Primary cutaneous peripheral T-cell lymphomas with a T-follicular helper phenotype: an integrative clinical, pathological and molecular case series study.

BACKGROUND: Primary cutaneous peripheral T-cell lymphomas with a T-follicular helper phenotype (pcTFH-PTCL) are poorly characterized, and often compared to, but not corresponding with, mycosis fungoides (MF), Sézary syndrome, primary cutaneous CD4+ lymphoproliferative disorder, and skin manifestations of angioimmunoblastic T-cell lymphomas (AITL). OBJECTIVES: We describe the clinicopathological features of pcTFH-PTCL in this original series of 23 patients, and also characterize these cases molecularly. METHODS: Clinical and histopathological data of the selected patients were reviewed. Patient biopsy samples were also analysed by targeted next-generation sequencing. RESULTS: All patients (15 men, eight women; median age 66 years) presented with skin lesions, without systemic disease. Most were stage T3b, with nodular (n = 16), papular (n = 6) or plaque (atypical for MF, n = 1) lesions. Three (13%) developed systemic disease and died of lymphoma. Nine (39%) patients received more than one line of chemotherapy. Histologically, the lymphomas were CD4+ T-cell proliferations, usually dense and located in the deep dermis (n = 14, 61%), with the expression of at least two TFH markers (CD10, CXCL13, PD1, ICOS, BCL6), including three markers in 16 cases (70%). They were associated with a variable proportion of B cells. Eight patients were diagnosed with an associated B-cell lymphoproliferative disorder (LPD) on biopsy, including Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (n = 3), EBV+ LPD (n = 1) and monotypic plasma cell LPD (n = 4). Targeted sequencing showed four patients to have a mutated TET2-RHOAG17V association (as frequently seen in AITL) and another a TET2/DNMT3A/PLCG1/SETD2 mutational profile. The latter patient, one with a TET2-RHOA association, and one with no detected mutations, developed systemic disease and died. Five other patients showed isolated mutations in TET2 (n = 1), PLCG1 (n = 2), SETD2 (n = 1) or STAT5B (n = 1). CONCLUSIONS: Patients with pcTFH-PTCL have pathological and genetic features that overlap with those of systemic lymphoma of TFH derivation. Clinically, most remained confined to the skin, with only three patients showing systemic spread and death. Whether pcTFH-PTCL should be integrated as a new subgroup of TFH lymphomas in future classifications is still a matter of debate. What is already known about this topic? There is a group of cutaneous lymphomas that express T-follicular helper (TFH) markers that do not appear to correspond to existing World Health Organization diagnostic entities. These include mycosis fungoides, Sézary syndrome, or primary cutaneous CD4+ small/medium-sized T-cell lymphoproliferative disorder or cutaneous extensions of systemic peripheral T-cell lymphomas (PTCL) with TFH phenotype. What does this study add? This is the first large original series of patients with a diagnosis of primary cutaneous PTCL with a TFH phenotype (pcTFH-PTCL) to be molecularly characterized. pcTFH-PTCL may be a standalone group of cutaneous lymphomas with clinicopathological and molecular characteristics that overlap with those of systemic TFH lymphomas, such as angioimmunoblastic T-cell lymphoma, and does not belong to known diagnostic groups of cutaneous lymphoma. This has an impact on the treatment and follow-up of patients; the clinical behaviour needs to be better clarified in further studies to tailor patient management.

[About a case of calcifying fibrous tumor of the pleura]. / À propos d'un cas de tumeur calcifiante de la plèvre.

Calcifying fibrous tumor is a rare soft tissue benign tumor (OMS 2002). Some pleural localisations are described, which affect slightly older individuals than the other soft tissue forms. The calcifying fibrous tumor is included in the 2004 World Health Organization classification of pleural tumors. A pleural tumor located in the right inferior pulmonary lobe is diagnosed in a 59-year-old man. This pleural tumor is macroscopically well-circumscribed. Histologically, the rare spindle tumoral cells are located between bundles of a collagenous tissue, sometimes hyalinized, with psammomatous or dystrophic calcifications. The tumoral cells have a fibrohistiocytic origin. They stain positively for antibodies against vimentin, factor XIIIa, CD68, CD163, CD34. Antibodies against smooth muscle actin, desmin, PS100, ALK1 and EBV are negative. Main differencial diagnoses are other benign pleural tumors (solitary fibrous tumor, inflammatory myofibroblastique tumor), some malignant tumors (desmoplastic malignant pleural mesothelioma) and pleural pseudotumors (calcified pleural plaques, chronic fibrous pleuritis, amylose, hyalinizing granuloma). Our case is the 15th pleural calcifying fibrous tumor being reported.

Primary adenoid cystic carcinoma of the skin metastatic to the lymph nodes: immunohistochemical study of a new case and literature review.

Primary cutaneous adenoid cystic carcinoma (PCACC) is a rare adnexal skin tumor first described in 1975, of which merely 62 cases have so far been studied in detail and reported in the English literature. PCACC is usually regarded as apocrine in origin/differentiation, but its precise histogenesis is still not well known. PCACC has in most cases a rather indolent course but can produce local recurrences and, more rarely, regional (lymph node) and distant (pulmonary) metastases. We report herein a Greek woman with a long-standing PCACC that grew slowly over several years and produced metastasis in the regional lymph nodes, highlighting the potentially aggressive course of this tumor. The primary and metastatic tumors were studied immunohistochemically and proved to express several (sweat gland-related) antigens (such as keratin 7, epithelial membrane antigen, CD10, and CD117) but neither hormonal receptors nor p63 or Gross Cystic disease Fluid Protein 15. The salient clinicopathologic features of this rare cutaneous adnexal tumor are reviewed.

Lupus miliaris disseminatus faciei: report of a new case and brief literature review.

Lupus miliaris disseminatus faciei (LMDF) is a rare dermatosis with characteristic clinicopathological features but of unknown etiolgy. We report a new typical case of LMDF. A 29-year-old man presented with an asymptomatic, micropapular midfacial eruption. Histological examination revealed a dermal granulomatous reaction with central areas of necrosis and occasionally degenerated hair follicles. Workup for sarcoidosis was negative. A moderate improvement was achieved with systemic treatment with doxycycline. A brief overview of the main features of LMDF is presented.

Neuropathological features in a female fetus with OPHN1 deletion and cerebellar hypoplasia.

We report the case of a 33-year-old pregnant woman. The third-trimester ultrasound scan during pregnancy revealed fetal bilateral ventricular dilatation, macrosomia and a transverse diameter of the cerebellum at the 30th centile. A brain MRI scan at 31 weeks of gestation led to a diagnosis of hypoplasia of the cerebellar vermis without hemisphere abnormalities and a non compressive expansion of the cisterna magna. The fetal karyotype was 46,XX. The pregnancy was terminated and array-CGH analysis of the fetus identified a 238 kb de novo deletion on chromosome Xp12, encompassing part of OPHN1 gene. Further studies revealed a completely skewed pattern of X inactivation. OPHN1 is involved in X-linked mental retardation (XLMR) with cerebellar hypoplasia and encodes a Rho-GTPase-activating protein called oligophrenin-1, which is produced throughout the developing mouse brain and in the hippocampus and Purkinje cells of the cerebellum in adult mice. Neuropathological examination of the female fetus revealed cerebellar hypoplasia and the heterotopia of Purkinje cells at multiple sites in the white matter of the cerebellum. This condition mostly affects male fetuses in humans. We report here the first case of a de novo partial deletion of OPHN1, with radiological and neuropathological examination, in a female fetus.

Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangements with intellectual deficiency and/or congenital malformations.

BACKGROUND: Apparently balanced chromosomal rearrangements (ABCR) are associated with an abnormal phenotype in 6% of cases. This may be due to cryptic genomic imbalances or to the disruption of genes at the breakpoint. However, breakpoint cloning using conventional methods (ie, fluorescent in situ hybridisation (FISH), Southern blot) is often laborious and time consuming. In this work, we used next generation sequencing (NGS) to locate breakpoints at the molecular level in four patients with multiple congenital abnormalities and/or intellectual deficiency (MCA/ID) who were carrying ABCR (one translocation, one complex chromosomal rearrangement and two inversions), which corresponded to nine breakpoints. METHODS: Genomic imbalance was previously excluded by array comparative genomic hybridisation (CGH) in all four patients. Whole genome paired-end protocol was used to identify breakpoints. The results were verified by FISH and by PCR with Sanger sequencing. RESULTS: We were able to map all nine breakpoints. NGS revealed an additional breakpoint due to a cryptic inversion at a breakpoint junction in one patient. Nine of 10 breakpoints occurred in repetitive elements and five genes were disrupted in their intronic sequence (TCF4, SHANK2, PPFIA1, RAB19, KCNQ1). CONCLUSIONS: NGS is a powerful tool allowing rapid breakpoint cloning of ABCR at the molecular level. We showed that in three out of four patients, gene disruption could account for the phenotype, allowing adapted genetic counselling and stopping unnecessary investigations. We propose that patients carrying ABCR with an abnormal phenotype should be explored systematically by NGS once a genomic imbalance has been excluded by array CGH.