Is immunohistochemical expression of GATA3 helpful in the differential diagnosis of transformed mycosis fungoides and primary cutaneous CD30-positive T cell lymphoproliferative disorders?

Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.

Anaplastic large-cell periprosthetic lymphoma of the breast: could fibrin be an early radiological indicator of the presence of disease?

PURPOSE: The onset characteristics of the anaplastic large cell lymphoma (BI-ALCL) are non-specific and the diagnosis is often difficult and based on clinical suspicion and cytological sampling. The presence of non-pathognomonic radiological signs may delay the diagnosis of BI-ALCL, influencing patient prognosis. This could have an important social impact, considering that the incidence of BI-ALCL correlates with the number of prosthetic implants, which is in constant increase worldwide. The aim of this study was to verify if fibrin can represent a potential early radiological sign of the disease. METHODS: In this study, we present two cases of our series and review the previous studies already described in literature, searching for any early radiological sign of the disease and reporting a diagnostic work-up process for an early diagnosis. RESULTS: Signs clearly recognizable only of magnetic resonance were the following: thickening and hyperemia of the fibrous capsule with seroma and amorphous material (fibrin) present in 8 out of 10 cases (80%) detected on magnetic resonance images (certain or doubtful). CONCLUSION: The presence of fibrin in the periprosthetic effusion, well detectable by magnetic resonance imaging, could represent an early pathognomonic sign of the disease.

EMMPRIN (CD147) is induced by C/EBPß and is differentially expressed in ALK+ and ALK- anaplastic large-cell lymphoma.

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is characterized by expression of oncogenic ALK fusion proteins due to the translocation t(2;5)(p23;q35) or variants. Although genotypically a T-cell lymphoma, ALK+ ALCL cells frequently show loss of T-cell-specific surface antigens and expression of monocytic markers. C/EBPß, a transcription factor constitutively overexpressed in ALK+ ALCL cells, has been shown to play an important role in the activation and differentiation of macrophages and is furthermore capable of transdifferentiating B-cell and T-cell progenitors to macrophages in vitro. To analyze the role of C/EBPß for the unusual phenotype of ALK+ ALCL cells, C/EBPß was knocked down by RNA interference in two ALK+ ALCL cell lines, and surface antigen expression profiles of these cell lines were generated using a Human Cell Surface Marker Screening Panel (BD Biosciences). Interesting candidate antigens were further analyzed by immunohistochemistry in primary ALCL ALK+ and ALK- cases. Antigen expression profiling revealed marked changes in the expression of the activation markers CD25, CD30, CD98, CD147, and CD227 after C/EBPß knockdown. Immunohistochemical analysis confirmed a strong, membranous CD147 (EMMPRIN) expression in ALK+ ALCL cases. In contrast, ALK- ALCL cases showed a weaker CD147 expression. CD274 or PD-L1, an immune inhibitory receptor ligand, was downregulated after C/EBPß knockdown. PD-L1 also showed stronger expression in ALK+ ALCL compared with ALK- ALCL, suggesting an additional role of C/EBPß in ALK+ ALCL in generating an immunosuppressive environment. Finally, no expression changes of T-cell or monocytic markers were detected. In conclusion, surface antigen expression profiling demonstrates that C/EBPß plays a critical role in the activation state of ALK+ ALCL cells and reveals CD147 and PD-L1 as important downstream targets. The multiple roles of CD147 in migration, adhesion, and invasion, as well as T-cell activation and proliferation suggest its involvement in the pathogenesis of ALCL.

Expression of p63 protein in anaplastic large cell lymphoma: implications for genetic subtyping.

Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas that bear chromosomal rearrangements of the TP53 homologue TP63 in a subset of cases that demonstrate aggressive clinical behavior. In the present study, we examined the relationship between p63 protein expression by immunohistochemistry and the results of fluorescence in situ hybridization using TP63 probes in 116 ALCLs. We also determined the relative expression of full-length TAp63 and truncated ΔNp63 isoforms (eg, p40) in ALCL cell lines and a subset of clinical cases. Overall, 35.3% of ALCLs were positive for p63 protein. Primary cutaneous and anaplastic lymphoma kinase-negative ALCLs were positive more frequently than anaplastic lymphoma kinase-positive ALCLs (P=.0034). As previously reported, cases with TP63 gene rearrangements expressed p63 uniformly. p63 expression in nonrearranged cases was associated with extra copies of TP63 on 3q28 (P<.0001). Extra copies of TP63 correlated with extra copies of the DUSP22 locus on 6p25.3 (P<.0001). Results of immunohistochemistry, Western blotting, and RNA sequencing indicated that p63 expression in nonrearranged cases was entirely attributable to TAp63 isoforms. Taken together, these findings indicate that ALCLs without TP63 rearrangements may express TAp63 isoforms of p63 and that this expression is associated with extra copies of TP63, probably due to widespread genomic copy number abnormalities rather than focal gains. Immunohistochemistry for p63 in ALCL is not specific for TP63 rearrangements but is useful clinically as a screening test to select cases for further testing by fluorescence in situ hybridization. Immunohistochemistry for ΔNp63 (p40) is not informative in the evaluation of ALCL.

ALK-negative anaplastic large cell lymphoma with loss of CD30 expression during treatment with brentuximab vedotin.

A 59-year-old woman with anaplastic large cell lymphoma (ALCL), ALK-negative, was treated with brentuximab vedotin (BV) against relapse after 6 regimens of systemic chemotherapy and radiation. Despite achieving an initial response, skin lesions worsened after 11 courses. A skin biopsy after the development of resistance to BV confirmed loss of CD30 expression by the tumor cells, suggesting a possible cause of resistance. This case shows that down-regulation of CD30 does occur during BV treatment, resulting in resistance to this drug. Because of this possibility, in the future, expression of CD30 should be carefully monitored with extended use of BV against ALCL.

A primary systemic ALCL present initially as cutaneous localized skin lesions: report of an unusual case.

Anaplastic large cell lymphoma (ALCL) is classified into systemic and primary cutaneous subtypes. A primary systemic ALCL present initially as cutaneous localized skin lesions is a rare presentation. We present an unusual case of a 13-year-old boy with systemic ALCL who presented with cutaneous nodules. The systemic nature of this lymphoma was confirmed by immunohistochemical positivity of anaplastic lymphoma kinase and epithelial membrane antigen. Confirmation of this diagnosis will lead to a poorer prognosis and more aggressive systemic therapy.

High-dose methotrexate monotherapy followed by radiation for CD30-positive, anaplastic lymphoma kinase-1-positive anaplastic large-cell lymphoma in the brain of a child.

The authors report the case of an 11-year-old immunocompetent boy with primary CNS CD30-positive anaplastic large-cell lymphoma (ALCL) that was also positive for anaplastic lymphoma kinase-1. His initial clinical manifestation was acute meningitis of unknown etiology. Findings on CT scanning were normal. Although he received empirical treatment against infection, his systemic and neurological status deteriorated. Subsequent MRI revealed newly emerged enhanced lesions and concomitant edema in the left parietal lobe. Diagnosis was confirmed following a brain biopsy and immunohistochemical staining. Three courses of systemic high-dose methotrexate (HD-MTX) treatment with 2-week intervals was started, followed by whole-brain radiation. His clinical course improved, and he has remained disease-free for more than 8 years without any additional treatment. Because ALCL originating in the brain is extremely rare and difficult to diagnose, no standard treatment has been established. This report suggests that systemic HD-MTX monotherapy can be an effective and worthwhile tailored therapeutic option for pediatric primary CNS ALCL.

Peripheral T-cell lymphomas with cytotoxic phenotype in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is relatively common, and patients occasionally develop other neoplasms; however, patients who develop other types of lymphomas are rare. We encountered 3 patients with CLL/SLL (one 59-y-old man and 2 women aged 56 and 66 y) who developed T-cell lymphomas. Both women developed ALK anaplastic large cell lymphomas (ALCLs), whereas the man developed CD8 peripheral T-cell lymphoma, not otherwise specified. All 3 T-cell lymphomas expressed granzyme B and perforin, indicating a cytotoxic immunophenotype. In 1 case, the first presentation was a lymph nodal composite lymphoma. In the other 2 cases, the T-cell lymphomas arose <1 year after the diagnosis of CLL/SLL and were identified in a lymph node in one case and in the spleen in the other. The patient with a composite lymphoma (SLL/ALK ALCL) was treated and was free of disease at last follow-up, whereas the other 2 patients succumbed to their disease, 1 month and 7 months after the diagnosis of T-cell lymphoma. Peripheral T-cell lymphomas rarely occur in CLL/SLL patients. On the basis of our small series, those with a cytotoxic phenotype appear to be more common in this setting. The occurrence of ALK ALCL in 2 older patients was especially surprising and suggested that CLL/SLL may have played a role in the development of ALCL.

Anaplastic large cell lymphoma associated with breast implants: a report of 13 cases.

We report 13 cases of anaplastic large cell lymphoma (ALCL) associated with breast implants. Patient age ranged from 39 to 68 years, and the interval from implant to ALCL was 4 to 29 years. All tumors were composed of large, pleomorphic cells that were CD30 and ALK1, and all 7 cases assessed had monoclonal T-cell receptor γ-chain rearrangements. Two patient subgroups were identified. Ten patients presented with effusion surrounded by fibrous capsule without a grossly identifiable tumor mass. Nine patients had stage I and 1 had stage II disease. Eight patients underwent implant removal and capsulectomy. Four patients received chemotherapy and 4 radiation therapy. All patients were alive without disease at last follow-up. A second subgroup of 3 patients had effusion and a distinct mass adjacent to the implant. One patient had stage I and 2 stage II disease. One patient had a 3-year history of lymphomatoid papulosis, and 1 patient had a 1-year history of CD30 T-cell lymphoma adjacent to the breast before the diagnosis of ALCL associated with breast implant. Two patients received chemotherapy and 1 radiation therapy. Two patients died 2 and 12 years after diagnosis, respectively. We conclude that the clinical behavior of ALCL associated with breast implants is heterogeneous. Patients who present with effusion without a distinct mass have an indolent disease course, similar to CD30 lymphoproliferative disorder of skin. In contrast, patients who present with a distinct mass may have advanced stage or possibly systemic disease and have a poorer prognosis.

Immunohistochemical expression of Mum-1, Oct-2 and Bcl-6 in systemic anaplastic large cell lymphomas.

AIMS AND BACKGROUND: Several transcription factors predominantly used for B-cell lineage identification are also expressed in a small percentage of T cells within germinal centers and interfollicular areas. The aim of the study was to evaluate the expression of Mum-1, Oct-2 and Bcl-6 in systemic anaplastic large cell lymphoma. METHODS: Thirty cases of anaplastic large cell lymphoma were retrieved from our archives and tissue microarray constructed. Immunohistochemistry was carried out using an avidin-biotin peroxidase complex method. RESULTS: A predominance of nuclear staining was observed for all transcription factors. Mum-1 was positive in all but one case (96.7%). Half of the cases displayed Oct-2 expression (15/30 cases). A considerable number of cases also had Bcl-6 expression (9/30). Bcl-6 staining was noted to be more common in ALK positive cases. CONCLUSION: Our findings emphasize that these markers are not restricted to B-cell lineage and that extensive expression can be observed in anaplastic large cell lymphoma of T/null cell phenotype.

Fine needle aspiration cytology of ALK1(-), CD30+ anaplastic large cell lymphoma post renal transplantation: a case report and literature review.

Post transplant lymphoproliferative disorders (PTLD) complicates the course of 0.3 to 3% of renal transplant patients receiving immunosuppression. Epstein-Barr virus (EBV) related non-Hodgkin's lymphomas of B-cell type is more common than those of T-cell origin. CD30 positive Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin's lymphoma (B or T cell type) that accounts for a small percentage of PTLD's. ALCL of T-cell type are a spectrum of disease ranging from primary cutaneous to systemic nodal ALCL. The systemic nodal ALCL is further subdivided into anaplastic lymphoma kinase-1 (ALK-1) positive or negative. ALK-1 protein is a gene fusion product of translocation (2;5) and carries prognostic implications. We present an unusual manifestation of ALK-1 negative CD30 positive ALCL in a post renal transplant patient in FNA cytology with all supportive adjuvant studies and differential diagnoses and review the cytology literature on this topic.

Spectrum of CD30+ lymphoid proliferations in the eyelid lymphomatoid papulosis, cutaneous anaplastic large cell lymphoma, and anaplastic large cell lymphoma.

PURPOSE: To report the clinicopathologic features of 3 patients with CD30(+) lymphoid proliferations of the eyelid. DESIGN: Retrospective case series. PARTICIPANTS: Patients with cutaneous CD30(+) lymphoproliferative lesions of the eyelid. METHODS: Three patients with CD30(+) non-mycosis fungoides T-cell lymphoid infiltrates of the eyelid were identified. The histories, clinical findings, pathologic features including immunohistochemical staining, treatments, and outcomes were reviewed and compared. MAIN OUTCOME MEASURES: Pathologic findings including immunohistochemical analysis. RESULTS: The patients included an 81-year-old man, an 18-year-old man, and a 42-year-old woman with CD30(+) lymphoid proliferations of the eyelid and adjacent soft tissue. The first patient had an isolated crateriform eyelid lesion that was classified as lymphomatoid papulosis (LyP). The second patient had an isolated multinodular lesion of the eyelid that was classified as cutaneous anaplastic large cell lymphoma (cALCL). The third patient presented with eyelid edema with an underlying mass and was found to have widely disseminated anaplastic large cell lymphoma (ALCL). Diagnoses were dependent on clinical findings. CONCLUSIONS: The CD30(+) lymphoid proliferations represent a spectrum of conditions ranging from indolent LyP, to moderately aggressive cALCL, to highly aggressive ALCL. Interpretation of the pathologic findings in CD30(+) lymphoid proliferations is based in part on clinical findings. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any material discussed in this article.

Primary cutaneous anaplastic large cell lymphoma of the medial canthus and orbit.

A 59-year-old man sought evaluation for a rapidly enlarging, nontender, ulcerated right medial canthal lesion unresponsive to antibiotics. Biopsy revealed CD30+ anaplastic large cell lymphoma. CT demonstrated contiguous spread in the orbit. Systemic evaluation for lymphoma was negative, and he underwent local radiotherapy. The lesion regressed completely, and he has remained disease free for 7 months. CD30+ anaplastic large cell lymphoma of the periocular skin and orbit are usually distinct, exceedingly rare entities; no reported cases had simultaneous involvement of both tissues. The authors present the first reported case, to their knowledge, of simultaneous skin and orbital involvement by anaplastic large cell lymphoma.