitheliotropic T cell dyscrasias ranging from minimal staining in prelymphomatous dyscrasias to significant staining in MF, likely reflecting the effects of PD-1 on inhibiting tumor surveillance regulatory T cell populations. PD-1 was consistently expressed in MF while it was consistently negative in primary CD30+ LPD, suggesting the possibility of using PD-1 as a means of distinguishing CD30+ MF from primary cutaneous ALCL.

Primary cutaneous anaplastic large cell lymphoma initially clinically considered to be pyoderma gangrenosum

Primary CD30+ anaplastic large cell lymphoma, which is generally seen in adults, is the second most common cutaneous T-cell lymphoma after mycosis fungoides. The lesions are characterized by red-brown plaque or nodules often with ulceration. Although usually solitary, there may occasionally be multiple lesions. Here in this case report, a 44-year old male patient with multifocal primary cutaneous anaplastic large cell lymphoma is presented. Primary cutaneous anaplastic large cell lymphoma is a rare disease especially when it is multifocal and has no systemic involvement like in this case. Therefore this case is found valuable to share.

Safety and Activity of Brentuximab Vedotin (BV) Plus Ifosfamide, Carboplatin, and Etoposide (ICE) for Relapsed/Refractory (Rel/Ref) Classical Hodgkin Lymphoma (cHL): Initial Results of a Phase I/II Trial

Background: When initial therapy for cHL fails, the standard approach is multiagent salvage chemotherapy followed by autologous stem cell transplant (ASCT). The success of ASCT can be predicted by achievement of complete remission (CR) by fluorodeoxyglucose positron emission tomography (PET) following salvage chemotherapy (Moskowitz, et al. Blood 2012;119:1665-70). Unfortunately, about half of patients (pts) are unable to achieve CR with first salvage. The anti-CD30 antibody-drug conjugate BV is effective as a single agent in rel/ref cHL (Younes, et al. JCO 2012;30:2183-9). Pre-ASCT salvage chemotherapy combinations with BV have been explored (LaCasce, et al. ASH 2015, #293; Garcia-Sanz, et al. ASH 2015, #582), as has a PET-adapted sequential approach with BV then ICE (Moskowitz, et al. Lancet Oncol 2015;16:284-92). We hypothesized that concurrent therapy with BV and ICE would be safe and produce high CR rates. We also sought to explore inflammatory microenvironment prognostic factors. (ClinicalTrials.gov #NCT02227199)Methods: Pts ≥ 18 years old with first relapse or primary refractory CD30+ cHL were eligible. Key inclusion criteria were ≥ 1 FDG-avid site of disease ≥ 1 cm; adequate marrow, hepatic, and renal function; and HIV-. Key exclusions were any prior BV; chemotherapy ≤ 3 weeks of enrollment; and pre-existing neuropathy > NCI-CTCAE Grade 1. All pts signed IRB-approved informed consent forms. Treatment included BV on Days 1 and 8, ifosfamide and mesna 5 g/m2 each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m2daily on Days 1-3. A 3+3 dose-escalation schema for BV was used to determine the maximum tolerated dose (MTD) with ICE: starting dose was 1.2 mg/kg on Days 1 and 8, escalated to 1.5 mg/kg on Days 1 and 8 or de-escalated to 1.2 mg/kg on Day 1 only, based on rate of dose-limiting toxicity (DLT). Once MTD of BV was established, subsequent pts received this dose. 2 21-day cycles were given with G-CSF support. PET was performed after Cycle 2, with response assigned per Cheson 2007. Stem cells were collected after Cycle 2 at discretion of treating investigator. Peripheral blood (PB) pre- and post-treatment, stem cell (PBSC) product, and (when available) archived formalin-fixed paraffin-embedded tissue from presentation and relapse were collected for correlative studies. Pre-treatment PB PD-L1 levels were measured by ELISA.Results: To date, 16 pts have enrolled and completed study treatment. Median age was 32 (range, 23-60). All received ABVD-based initial chemotherapy, and 5 (31%) received radiation. 11 (69%) did not obtain CR with initial therapy. Grade 3-4 neutropenia, lymphopenia, and anemia was seen in 2 (12%) pts each; thrombocytopenia in 4 (25%) pts. 6 (38%) pts experienced Grade 3-4 non-heme toxicity, but no single toxicity occurred in > 1 pt. Neuropathy was seen in 5 (31%) pts: 4 Grade 1, and 1 Grade 3. 1 DLT (sepsis) was observed in the 9 pts treated in the dose-escalation phase, defining 1.5 mg/kg on Days 1 and 8 as the MTD of BV with ICE.Overall response rate for all enrolled patients was 94% (n=14), with 88% (n=14) and 69% (n=11) achieving CR by investigator and central independent radiographic review, respectively. 15 (94%) pts underwent PBSC collection, all of which were successful. 12 (75%) pts proceeded to ASCT immediately following this treatment. With a median follow-up of 6.5 (range, 2-20) months, there have been 3 (19%) relapses (2 were in CR after BV-ICE) and no deaths.Counts of CD68+ macrophages (15%, 14%), granzyme+ cytotoxic cells (6.2%, 8.7%), and CD20+ B cells (24%, 14%) by immunohistochemistry were not significantly different between presentation and relapse (respectively). Levels of PD-L1 were below the limit of detection (500 pg/mL) in all pts.Conclusions: Pts with rel/ref cHL can safely receive BV up to 1.5mg/kg on Days 1 and 8 per cycle of ICE. Apart from generally-mild neuropathy, adding BV does not appreciably change the toxicity profile of ICE. Observed response rates by PET are very encouraging. Inflammatory cell composition appears similar at presentation and relapse. Without more sensitive testing, circulating levels of PD-L1 are unlikely to be of use in this setting. Enrollment is ongoing, and updated clinical and correlative data, including the use of next-generation sequencing-based detection of lymphoma-specific DNA sequence as a novel method of response assessment, will be presented at the meeting. DisclosuresGopal:Seattle Genetics: Research Funding.

Primary esophageal CD30-positive ALK-positive anaplastic large cell lymphoma with MUM1 expression

We report a case of primary esophageal CD30+/ALK+/MUM1+ anaplastic large cell lymphoma (ALCL) and discuss its diagnosis and treatment, specifically in regard to the unusual expression of the B cell marker, MUM1. A 29-year-old Mexican male presented with an esophageal mass with stenosis and dysphagia. Endoscopic samples were sent for hematoxylin–eosin staining and immunohistochemical analysis. Pathologic and immunohistochemical examination resulted in a diagnosis of primary ALCL of the esophagus with CD30+/ALK+/MUM1+ phenotype. This diagnosis was confirmed by molecular analysis [fluorescence in situ hybridization (FISH)]. Initially, two cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy were given, but the patient exhibited progressive disease. Subsequent treatment consisted of four cycles of ifosfamide, carboplatin, and etoposide (ICE). As of the 12-month follow-up examination, the patient is in complete remission. This case suggests that ALCL of the esophagus should be considered in the differential diagnosis of esophageal neoplasms. Biopsy through esophagoscopy or surgical exploration is recommended, and treatment with chemotherapy or radiotherapy can achieve long-term survival.

Primary cutaneous CD 30+ T-cell lymphoproliferative disorder presenting as paraphimosis: A case report and review of the literature

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PC-CD30+ LPD) as a group are one of the more common types of T-cell lymphoma. More specifically primary cutaneous anaplastic lymphoma (PC-ALCL), one of these lymphoproliferative disorders, is the second most common cutaneous T-cell lymphoma. We report an unusual presentation of PC-ALCL. A 90-year-old, uncircumcised male presented with a 3-week history of painful penile swelling and discharge. The patient was treated with cephalexin and underwent emergent circumcision for paraphimosis. The diagnosis of ALCL was made on microscopic evaluation of the foreskin along with follow-up staging studies. A literature review revealed 31 previously reported cases of penile lymphoma, one of which reported a primary penile CD30+ T-cell lymphoma similar to ours. Only one case report described a lymphoma presenting as paraphimosis. Our case is the second reported case of PC-ALCL of the penis and the first of its kind to present as paraphimosis. Lymphomas must be included in the differential diagnosis of penile lesions and paraphimosis. When present, clinicians should be able to differentiate primary cutaneous lymphoma from lymphomas with secondary skin involvement. All foreskins should be submitted to pathology for proper evaluation of penile lesions.

Mycosis fungoides and CD30+ cutaneous T-cell lymphoma simulating pyoderma gangrenosum in a patient with ulcerative colitis

Pyoderma gangrenosum is estimated to occur in 5% to 12% of ulcerative colitis patients. Primary CD30+ cutaneous large cell lymphoma is the second most common cutaneous lymphoma. It may coexists with mycosis fungoides. We report a 38-years-old female patient with 12 year history of ulcerative colitis, treated previously with 5-aminosalicylic acid and systemic corticosteroids. The disease has been in remission for the past 1.5 years, with no maintenance treatment. The patient then developed a rapidly progressing ulcerated lesion clinically simulating pyoderma gangrenosum. Physical examination revealed also a small number of hairless hypopigmented patches on the upper and lower limbs which she claimed to have appeared 4 years ago. Surprisingly a histological evaluation of the ulcer revealed a CD30+ primary cutaneous large cell lymphoma, while histology of hypopigmented lesions revealed mycosis fungoides, patch stage. T-cell receptor gene rearrangement from the two lesions didn't reveal the same T Cell clonalitiy and the patients lymphoma was stable. Our case presents the rare coexistence of primary mycosis fungoides and primary CD30+ cutaneous large cell lymphoma, rather than the CD30+ cutaneous large cell lymphoma developing from mycosis fungoides. This case also presents the development of a pyoderma gangrenosum-like lesion of CD30+ cutaneous large cell lymphoma in a patient with ulcerative colitis. An observation that emphasizes the need for a high index of suspicion in cases diagnosed as pyoderma gangrenosum based solely on clinical appearance.

Primary Cutaneous CD4+ Small/Medium-sized Pleomorphic T-cell Lymphoma Expresses Follicular T-cell Markers

Cutaneous CD4 small/medium-sized pleomorphic T-cell lymphoma (CSTCL) is a cutaneous T-cell lymphoma defined by a predominance of small-to-medium-sized CD4 pleomorphic T cells, with a favorable clinical course. Cases are also characterized by the presence of a rich infiltrate of reactive B cells. Recently, it has been reported that follicular helper T cells (TFH cells) display a distinct gene expression profile, positive for PD-1, CXCL13, and BCL-6. We report for the first time the expression of PD-1 and other TFH cell markers in CSTCLs and discuss its biologic significance. Sixteen CSTCLs were included in this study, and also 20 reactive inflammatory conditions, 10 primary cutaneous marginal zone, 10 follicular center lymphomas, and 5 primary CD30 cutaneous lymphomas. They were immunohistochemically analyzed for a large panel of markers. Double immunoperoxidase labeling of paraffin sections was performed for PD-1, OCT-2, and BCL-6. Clonal Ig and T-cell receptor rearrangements and Epstein-Barr virus-encoded RNA expression were also evaluated. Morphologic and clinical data were reviewed. Histologic examination showed a dense polymorphic lymphoid infiltrate throughout the dermis. Atypical large CD4 cells were positive for PD-1, CXCL13, and BCL-6 in all cases, and were attached in small clusters, or formed rosettes around CD30/OCT-2+ B blast cells. Epstein-Barr virus was not apparent in any of the cases. A dominant T-cell clone was identified in 14 cases, whereas polymerase chain reaction IgH gene rearrangement studies showed that all cases were polyclonal. None of the patients had lymphadenopathy or showed any evidence of systemic disease, nor did they have any previous history of mycosis fungoides or drug reactions. FTH cell markers are not exclusive to angioimmunoblastic lymphadenopathy but may also be seen in neoplastic cells of CSTCLs. Moreover, these findings suggest that B-cell stimulation by FTH could also take place in some cutaneous T-cell lymphomas.

CD30-Positive T-Cell Lymphoproliferative Disorder of the Oral Mucosa—An Indolent Lesion: Report of 4 Cases

Four cases of CD30-positive T-cell lymphoproliferative disorder (CD30+ LPD) of the oral mucosa are described. This article aims to draw attention to this entity and to emphasize its usual benign clinical behavior despite its resemblance to T-cell lymphoma. All the patients were adults. Three of the lesions were on the dorsal surface of the tongue and 1 affected the buccal mucosa. All biopsies showed a dense lymphoid infiltrate composed of CD30+ atypical T cells with a polymorphous infiltrate in the background, which included eosinophils. In 1 case, monoclonal T-cell expansion was detected by molecular techniques. Three cases tested for Epstein-Barr virus were all negative. It is concluded that primary CD30+ T-cell LPD of the oral mucosa can be regarded as the oral counterpart of cutaneous CD30+ LPD such as lymphomatoid papulosis or anaplastic large cell lymphoma. Recognition of the condition is important to avoid overtreatment.

Analysis of Primary CD30+ Cutaneous Lymphoproliferative Disease and Survival From the Surveillance, Epidemiology, and End Results Database

Primary CD30+ cutaneous lymphoproliferative disease (PCLPD) is a spectrum of indolent cutaneous T-cell lymphomas. The primary intention of the analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database was to report epidemiologic information and overall survival of patients with PCLPD. We investigated the SEER database from 1973 to 2004 and performed univariable and multivariable survival analysis. A total of 268 cases of PCLPD were recorded from 1973 to 2004. Median age at diagnosis was 61 years (range, 5 to 98 years). Among cases, 58% were male, and 42% female. Race distribution was 87% white, 7% black, and 4% Asian/Pacific Islander. A total of 157 patients had primary, localized PCLPD. For the total population (N = 268), overall survival at 3 years was 81% (95% CI, 74% to 87%). Population-matched relative survival at 3 years was 87% (SE, 3.6%). Disease-specific survival at 5 years was 92% (95% CI, 86% to 95%). Head and neck skin site predicted for inferior overall survival in patients with primary, localized PCLPD on univariable analysis (hazard ratio [HR] = 4.4; P = .008; 95% CI, 1.5 to 13.2), and was suggestive of decreased overall survival on multivariate analysis (HR = 3.0; P = .06; 95% CI, 0.95 to 9.7). Localized PCLPDs are rare diseases with an excellent overall survival and occur more frequently in whites and in men. Head and neck skin primary site may be associated with poorer survival. CONCLUSIONS regarding subsets demonstrating association with survival should be taken with caution, given the small number of deaths analyzed.

Treatment of lymphomatoid papulosis with imiquimod 5% cream

To the Editor: Lymphomatoid papulosis is a cutaneous primary CD30+ lymphoproliferative disorder related to mycosis fungoides with a chronic course and an increased risk of lymphoma.1 None of the current available therapies is curative and this subjects the patient to multiple repeated and protracted treatment cycles with attendant acute and long-term toxicity.2 Because lymphomatoid papulosis responds to systemic interferon alfa-2a with a 5-month remission3 and because mycosis fungoides (a related lymphoproliferative disease) responds to topical imiquimod 5% cream (an inducer of local interferon production),4 it seems reasonable that lymphomatoid papulosis might respond to topical imiquimod cream.

Extracutaneous Tumour Mass Following Bexarotene and Interferon Therapy of Primary Cutaneous CD30+ Large Cell Lymphoma

) no prior or concurrent lymphomatoid papulosis (LyP), mycosis fungoides (MF), or other type of cutaneous lymphoma or extracutaneous localization at presentation (1, 2).Lesions of primary cu-taneous CD30+ ALCL tend to be large nodules, tumours, or subcutaneous masses that often ulcerate. Primary cu-taneous CD30+ lymphoproliferative disorders, including CD30+ ALCL, LyP and borderline cases, represent a clinical and histological continuum. In contrast to primary systemic and secondary CD30+ ALCL (e.g. large-cell transformation of MF), the primary cutaneous variant is characterized by an indolent clinical course with 5- and 10-year survival rates exceeding 95% and disseminated or extracutaneous disease in less than 10% (1). There is no uniform therapeutic approach for CD30+ ALCL, but most patients receive combinations of surgery, local radiation and/or chemotherapy (2, 3). Bexarotene, a retinoid X-receptor (RXR)-selective reti-noid, has recently been approved by the Food and Drug Administration (FDA) for cutaneous T-cell lymphoma including refractory MF and Sezary syndrome (4). There are only anecdotal reports on the treatment of CD30+ ALCL with bexarotene (5, 6). We describe here a patient with a predominantly inter-triginous manifestation of primary cutaneous ALCL, who rapidly developed extracutaneous tumour mass following bexarotene and interferon-α (IFN-α).CASE REPORTA 41-year-old Caucasian woman was referred to our hospital with a 10-month history of progressive cuta-neous tumours located mainly in the intertriginous areas such as the axillae, submammary region and inguinal folds (Fig. 1). Apart from slight pruritus she felt other-wise healthy, and had no concomitant diseases except obesity. Several skin biopsies showed mainly dermal and in part subcutaneous infiltration of atypical large lymphoid cells with pleomorphic nuclei and prominent nucleoli. Immunophenotyping revealed that these cells were strongly positive for CD30, CD4 and CD3, and negative for CD20 and CD56. A complete work-out, including clinical and bone marrow examinations, sonography and computerized tomography (CT), showed no evidence for systemic disease. A diagnosis of primary cutaneous CD30+ ACLC was made. Surgi-cal treatment was not considered because of the number of skin lesions. Hence, local radiotherapy with a total dose of 40 Gy given as 20 daily 2-Gy fractions was performed, resulting in a marked decrease of tumour load. However, she experienced new lesions shortly after finishing radiotherapy, and therefore monthly cycles of extracorporeal photophoresis (ECP) in combination with 3×4.5 MIU/week IFN-α-2b were initiated. After a stable outcome for 9 months, new lesions appeared, so bexarotene was added at a dosage of 300 mg/m