Oncogenic alterations in KIR3DL1 in cutaneous acral CD8+ lymphoproliferative disorder.

BACKGROUND: Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (TLPD) is a rare and indolent lymphoma entity. Although TLPD was first identified many years ago, the molecular pathogenesis is still not fully understood. OBJECTIVES: In order to better understand the molecular pathogenesis of cutaneous acral CD8+ TLPD and to identify further discriminatory markers to differentiate this lymphoma subtype from other CD8+ cutaneous lymphomas, we analysed five cases of cutaneous acral CD8+ TLPD for putative molecular alterations. METHODS: Somatic alterations were assessed using whole-exome and targeted sequencing of paraffin-embedded tissue. Results were evaluated using immunohistochemical staining of respective relevant proteins. CD8+ cutaneous T-cell lymphomas (n = 12) served as control for KIR3DL1 staining. RESULTS: Copy number variation analysis revealed a homozygous deletion of the KIR3DL1 gene in two of the analysed cases. This resulted in loss of KIR3DL1 protein expression, which was observed in all cases of cutaneous acral CD8+ TLPD. In contrast, KIR3DL1 expression was more variable in other CD8+ cutaneous T-cell lymphomas with 50% of analysed cases (n = 12) found to be positive. In addition, one further case of acral CD8+ TLPD harboured a loss-of-function mutation in the PIK3R1 gene, presumably activating the phosphoinositide 3-kinase-AKT pathway. CONCLUSIONS: Alterations of the KIR3DL1 gene may be of pathogenetic relevance for acral CD8+ TLPD. Loss of KIR3DL1 protein expression may support the diagnosis of this indolent lymphoma entity; however, this is not a subtype-specific discriminative feature.

Cutaneous acral CD8+ T-cell lymphoproliferative disorder (TLPD) is a very rare form of lymphoma, with only around 60 cases reported worldwide. The progression of this lymphoma is usually slow, and most people will present with a solitary plaque or a small papule, without any risk of rapid worsening. For this reason, treatment directly on the skin with topical steroids, excision or radiation are usually sufficient. However, it can be difficult to differentiate this type of lymphoma from other CD8+ cutaneous types upon microscopy. This is important because other CD8+ cutaneous lymphomas can follow an aggressive course and will need to be treated differently, using systemic therapies. Previous findings have shown that abnormal expression of a protein (called CD68) in a dotlike pattern is a specific feature of acral CD8+ TLPD and could help to accurately diagnose this lymphoma. Until now, the underlying molecular differences in cutaneous acral CD8+ TLPD have not been identified. Therefore, this German study was carried out to look at the genetic alterations in the tissue of five patients with this type of lymphoma. To do this, we used a method that examined whole-exome and targeted gene sequencing. We detected alterations in a gene important for T-cell function (called KIR3DL1), in two of five analysed cases. Of note, a loss of KIR3DL1 protein expression has been observed in all analysed cases of acral CD8+ TLPD. Our study findings suggest that genetic defects in KIR3DL1 in acral CD8+ TLPD could be a novel diagnostic marker for this lymphoma subtype and may help to better distinguish it from other, potentially aggressive forms of cutaneous lymphoma.

Clinical, histopathological and prognostic features of primary cutaneous acral CD8+ T-cell lymphoma and other dermal CD8+ cutaneous lymphoproliferations: results of an EORTC Cutaneous Lymphoma Group workshop.

BACKGROUND: The differential diagnosis of atypical dermal nonepidermotropic CD8+ lymphocytic infiltrates includes a heterogeneous spectrum of lymphoproliferations with overlapping histological and phenotypic features, but divergent clinical manifestations and prognoses. As these neoplasms are rare, more data on their clinicopathological presentation and course are needed. OBJECTIVES: To assess the clinical, histological and immunophenotypic features; outcomes of; and differences between dermal CD8+ lymphoproliferations. METHODS: Retrospective analysis of a series of 46 patients and biopsies by the international EORTC Cutaneous Lymphoma Group. RESULTS: The dermal CD8+ lymphoproliferations (n = 46) could be assigned to one of three groups: (i) cutaneous acral CD8+ T-cell lymphoma (n = 31), characterized mostly by a solitary nodule arising at acral sites, a monotonous dermal infiltrate of small-to-medium-sized CD8+ lymphocytes with a characteristic dot-like pattern of CD68, a low proliferation rate and an excellent prognosis; (ii) primary cutaneous CD8+ peripheral T-cell lymphoma, unspecified/NOS (n = 11), presenting with one or multiple rapidly evolving tumours, mostly medium-sized pleomorphic CD8+ tumour cells with expression of several cytotoxic markers, and high proliferative activity; and (iii) cutaneous CD8+ lymphoproliferations (n = 4), associated with congenital immunodeficiency syndromes in two patients with persisting localized or disseminated violaceous to brownish plaques on the extremities, a histiocyte-rich infiltrate of mostly small CD8+ lymphocytes with subtle atypia and a protracted course; and papular CD8+ eruptions in two patients with acquired immunosuppression. CONCLUSIONS: A constellation of distinct clinical, histopathological and phenotypic features allows discrimination and assignment of dermal CD8+ infiltrates into distinct disease entities. Primary cutaneous acral CD8+ lymphoma, assigned a provisional category in current lymphoma classifications, is a distinct and reproducible entity. A correct diagnosis is essential to avoid unnecessarily aggressive treatment for indolent CD8+ lymphoproliferations and to identify cases with underlying immuno-deficiency or potential for dismal outcome.

EBER in situ hybridization in subcutaneous aluminum granulomas/lymphoid hyperplasia: A diagnostic clue to differentiate injection-associated lymphoid hyperplasia from other forms of pseudolymphomas and cutaneous lymphomas.

BACKGROUND: Subcutaneous vaccination or desensitization may induce persistent nodules at the injection sites. Without the knowledge of prior injection, histopathological work-up may be challenging. OBJECTIVE: Aim of this study was to contribute to the histopathological work-up of unclear subcutaneous nodules, especially their differentiation from cutaneous lymphoma. METHODS: We retrospectively reviewed clinical data and histopathological slides of four patients with subcutaneous nodules, which were suspected to suffer from cutaneous T- or B-cell lymphoma. Sections of these cases and 12 negative controls were stained with hematoxylin and eosin and a standardized immunohistochemical panel of B- and T-cell markers including EBER in situ hybridization as well as electron microscopy. RESULTS: In all cases, large histiocytes with granular cytoplasm compatible with intracellular aluminum hydroxide were present. EBER in situ hybridization revealed positive staining of these granular histiocytes while staining was absent in negative controls. LIMITATIONS: Post hoc completion of medical history revealed that vaccination or specific immunotherapy had been applied before at the biopsy site in only three out of four patients; one patient was lost to follow-up. CONCLUSION: EBER in situ hybridization is an adjunctive tool to differentiate aluminum-induced granuloma/lymphoid hyperplasia from other forms of pseudolymphoma and cutaneous B- or T-cell lymphomas.

Clonal expansion of large granular lymphocytes in patients with spondyloarthritis and psoriatic arthritis treated with TNFα inhibitors.

To determine the prevalence of clonal T-large granular lymphocyte (T-LGL) cells in patients with spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to define possible risk factors for this condition. We present a cross-sectional analysis with retrospective and prospective aspects. 115 SpA patients, 48 PsA patients and 51 controls were recruited between December 28, 2017 and January 23, 2019. Flow cytometry (FACS) was performed to screen for aberrant T-LGL cells. Molecular analysis was then employed to confirm the diagnosis in patients with suggestive FACS findings. Patients with clonal T-LGL populations were followed prospectively by FACS analysis. Electronic patient files were retrospectively analyzed to determine risk factors. Median age was 49 years for SpA, 55.5 years for PsA, and 54 years for controls. Median disease duration of SpA and PsA was 15 years and 11 years, respectively. 79.8% of patients had received biologics at some point, 75.5% had ever received tumor necrosis factor (TNF) inhibitors. 59.5% were treated with TNF inhibitors at the time of study inclusion. We identified clonal T-LGL expansions in 13 individuals equaling a prevalence of 6% (13/214). T-LGL patients were taking TNF inhibitors more frequently at the time of study inclusion (p = 0.022) and were more likely to have ever been treated with TNF inhibition (p = 0.046). Clonal T-LGL expansions can be detected in patients with SpA, PsA and also in healthy controls. Confirming earlier results, exposure to TNFα-blocking agents appears to increase the risk of developing clonal expansions of T-LGL cells.

T-cell pseudolymphoma in recurrent herpes simplex virus infection.

BACKGROUND: In cases of herpes virus infection without typical histologic (and clinical) signs it is difficult to achieve the correct diagnosis by histology alone. Some of those cases are prone to be misdiagnosed as cutaneous lymphoma. METHODS: This retrospective study included five patients with herpes simplex virus (HSV)-associated pseudolymphoma. We investigated clinical, histomorphologic and immunophenotypic features of all patients. RESULTS: All biopsy specimens presented a superficial and deep perivascular lymphohistiocytic infiltrate with epidermotropism, atypia and admixed plasma cells to varying degrees. Four of five samples showed lining-up of lymphocytes in the junctional zone with predominance of CD8+ lymphocytes, in contrast to the dermal part (inverse CD8:CD4 ratio). Papillary edema was found in four of five cases. Clinically, patchy erythema located on the buttocks and adjacent areas was typical, sometimes with erosions and crusts. Medical history of recurrent blisters, pain or itching was additionally helpful. CONCLUSION: We point out subtle but consistent histomorphologic criteria, which were helpful to diagnose HSV-associated pseudolymphoma in context with the clinical presentation.

Primary cutaneous diffuse large B-cell lymphoma, NOS and leg type: Clinical, morphologic and prognostic differences.

BACKGROUND AND OBJECTIVES: Primary cutaneous diffuse large B-cell lymphoma, NOS (PCLBCL/NOS) is a rare PCLBCL. Only few data are available for this tumor. The aim of this study was to identify clinical and/or immunohistochemical markers (in addition to Bcl-2) that characterize PCLBCL/NOS, assist in differentiating it from PCLBCL, leg type (PCLBCL/LT) and help to assess the clinical course/prognosis. PATIENTS AND METHODS: Bcl-2- PCLBCL/NOS) cases (n = 14 were compared with Bcl-2+ PCLBCL/LT cases (n = 29). RESULTS: PCLBCL/NOS patients were younger, predominantly male and had better survival rates than patients with PCLBCL/LT. Patients with PCLBCL/NOS presented more often with larger plaques limited to one or two contiguous body regions, whereas PCLBCL/LT cases often presented with disseminated lesions. Neoplastic cells had a higher proliferation rate (Ki67) in PCLBCL/LT patients. The tumor microenvironment of PCLBCL/NOS had a more prominent CD3+ infiltrate. Overall survival data for the whole cohort (n = 37) revealed that female gender and Bcl-2 expression correlated with a worse survival rate. Bcl-6 expression and centroblastic subtype correlated with better outcomes. None of the other markers studied (e.g. GCB/non-GCB subtype) correlated with survival rate. CONCLUSIONS: PCLBCL/NOS and PCLBCL/LT differ in their clinical behavior and outcomes. Bcl-2 still seems to be the best marker for discriminating between these two subgroups. Bcl-2, female gender and Bcl-6 represent prognostic markers for PCLBCL.

SYK expression in monomorphic epitheliotropic intestinal T-cell lymphoma.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), formerly known as type II enteropathy associated T-cell lymphoma (type II EATL), is a rare, aggressive primary intestinal T-cell lymphoma with a poor prognosis and an incompletely understood pathogenesis. We collected 40 cases of MEITL and 27 cases of EATL, formerly known as type I EATL, and comparatively investigated the T-cell receptor (TCR) itself and associated signaling molecules using immunohistochemistry, amplicon deep sequencing and bisulfite pyrosequencing. The TCR showed both an αß-T-cell origin (30%) and a γδ-T-cell derivation (55%) resulting in a predominant positive TCR phenotype in MEITL compared with the mainly silent TCR phenotype in EATL (65%). The immunohistochemical expression of the spleen tyrosine kinase (SYK) turned out to be a distinctive feature of MEITL (95%) compared with EATL (0%). Aberrant SYK overexpression in MEITL is likely caused by hypomethylation of the SYK promoter, while no common mutations in the SYK gene or in its promoter could be detected. Using amplicon deep sequencing, mutations in DNMT3A, IDH2, and TET2 were infrequent events in MEITL and EATL. Immunohistochemical expression of linker for activation of T-cells (LAT) subdivided MEITL into a LAT expressing subset (33%) and a LAT silent subset (67%) with a potentially earlier disease onset in LAT-positive MEITL.

Paraproteinaemia in Primary Cutaneous Marginal Zone Lymphoma.

Primary cutaneous marginal zone lymphomas (PCMZL) frequently exhibit lymphoplasmacytoid/plasmacytic differentiation, implying the capacity to produce monoclonal immunoglobulins. As these paraproteins are secreted, and thus are measurable in blood and urine, they may correlate with disease burden and serve as tumour markers reflecting therapeutic response. This study retrospectively analysed the records of 23 patients with PCMZL. During treatment and follow-up, laboratory tests, including full blood count, lactate dehydrogenase, serum protein electrophoresis and turbidimetric analyses, were conducted. Thirty-nine percent of cases showed a suspicious serum protein electrophoresis in terms of paraproteinaemia. In 44% of cases the heavy and light chain restriction in tissue samples correlated with serological findings. Altogether, 89% of the PCMZL patients with paraproteinaemia eventually experienced a relapse, in contrast to 62% of the group without paraproteinaemia. This study analysed the incidence and clinical implications of paraproteinaemia in patients with PCMZL. A clear correlation was found between paraproteinaemia, tumour relapse and therapeutic intervention.

Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2 mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P = .01). High expression of cytotoxic gene-signature within the TBX21 subgroup also showed poor clinical outcome (P = .05). In AITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P = .004).

3.0 Tesla breast magnetic resonance imaging in patients with nipple discharge when mammography and ultrasound fail.

OBJECTIVES: To compare 3.0 Tesla breast magnetic resonance imaging (MRI) with galactography for detection of benign and malignant causes of nipple discharge in patients with negative mammography and ultrasound. METHODS: We prospectively evaluated 56 breasts of 50 consecutive patients with nipple discharge who had inconspicuous mammography and ultrasound, using 3.0 Tesla breast MRI with a dedicated 16-channel breast coil, and then compared the results with galactography. Histopathological diagnoses and follow-ups were used as reference standard. Lesion size estimated on MRI was compared with the size at histopathology. RESULTS: Sensitivity and specificity of MRI vs. galactography for detecting pathologic findings were 95.7 % vs. 85.7 % and 69.7 % vs. 33.3 %, respectively. For the supposed concrete pathology based on MRI findings, the specificity was 67.6 % and the sensitivity 77.3 % (PPV 60.7 %, NPV 82.1 %). Eight malignant lesions were detected (14.8 %). The estimated size at breast MRI showed excellent correlation with the size at histopathology (Pearson's correlation coefficient 0.95, p < 0.0001). CONCLUSIONS: MRI of the breast at 3.0 Tesla is an accurate imaging test and can replace galactography in the workup of nipple discharge in patients with inconspicuous mammography and ultrasound. KEY POINTS: • Breast MRI is an excellent diagnostic tool for patients with nipple discharge. • MRI of the breast reveals malignant lesions despite inconspicuous mammography and ultrasound. • MRI of the breast has greater sensitivity and specificity than galactography. • Excellent correlation of lesion size measured at MRI and histopathology was found.

Childhood mycosis fungoides with a CD8+ CD56+ cytotoxic immunophenotype.

Primary cutaneous T-cell lymphomas mostly occur in patients of middle and higher age. Their rarity and an oftentimes atypical clinical presentation in childhood as well as the reluctance of taking biopsies in children are reasons for a delayed diagnosis. We report the case of an 11-year-old boy with a 7-year history of slowly progressive CD8+CD56+ mycosis fungoides of the cytotoxic immunophenotype. His trunk and extremities were affected by extensive pale-erythematous patches and plaques with fine scaling. In addition, several poikilodermatous lesions were present on his thighs. Improvement was achieved by topical mometasone furoate treatment. On the basis of our observation, a brief review on cutaneous T-cell lymphomas in childhood and on CD8+ subtypes in particular is given. Clinicopathological correlation is crucial for establishing the correct diagnosis and for estimation of the prognosis.

Alternative BRAF mutations in BRAF V600E-negative hairy cell leukaemias.

The BRAF V600E mutation in exon 15 is considered the disease-defining mutation in hairy cell leukaemia (HCL), but single HCL cases lacking this mutation have been described. In 24 HCL, as well as in 194 various mature B- and T-cell neoplasms, we extended the search for BRAF mutations to exon 11. Two V600E-negative HCL contained novel, potentially functionally relevant mutations in exon 11 (F468C and D449E), while one other HCL was BRAF wild-type in exons 2-17. All non-HCL lymphomas lacked BRAF mutations. We therefore suggest screening of BRAF V600E-negative HCL for alternative exon 11 mutations in the diagnostic setting.

Intraoperative 3-D imaging improves sentinel lymph node biopsy in oral cancer.

PURPOSE: The aim of this study was to prospectively evaluate the feasibility and potential advantages of freehand single-photon emission computed tomography (fhSPECT) compared with conventional intraoperative localization techniques for sentinel lymph node biopsy (SLNB) in oral cancer. METHODS: Between November 2012 and February 2014, 23 consecutive patients with clinical T1/T2 oral squamous cell carcinoma and a cN0 neck were recruited. All patients underwent SLNB followed by elective neck dissection (END). All patients received preoperative lymphoscintigraphy. To detect the SLNs intraoperatively, fhSPECT with a combination of conventional acoustic SLN localization and 3-D visual navigation was used. RESULTS: All but one of the SLNs detected by preoperative imaging were successfully mapped intraoperatively by fhSPECT (detection rate 98%), including those in six patients with a tumour in the floor of the mouth. A histopathology analysis revealed positive SLNs in 22% of patients. No further metastases were found in LNs resected during END. SLNB correctly predicted the final LN stage in all patients (accuracy 100%). Additional radioactive LNs, which were not present on preoperative lymphoscintigraphy, were observed in three patients. CONCLUSION: FhSPECT is a feasible technology that allows the accurate identification of SLNs in oral cancer. FhSPECT overcomes the shine-through phenomenon, one of the most important limitations of SLNB, thereby confirming the importance of SLNB in patients with cN0 oral cancer.

Primary cutaneous marginal zone lymphomas with plasmacytic differentiation show frequent IgG4 expression.

The expression of IgG4 in malignant B-cell lymphomas has only partially been studied. Recent reports described single cases of marginal zone lymphomas arising in the ocular adnexae that express IgG4. Moreover, a subset of dura-associated marginal zone lymphomas appear to express IgG4 as well. We investigated IgG4 expression in a more systematic manner in a large cohort of marginal zone lymphoma specimens derived from the archive of our institute. Overall, we examined 169 marginal zone lymphomas of various primary sites that displayed a distinct plasmacytic differentiation and light chain restriction, allowing for a detailed investigation of the immunoglobulin heavy chain expression in these tumors by immunohistochemistry. Unexpectedly, primary cutaneous marginal zone lymphomas showed frequent IgG4 expression. Although only 1 out of 120 noncutaneous marginal zone lymphomas, located in the ocular adnexae, expressed IgG4, 19 of 49 (39%) primary cutaneous marginal zone lymphomas showed this feature, constituting the highest expression rate of IgG4 reported to date in any B-cell lymphoma. None of the IgG4-positive cutaneous marginal zone lymphomas with available clinical data showed evidence of a preexisting systemic IgG4-related disease, suggesting a localized immunologic IgG4-driven pathogenetic process at early stages of the disease. IgG4-positive and IgG4-negative primary cutaneous marginal zone lymphomas did not significantly differ in architectural features of the infiltrate or the composition of the reactive T-cell infiltrate as determined by analysis of T-cell content, CD4/CD8 ratio, and content of FOXP3- and PD1-positive T cells. Although the pathogenetic role of IgG4 expression in a significant subset of primary cutaneous marginal zone lymphomas with plasmacytic differentiation remains unclear at present, the demonstration of IgG4 expression in a marginal zone lymphoma involving the skin might be a helpful clue in the routine diagnostic setting, as these tumors will almost invariably be of primary cutaneous origin with an extremely low risk of spread to noncutaneous sites and an excellent prognosis.

Primary cutaneous marginal zone lymphoma with sequential development of nodal marginal zone lymphoma in a patient with selective immunoglobulin A deficiency.

Multiple lymphoma subtypes occurring within one patient is rare in the context of B-cell lymphoma, and only few such cases have been reported in association with primary cutaneous marginal zone lymphoma (PCMZL). We herein describe the case of a 43-year-old patient who was diagnosed with PCMZL and subsequently developed a clonally unrelated nodal marginal zone lymphoma (MZL). At the time of diagnosis of PCMZL, multiple skin lesions were present. The atypical lymphoid infiltrate showed monotypic expression of immunoglobulin light chain lambda and heavy chain (IgM) on immunohistochemistry and an identical B-cell clone. No sign of systemic lymphoma was present in staging examinations. Complete remission was achieved utilizing rituximab. After a 3-year clinical course of repetitive cutaneous relapses and remissions, the patient additionally developed nodal lymphoma involvement by MZL which, however, harbored an immunophenotype and a genetic clone distinct from the cutaneous lymphoma counterpart. Therefore, the rare occurrence of two different types of MZL with sequential evolution was diagnosed. In this uncommon case, we hypothesize that selective immunoglobulin A deficiency may play a promoting role for the metachronous development of the two MZL that occurred in our patient.

Extrafacial indolent CD8-positive cutaneous lymphoid proliferation with unusual symmetrical presentation involving both feet.

Indolent CD8+ cutaneous lymphoid proliferation represents a recently described entity among cutaneous T-cell lymphomas that typically presents with solitary skin lesions on the face or at acral sites and usually follows an indolent clinical course. Histopathologically, this entity is characterized by a dense dermal infiltrate of non-epidermotropic, small- to medium-sized pleomorphic CD8+ T-cells of the non-activated cytotoxic phenotype showing a clear-cut grenz zone and a low proliferation index. Distinction from otherwise aggressive T-cell lymphomas bearing a cytotoxic CD8+ phenotype is fundamental. We herein present an unusual case of indolent CD8+ cutaneous lymphoid proliferation presenting in bilateral symmetrical distribution on both feet and lacking the otherwise described grenz zone. Our case widens the spectrum of possible clinical and histomorphological variations of this entity. Taking into account the distinctive and unique clinical and microscopic features of all hitherto published cases of indolent CD8+ cutaneous lymphoid proliferation we suppose that this lymphoma subtype has to be included as a new and distinct entity in the World Health Organisation (WHO)-/European Organisation for Research and Treatment of Cancer (EORTC)-classification of cutaneous lymphomas.

Primary cutaneous follicular helper T-cell lymphoma: diagnostic pitfalls of this new lymphoma subtype.

The recently proposed entity of cutaneous follicular helper T (T(FH)) cell lymphoma (CT(FH)CL) harbors distinct clinical and histopathologic features. Here, diagnostic pitfalls are exemplified in a case report and by review of the literature. A 45-year-old patient developed rapidly growing nodules and plaques on upper arms and buttocks, which were initially misdiagnosed as primary cutaneous follicle center B-cell lymphoma (CFCL). Consequently, systemic therapy with rituximab failed and consecutive skin biopsies revealed CT(FH)CL (CD3+CD4+CD10+PD-1+bcl6+ICOS+CXCL13+). Interestingly, the prima vista PD-1-positive and CD10-positive tumor cells lost PD-1 expression in follow-up biopsies while retaining CD10, ICOS and CXCL13 expression. All biopsy specimens displayed an identical clonal T-cell population. Initially, nodules were controlled by local radiotherapy and oral psoralen combined with ultraviolet A (PUVA) therapy. However, disease recurred and progressed rapidly with disseminated nodules. Treatment with bexarotene, methotrexate and polychemotherapy failed to stop disease progression. Finally, modified total skin electron beam radiation resulted in complete remission. Disease stabilized on maintenance therapy with bexarotene in combination with ultraviolet A (UVA) therapy. The case highlights that because of concomitant B-cell stimulation, CT(FH)CL clinicopathologically is prone to be mistaken for CFCL. Importantly, CT(FH)CL might lose PD-1 while retaining CD10 expression in later stages, which may lead to confusion in distinguishing CT(FH)CL from CFCL.

Periocular cutaneous oncocytoma with signs of disrupted oxygen metabolism.

Oncocytomas are benign tumors most often occurring in salivary or lacrimal glands and thyroid tissue. As cutaneous oncocytoma is exceptionally rare, this tumor is uncommonly encountered by dermatopathologists. Herein, we illustrate the case of an 80-year-old man who presented with a slowly growing papule of the lower eyelid. Histopathologically, the adenomatous tumor was composed of large monomorphic cells with eosinophilic granular cytoplasm. Electron microscopy revealed abundant, enlarged and abnormally shaped mitochondria. These findings were consistent with an oncocytoma of the skin. The presented case is unique in that the thorough work-up of the tumor tissue revealed not only hyperplastic mitochondria, representing the ultrastructural correlate of the observed granular cytoplasm, but additionally disclosed functional consequences with elevated levels of reactive oxygen specimen (ROS) within the tumor. Disrupted oxygen metabolism may result from cellular aging processes and may putatively represent the underlying pathogenesis of oncocytoma.