Total skin electron beam therapy for cutaneous T-cell lymphomas in the Netherlands: A retrospective analysis of treatment outcomes and selection for high or low dose schedule.

PURPOSE: Total skin electron beam therapy (TSEBT) is used mostly in the treatment of cutaneous T cell lymphoma. In this study we describe the results of TSEBT applied in the Netherlands using two different schedules, a conventional dose schedule of 35 Gy and a low-dose schedule of 12 Gy. We aimed to evaluate the treatment results in and compare treatment outcomes between the two treatment groups and to further define indications for both doses. METHODS: In the LUMC, Leiden, we performed a retrospective analysis of 51 patients treated with TSEBT between January 2008 and December 2018, with follow-up untill December 2019. Thirty one patients were treated with 35 Gy and twenty with 12 Gy. The dose was chosen based on the severity of skin involvement. Outcome measures were time to meaningful progression, survival, response rate and toxicity. RESULTS: Time to meaningful progression was 5.1 months with no significant differences between dose groups (P = 0.77). Overall survival was 27.4 months. Both time to progression and survival were significantly better for T2 vs T3 stage. Overall response rate was 80.4 %. Both dose groups showed improvement of symptoms. Treatment was generally well tolerated. CONCLUSIONS: Both high-dose and low-dose TSEBT offer similar results for TMP and OS. It remains unclear which patients benefit most from a high-dose schedule. We propose to use the low-dose schedule as a standard for TSEBT and use supplementary boosts or escalation to high-dose treatment for patients unresponsive to the low-dose schedule.

Children's use of psychosocial care in a population-based longitudinal study: less likely for girls, children with a non-Western background and children with a high quality of life.

Knowledge on determinants of children's psychosocial care use is important to improve their access to care. This study examined the independent contributions of need and predisposing factors to psychosocial care use in 9-year-old children, guided by the Gateway Provider Model. Data of the Generation R Study, a prospective cohort of children born in Rotterdam, the Netherlands, were analysed using multivariable logistic regression (n = 4714). Need (quality of life, presence and type of emotional/behavioural problems) and predisposing factors (sex, ethnic background and maternal educational level) were measured using parent questionnaires at multiple time points between ages 1.5 and 9 years. Psychosocial care use was parent-reported at 9 years old (9.6% among children with Western background, 7.3% among children with non-Western background). Having emotional/behavioural problems at 5 and 9 years old was associated with more care use, while having a higher quality of life, being a girl and having a Moroccan/Turkish or other non-Western background were associated with less care use. Externalising and internalising problems, as well as several types of problems, at 5 and 9 years old were associated with psychosocial care use. Stratified analyses revealed that, in children with non-Western backgrounds, only a poorer psychosocial quality of life was associated with psychosocial care use. To conclude, girls with a Western background and children with a non-Western background were less likely to receive care compared to their peers. Children with parent-reported emotional/behavioural problems at 5 and 9 years old and decreased quality of life at 5 years old were more likely to receive psychosocial care use at 9 years old. Our findings hold relevance for preventive policies.

Frequency and prognosis of associated malignancies in 504 patients with lymphomatoid papulosis.

BACKGROUND: Lymphomatoid papulosis (LyP) can be associated with other haematological malignancies (HM), but reported percentages vary from 20% to over 50%. OBJECTIVE: To evaluate the frequency and prognostic significance of associated HM and non-HM in LyP patients. METHODS: In this multicentre cohort study, the complete Dutch LyP population was included from the Dutch Cutaneous Lymphoma Registry between 1985 and 2018. Clinical and histopathological information was retrieved from every individual patient. RESULTS: After a median follow-up of 120 months (range, 6-585), an associated HM was observed in 78/504 (15.5%) patients. Most common associated HM were mycosis fungoides (MF; n = 31) and anaplastic large-cell lymphoma (ALCL; n = 29), while 19 patients had another HM of B-cell (n = 14) or myeloid origin (n = 5). Even after a 25-year follow-up period, percentages of associated HM did not exceed 20%. Thirty-nine of 465 patients (8.4%) without a prior or concurrent associated HM developed an associated HM during follow-up, after a median of 68 months (range of 3-286 months). Nine of 78 patients died of associated HM, including 6/22 patients developing extracutaneous ALCL, while all patients with associated MF or skin-limited ALCL had an excellent prognosis. Compared with the general population, LyP patients showed an increased risk (relative risk, 2.8; 95% confidence intervals, 2.4-3.3) for non-HM, in particular cutaneous squamous cell carcinoma, melanoma and intestinal/lung/bladder cancer. CONCLUSIONS: An associated HM was reported in 15.5% of the LyP patients, particularly MF and ALCL. Although the frequency of associated HM is lower than suggested and the prognosis of most patients with associated HM is excellent, a small subgroup will develop aggressive disease, in particular extracutaneous ALCL. Furthermore, LyP patients have a higher risk of developing other malignancies. Clinicians should be aware of these risks, and LyP patients require close monitoring.

TOX expression in cutaneous T-cell lymphomas: an adjunctive diagnostic marker that is not tumour specific and not restricted to the CD4(+) CD8(-) phenotype.

BACKGROUND: TOX (thymocyte selection-associated high-mobility group box) was shown to be aberrantly expressed in mycosis fungoides (MF) and Sézary syndrome (SS) and is suggested to have additional diagnostic value. However, data on expression in other types of cutaneous T-cell lymphoma (CTCL) are scarce and it is unknown whether TOX is expressed only by MF with a CD4(+)  CD8(-) phenotype. OBJECTIVES: To investigate TOX expression in various types of CTCL with different T-cell phenotypes. METHODS: Immunohistochemical expression of TOX was evaluated on 153 skin biopsies of 132 patients with CTCL and 60 patients with benign inflammatory dermatoses (BIDs). RESULTS: TOX was expressed by > 50% of the neoplastic T cells in 49 of 59 patients (83%) with MF and in 19 of 22 patients (86%) with SS. The TOX(+) cases of MF included 34 of 35 cases (97%) with a CD4(+)  CD8(-) phenotype, but also five of eight cases (63%) with a CD4(-)  CD8(+) phenotype and 10 of 16 cases (63%) with a CD4(-)  CD8(-) phenotype. TOX expression in other types of CTCL was common but showed variable intensity. Although only one of 60 patients (2%) with a BID expressed TOX in > 50% of the skin-infiltrating T cells, some caution is warranted, as the majority of BIDs had TOX(+) T cells varying between 11% and 50%. CONCLUSIONS: TOX expression is not tumour specific, is not restricted to CTCL with a CD4(+)  CD8(-) phenotype, and, on its own, is insufficient for diagnosis of CTCL. However, it may have an adjunctive diagnostic role in conjunction with other clinical and histological data.

Expression of programmed death-1 in skin biopsies of benign inflammatory vs. lymphomatous erythroderma.

BACKGROUND: Histological differentiation between Sézary syndrome (SS) and erythrodermic inflammatory dermatoses (EID) can be very difficult. Recent studies show that programmed death-1 (PD-1) is strongly expressed by the neoplastic cells in skin biopsies of SS, while similar studies in EID are lacking. OBJECTIVES: To determine whether the number and distribution of PD-1(+) T cells could be used as an adjunct in the differentiation between SS and EID. METHODS: Expression of PD-1 and a panel of T-cell markers was investigated in skin biopsies from 30 patients with various types of EID (12 idiopathic, 10 atopic, six psoriatic and two paraneoplastic) and 25 patients with SS. RESULTS: Expression of PD-1 by > 50% of the infiltrating T cells was observed in 23 of 25 (92%) SS cases and in only four of 30 (13%) EID cases. PD-1 is expressed by neoplastic CD4(+) T cells in SS, while in contrast, PD-1 was predominantly expressed by dermal and epidermal CD8(+) T cells in EID. Expression of CD7 by ≤ 20% of the infiltrating T cells was observed only in SS (13 of 24; 54%), and not in any of the 30 cases of EID. CONCLUSIONS: While PD-1 is expressed by CD4(+) neoplastic T cells in SS, our results suggest that PD-1 is expressed mainly by activated dermal and epidermal CD8(+) T cells in EID. Expression of PD-1 by > 50% of CD4(+) T cells and expression of CD7 by ≤ 20% of the infiltrating T cells strongly support a diagnosis of SS in skin biopsies of patients with erythroderma.

Langerhans cell histiocytosis first presenting in the skin in adults: frequent association with a second haematological malignancy.

BACKGROUND: Langerhans cell histiocytosis (LCH) in adults first presenting in the skin is rare. Guidelines for staging, treatment and follow-up are lacking. OBJECTIVES: To better define staging procedures, treatment results and clinical course in adult patients with LCH first presenting in the skin. METHODS: Eighteen adult patients with LCH first presenting in the skin were collected from five centres collaborating in the Dutch Cutaneous Lymphoma Group. Clinical records and (skin) biopsy specimens were reviewed and follow-up data were obtained. A literature search on adult patients with LCH presenting in the skin was performed. RESULTS: Staging procedures showed extracutaneous disease in three of 16 patients who were adequately staged. One patient had a histologically confirmed lytic LCH bone lesion, while two patients had a myelodysplastic syndrome. During follow-up two of 18 patients developed extracutaneous localizations of LCH. Five patients developed a second haematological malignancy, including (myelo)monocytic leukaemia (two cases), histiocytic sarcoma (one case), diffuse large B-cell lymphoma (one case) and peripheral T-cell lymphoma (one case). Review of the literature revealed six other adult patients with a second haematological malignancy preceding or following a diagnosis of LCH. CONCLUSIONS: The results of the present study suggest an increased risk of a second haematological malignancy in adult patients with LCH presenting in the skin. Extensive staging at presentation and long-term follow-up are therefore warranted in such patients.

Array-based comparative genomic hybridisation analysis reveals recurrent chromosomal alterations in primary diffuse large B cell lymphoma of bone.

AIMS: Primary non-Hodgkin's lymphoma of bone (PLB) is a rare subtype of primary extranodal diffuse large B cell lymphoma. PLB has morphological homogeneity and a relatively favourable clinical behaviour. Recent studies report that array-based comparative genomic hybridisation (array-CGH) analysis can be used to classify lymphomas into clinically and biologically relevant phenotypes and possibly reveal differences in oncogenic mechanisms. Here the authors performed the first array-CGH study to detect illness related genomic alterations in nine, clinically well-staged primary lymphoma of bone cases. METHODS: Nine frozen samples from primary lymphoma of bone patients were immunophenotyped and subsequently investigated using a well-established array-CGH platform. The array-CGH results were confirmed by fluorescence in situ hybridisation. Clinical data and follow-up were obtained for all nine patients. RESULTS: Of the nine patients, eight reached complete remission, and one had progressive disease and died of primary lymphoma of bone. Frequent aberrations were: loss of 14q32 (n=7), trisomy 7 (n=6), gain of the long arm of chromosome 1 (n=5) and amplification of 2p16.1 (n=4). No statistically significant correlation between genetic abnormalities and clinical outcome was found. CONCLUSIONS: The authors found several recurrent genomic aberrations, including five cases with gain of 1q and four cases with 2p16.1 amplification. These findings are associated with a germinal centre-like phenotype and favourable treatment outcome, and differ from chromosomal aberrations found in other extranodal lymphomas. These findings further substantiate the notion that primary lymphoma of bone should be considered as a distinct entity not only on clinic-pathological grounds but also on the genomic level as well.

Primary lymphoma of bone: extranodal lymphoma with favourable survival independent of germinal centre, post-germinal centre or indeterminate phenotype.

AIMS: To determine prognostic significance of immunohistochemical markers and investigate possible germinal centre (GC) derivation in primary lymphoma of bone (PLB). METHODS: Immunohistochemical expression of BCL-6, CD10, BCL-2, p53, CD30, CD44 and MUM-1 was studied in 36 patients with PLB. All cases were clinically staged and cases of secondary bone involvement of primary nodal lymphomas were excluded, prior to immunostaining. Clinical charts were reviewed for clinical symptoms and therapy given; survival post-biopsy was calculated. RESULTS: All patients presented with pain and a palpable mass. The majority showed centroblastic-multilobated morphology; half of the cases (19/36) had a GC phenotype (CD10+BCL-6+ or CD10-BCL-6+MUM-1-), whereas 8/36 cases had a non-GC phenotype (CD10-BCL-6- or CD10-BCL-6+MUM-1+). Nine cases were of indeterminate phenotype (CD10-BCL-6+; MUM-1 not available). Eight of 22 evaluated patient samples showed immunoreactivity for MUM-1. Most patients (31/36) received combination therapy in the form of polychemotherapy and radiotherapy. The five-year overall survival was 75%. No significant difference in survival was found between the three different tumour phenotypes, or for the tested antigens individually. Age at presentation and stage of disease had a significant influence on five-year overall survival. Survival rates were 90% for the patients <60 years of age and 40% for those > or =60 years. Survival rates were 90% for stage I and 41% for stage IV. CONCLUSION: This study illustrates the homogeneity of PLB. The majority of cases are of the GC phenotype which has a favourable prognosis.

Granulocytosis and thrombocytosis in renal cell carcinoma: a pro-inflammatory cytokine response originating in the tumour.

BACKGROUND: In up to 20% of patients with renal cell cancer (RCC) an inflammatory response consisting of low-grade fever, weight loss and an elevated ESR and CRP may occur with modest granulocytosis and thrombocytosis. Clinical and experimental data suggest a pathogenic role for tumour-derived cytokine production, especially interleukin-6. CASE REPORT: A 79-year-old female with RCC presented with low-grade fever, weight loss and overt granulocytosis and thrombocytosis. Radiological examination revealed a right-sided renal tumour. During nephrectomy a gradient between the IL-6 levels in the renal artery and vein was demonstrated, providing direct evidence for in vivo production of IL-6 by the tumour affected kidney, which was confirmed by the demonstration of IL -6 in the tumour cells by immunohistochemical staining and in the supernatant of the homogenised tumour. Cytogenetic examination revealed complex abnormalities including a gain of chromosome 7. In addition we demonstrated production of IL-1alpha, IL-1beta, IL-8 and ICAM-1 in the tumour with systemic elevated levels of IL-6 and IL-8 with secondary increased serum G-CSF and TPO levels. CONCLUSION: We have provided direct evidence for the production of pro-inflammatory cytokines by renal cancer cells in a patient with RCC and a profound inflammatory response, with a central role of IL-6, probably due to a gain of chromosome 7. The extreme granulocytosis and thrombocytosis may have resulted from the secondary systemic production of G-CSF and TPO.

Diagnostic and prognostic evaluation of phenotypic markers TRAF1, MUM1, BCL2 and CD15 in cutaneous CD30-positive lymphoproliferative disorders.

BACKGROUND: CD30 is expressed in various types of cutaneous lymphomas, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (C-ALCL), some cases of mycosis fungoides showing large cell transformation (MF-TR) and skin localizations of systemic anaplastic lymphoma kinase (ALK)-positive or ALK-negative ALCL. Differentiation between these entities is often not possible on the basis of histology alone, but several markers, including TRAF1, MUM1 and BCL2, have been reported to provide additional diagnostic information. OBJECTIVE: To evaluate the diagnostic and prognostic significance of these markers in a large group of cutaneous CD30-positive lymphoproliferations. METHODS: An immunohistochemical study on the expression of TRAF1, MUM1, BCL2 and CD15 was performed on skin biopsies from 28 patients with C-ALCL, 39 patients with LyP, 11 patients with CD30-positive MF-TR, two with ALK-positive ALCL and six with ALK-negative ALCL. In addition, the prognostic significance of these markers was evaluated. RESULTS: TRAF1 was expressed in roughly 70-80% and MUM1 was expressed in 70-100% of all the groups of cutaneous CD30-positive lymphoproliferations. Highest levels of BCL2 were expressed in MF-TR (73%), in contrast to 21% in C-ALCL and 36% in LyP. Highest levels of CD15 were expressed in C-ALCL (43%), compared with 18% in LyP and 9% in MF-TR. A relationship with survival was not clear. CONCLUSIONS: The results of the present study suggest that TRAF1, MUM1, BCL2 and CD15 cannot be considered as useful diagnostic or prognostic marker in cutaneous CD30-positive lymphoproliferations. Differentiation between these different conditions should be based on a combination of clinical, histological and immunophenotypical criteria.

Myomatous erythrocytosis syndrome: further proof for the pathogenic role of erythropoietin.

BACKGROUND: Myomatous erythrocytosis syndrome is defined by the combination of erythrocytosis, myomatous uterus and persistent restoration of normal haematological values after hysterectomy. A pathogenic role of erythropoietin is suggested by clinical and experimental data. CASE REPORT: A postmenopausal patient is described with the classical clinical signs of the myomatous erythrocytosis syndrome. During hysterectomy we demonstrated a large gradient between the erythropoietin levels in the uterine vein and artery, providing direct evidence for in vivo erythropoietin production by the myomatous uterus. CONCLUSION: While erythropoietin and its receptor are consecutively expressed in normal and myomatous uterine tissue, it is amazing that erythrocytosis occurs so rarely in such a frequent disorder as uterine myomatous. We strongly advocate cytogenetic examination of the myomatous tissue of subsequent patients with this entity.

Aldosterone-to-renin ratio as a screening test for primary aldosteronism--the Dutch ARRAT Study.

Since the introduction of the aldosterone-to-renin ratio (ARR ) as a screening tool for primary aldosteronism (PA), there has been a marked increase in the reported prevalence of this condition among hypertensive subjects. A meta-analysis from the literature shows a PA prevalence of almost 8% among hypertensive patients, with a twofold higher prevalence in referred patients as compared with primary care patients (9.0 vs 4.3%). However, the usefulness of the ARR remains subject of debate, because of doubts on its validity, and the many factors affecting the ARR , including posture, time of day of blood sampling, and use of antihypertensive medication. Furthermore, there is no clear cut-off value and it is unknown what population should be screened. Recently, The Dutch ARR AT Study was initiated. This is a multicentre, prospective trial aiming to evaluate the test characteristics of the ARR within a Dutch population of therapy-resistant hypertensive patients. The effect of antihypertensive medication on the ARR will be studied. Furthermore, from this study the prevalence of PA in this population will follow. Last, the blood pressure response to the selective aldosterone-receptor-antagonist eplerenone will be evaluated. The Dutch ARR AT Study will run until the end of 2009 and will contribute to the formulation of uniform guidelines for the screening for PA in the Netherlands.

Differences in measured and self-reported height and weight in Dutch adolescents.

BACKGROUND/AIMS: Monitoring overweight prevalence and its trends in Dutch youth is frequently based on self-reported data. The validity of self-reported data especially in young adolescents is not sufficiently known. The purpose of this study is to study the validity of self-reported height and weight in 12- to 13-year-olds, to identify sociodemographic correlates and to explore whether correction factors can be developed to estimate the prevalence of overweight in youth. METHODS: 5,525 12- to 13-year-old pupils in the Rotterdam area filled in a confidential questionnaire on health topics, including their height and weight. In a sub-sample of 499 pupils both self-reported and measured height and weight were available. RESULTS: Self-reported data led to a considerable underestimation of Body Mass Index and consequently the prevalence of overweight. Underestimation was higher in pupils who regarded themselves as more fat, were of non-Dutch origin and in lower education levels. CONCLUSION: Self-reported height and weight appeared to be inappropriate to estimate the overweight prevalence in 12- to 13-year-olds, unless the figures were adjusted. Using adjusted self-reported BMI on an individual level is questionable. Actual measurements of height and weight are necessary to draw up valid correction formulas in new samples.

Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases.

BACKGROUND: Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is a low-grade B-cell lymphoma that originates in the skin, with no evidence of extracutaneous disease. Studies focusing on the optimal treatment of PCMZL have not been published thus far. We describe 50 patients with PCMZL to further characterize clinical characteristics and outcome and, in particular, to evaluate our current therapeutic approach. OBSERVATIONS: The majority of the patients (36/50 [72%]) presented with multifocal skin lesions, and 14 patients (28%) presented with solitary or localized lesions. The initial treatment of patients with solitary lesions consisted of radiotherapy or excision, whereas patients with multifocal lesions received a variety of initial treatments, most commonly radiotherapy and chlorambucil therapy. Cutaneous relapses developed in 19 (48%) of 40 patients who had complete remission and were more common in patients with multifocal disease. After a median period of follow-up of 36 months, 2 patients developed extracutaneous disease, but none of the patients died of lymphoma. CONCLUSIONS: Patients with PCMZL who have solitary lesions can be treated effectively with radiotherapy or excision. For patients with PCMZL who have multifocal lesions, chlorambucil therapy and radiotherapy are suitable therapeutic options. In case of cutaneous relapses, the beneficial effects of treatment should carefully be weighed against the potential adverse effects.

FISH analysis of MALT lymphoma-specific translocations and aneuploidy in primary cutaneous marginal zone lymphoma.

Primary cutaneous marginal zone lymphomas (PCMZL) share histological and clinical characteristics with mucosa-associated lymphoid tissue (MALT) lymphomas suggesting a common pathogenesis. A number of recurrent structural and numerical chromosomal aberrations have been described in MALT lymphoma, but their incidence in PCMZL is largely unknown, as is their relation with clinical and pathological data. In this study, the incidence of t(11;18)(q21;q21), t(1;14)(p22;q32), two different t(14;18)(q32;q21), involving either IGH/MALT1 or IGH/BCL2, and numerical aberrations of chromosomes 3, 7, 12 and 18 were analysed in 12 patients with PCMZL, with follow-up of up to 10 years. Nuclei were isolated from paraffin wax sections for dual-colour interphase fluorescence in situ hybridization (FISH) using various probe sets either flanking or spanning the involved genes. T(14;18)(q32;q21), with breakpoints in IGH and MALT1, was found in three cases. All three had partly monocytoid histological appearances and lacked blastic transformation. An additional trisomy of chromosome 3 was detected in one of these cases. Trisomy 18 was present in two lymphomas without monocytoid morphology. No definite correlation was seen with any clinical feature, including Borrelia serology. Neither t(11;18)(q21;q21), nor t(1;14)(p22;q32) or any other translocation involving IGH, BCL10, MALT1, BCL2 and API2, amplification or deletion of chromosomal region 11q21, 18q21, 1p22, and 14q32 was detected. These results indicate that a subgroup of PCMZL with partly monocytoid morphology is genetically related to MZL at other extranodal sites.

CD56+ hematological neoplasms presenting in the skin: a retrospective analysis of 23 new cases and 130 cases from the literature.

BACKGROUND: The aim of this study was to define prognostic parameters and guidelines for diagnosis and treatment for CD56+ hematological neoplasms with first presentation in the skin. PATIENTS AND METHODS: The study group included 153 cases (23 new and 130 from the literature). According to the World Health Organization classification, the group included 15 nasal and 38 nasal-type natural killer (NK)/T-cell lymphomas, 63 blastic NK-cell lymphomas, 14 cutaneous CD30+ lymphoproliferations, 10 cases of myeloid leukemia, six cases of subcutaneous panniculitis-like T-cell lymphoma (SCPLTCL) and seven peripheral T-cell lymphomas, unspecified. RESULTS: In general, these CD56+ hematological neoplasms had a poor prognosis, with only 27% of patients alive after a median follow-up of 12 months. The median survival was 13 months. Nasal and nasal-type NK/T-cell lymphomas and CD56+ SCPLTCL had the worst prognosis, with a median survival of 5, 6 and 5 months, respectively. Only nasal-type NK/T-cell lymphomas presenting with only skin lesions had a somewhat better prognosis (median survival 27 months). In blastic NK-cell lymphomas (median survival 14 months), age