Wnt/ß-Catenin-Activated Nonpilomatrical Carcinoma of the Skin: A Case Series.

Among skin epithelial tumors, recurrent mutations in the APC/CTNNB1 genes resulting in activation of the Wnt/ß-catenin pathway have been reported predominantly in neoplasms with matrical differentiation. In the present study, we describe the morphologic, immunohistochemical, and genetic features of 16 primary cutaneous carcinomas harboring mutations activating the Wnt/ß-catenin pathway without evidence of matrical differentiation, as well as 4 combined tumors in which a similar Wnt/ß-catenin-activated carcinoma component was associated with Merkel cell carcinoma (MCC) or pilomatrical carcinoma. Among the pure tumor cases, 6 of 16 patients were women with a median age of 80 years (range, 58-98 years). Tumors were located on the head and neck (n = 7, 44%), upper limb (n = 4, 25%), trunk (n = 3, 18%), and leg (n = 2, 13%). Metastatic spread was observed in 4 cases resulting in death from disease in 1 patient. Microscopically, all cases were poorly differentiated neoplasms infiltrating the dermis and/or subcutaneous tissue. In 13 cases, solid "squamoid" areas were associated with a basophilic component characterized by rosette/pseudoglandular formation resulting in a biphasic appearance. Three specimens consisted only of poorly differentiated carcinoma lacking rosette formation. Immunohistochemical studies showed frequent expression of EMA (100%), BerEP4 (100%), cytokeratin 7 (94%), chromogranin A (44%), synaptophysin (82%), and cytokeratin 20 (69%). Complete loss of Rb expression was observed in all but 1 case. Nuclear ß-catenin and CDX2 expressions were detected in all cases. Recurrent pathogenic somatic mutations were observed in APC (60%), CTNNB1 (40%), and RB1 (n = 47%). Global methylation analysis confirmed that cases with rosette formation constituted a homogeneous tumor group distinct from established skin tumor entities (pilomatrical carcinoma, MCC, and squamous cell carcinoma), although the 3 other cases lacking such morphologic features did not. In addition, we identified 4 combined neoplasms in which there was a component showing a similar poorly differentiated rosette-forming carcinoma demonstrating Rb loss and ß-catenin activation associated with either MCC (n = 3) or pilomatrical carcinoma (n = 1). In conclusion, we describe a distinctive neoplasm, for which we propose the term "Wnt/ß-catenin-activated rosette-forming carcinoma," morphologically characterized by the association of rosette formation, squamous and/or neuroendocrine differentiation, diffuse CDX2 expression, Rb loss, and mutations in CTNNB1/APC genes.

Pustular mycosis fungoides has a poor outcome: a multicentric clinico-pathological and molecular case series study.

BACKGROUND: Mycosis fungoides (MF) has usually an indolent course. However, some patients develop a more aggressive disease and few prognostic parameters have been identified. Isolated cases of pustular MF (pMF) suggest an unfavourable prognosis. OBJECTIVES: We aim to describe the clinico-pathological characteristics and prognostic value of pMF. METHODS: We retrospectively collected data of all cases of MF with histological pustules diagnosed from 2009 to 2020. The outcomes and clinico-pathological characteristics of pMF at diagnosis (pMFD) were compared to those of a cohort of non-pustular MF (NpMF). RESULTS: 33 pMF (including 22 pMFD) and 86 NpMF cases were included. The median age at diagnosis of pMF was 61 years [IQR=50-75]. The median follow-up of pMFD was 32 months [IQR=14-49]. Clinically, 33% of pMF had pustules. Large-cell transformation (LCT) occurred in 17 cases. pMFD were at a significantly more advanced-stage and more showed LCT at diagnosis than NpMF (50% vs 7%, p<0.001 and 23% vs 0%, p<0.001, respectively). In multivariate Cox analysis, the presence of histological pustule at diagnostic was associated with shorter OS in all patients (HR=13.90, CI95%[2.43-79]; p=0.003), and in early-stage patients (HR=11.09, CI95%[1.56-78.82]; p=0.02). In multivariate Fine and Gray model analysis, pMFD was associated with a higher cumulative incidence of LCT (SHR=13.90, CI95% [2.43-79]; p=0.003) in all patients. Median OS after the occurrence of histological pustules during follow-up of all pMF patients was 37 months, with a five-year OS of 25% (CI95% [0.06-0.5]). CONCLUSION: pMF often follows an aggressive course, with a high risk of LCT and shorter survival, even for early-stage patients. Histological pustules at diagnostic of MF might represent an independent poor prognostic factor, to be confirmed by further studies. Because pustules are not always clinically identified, histological pustules should be mentioned in pathology reports of MF and prompt discussion of a closer follow-up.

Distinct regulations driving YAP1 expression loss in poroma, porocarcinoma and RB1-deficient skin carcinoma.

AIMS: Recently, YAP1 fusion genes have been demonstrated in eccrine poroma and porocarcinoma, and the diagnostic use of YAP1 immunohistochemistry has been highlighted in this setting. In other organs, loss of YAP1 expression can reflect YAP1 rearrangement or transcriptional repression, notably through RB1 inactivation. In this context, our objective was to re-evaluate the performance of YAP1 immunohistochemistry for the diagnosis of poroma and porocarcinoma. METHODS AND RESULTS: The expression of the C-terminal part of the YAP1 protein was evaluated by immunohistochemistry in 543 cutaneous epithelial tumours, including 27 poromas, 14 porocarcinomas and 502 other cutaneous tumours. Tumours that showed a lack of expression of YAP1 were further investigated for Rb by immunohistochemistry and for fusion transcripts by real-time PCR (YAP1::MAML2 and YAP1::NUTM1). The absence of YAP1 expression was observed in 24 cases of poroma (89%), 10 porocarcinoma (72%), 162 Merkel cell carcinoma (98%), 14 squamous cell carcinoma (SCC) (15%), one trichoblastoma and one sebaceoma. Fusions of YAP1 were detected in only 16 cases of poroma (n = 66%), 10 porocarcinoma (71%) all lacking YAP1 expression, and in one sebaceoma. The loss of Rb expression was detected in all cases except one of YAP1-deficient SCC (n = 14), such tumours showing significant morphological overlap with porocarcinoma. In-vitro experiments in HaCat cells showed that RB1 knockdown resulted in repression of YAP1 protein expression. CONCLUSION: In addition to gene fusion, we report that transcriptional repression of YAP1 can be observed in skin tumours with RB1 inactivation, including MCC and a subset of SCC.

Recurrent FOXK1::GRHL and GPS2::GRHL fusions in trichogerminoma.

We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in-frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well-delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests ('cell balls') was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20-positive Merkel cells were detected. RNA sequencing (RNA-seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT-qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA-seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland.

[A particular presentation of a T cell large granular lymphocytic leukaemia]. / Une présentation particulière de leucémie à grands lymphocytes granuleux.

T cell prolymphocytic leukemia (T-PLL) is a rare, aggressive neoplasm derived from post-thymic T cells. Patients are typically middle-aged with a slight male predominance who present with a high white blood cell count, hepatosplenomegaly, lymphadenopathy, and other symptoms typically associated with leukemia. Although cutaneous involvement has been reported in up to 30% of cases of T-PLL, to our knowledge, none have presented with a presentation resembling livedoid vasculopathy. In the correct clinical context, an underlying hematolymphoid neoplasm should be included in the differential diagnosis of a patient presenting with livedoid vasculopathy.

Harmonization of programmed death-ligand 1 immunohistochemistry and mRNA expression scoring in metastatic melanoma: a multicentre analysis.

AIMS: The aim of this multicentre study was to harmonize programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and melanoma scoring. To provide a reference for PD-L1 expression independently of the IHC protocol, PD-L1 mRNA expression was compared with IHC. METHODS AND RESULTS: Standardized PD-L1 assays (22C3, 28-8, SP142, SP263) and laboratory-developed tests (QR1, 22C3) were evaluated on three IHC platforms with a training set (seven cases). mRNA expression was determined by RNAscope (CD274/PD-L1 probe) and analysed with image analysis. PD-L1 IHC findings were scored by seven blinded pathologists using the tumour proportion score (TPS), the combined positive score (CPS), and the MELscore. This method was validated by three blinded pathologists on 40 metastatic melanomas. Concordances among various antibody/platforms were high across antibodies [intraclass correlation coefficient (ICC) >0.80 for the CPS], except for SP142. Two levels of immunostaining intensity were observed: high (QR1 and SP263) and low (28-8, 22C3, and SP142). Reproducibilities across pathologists were higher for QR1 and SP263 (ICC ≥0.87 and ICC ≥0.85 for the TPS and the CPS, respectively). QR1, SP263 and 28-8 showed the highest concordance with mRNA expression. We developed a standardized method for PD-L1 immunodetection and scoring, tested on 40 metastatic melanomas. Concordances among antibodies were excellent for all criteria, and concordances among pathologists were better for the MELscore than for other scores. CONCLUSION: Harmonization of PD-L1 staining and scoring in melanomas with good concordance is achievable with the PD-L1 IHC protocols applied to other cancers; this reproducible approach can simplify daily practice.

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.

[Rosai-Dorfman-Destombes disease with a misleading laryngeal presentation]. / Une maladie de Rosai­Dorfman­Destombes de présentation laryngée trompeuse.

Rosai-Dorfman-Destombes disease is a rare non-Langerhansian cell histiocytosis characterized by the accumulation of large activated histiocytes in the affected tissues with images of emperipolesis. The diagnosis is not really problematic in the classical forms, with a lymph node presentation, whose histology is very suggestive. However, it can be much more difficult in the extra-nodal forms, which are misleading in both their clinical and histological presentation. We report here a case illustrating this diagnostic difficulty. Firstly, clinically, the disease was revealed by an unusual laryngeal location, responsible for acute obstructive respiratory distress and requiring urgent surgical management. Secondly, histologically, the diagnosis was not evoked in the first instance by analysis of the laryngeal lesion. Indeed, there was a not specific appearing polymorphic infiltrate, associating small lymphocytes, plasma cells and numerous histiocytes, without evidence for a lymphoma after immunohistochemistry and lymphocyte clonality analysis. However, after re-examination of the slides, the histiocytes sometimes appeared large or xanthomised and have a PS100+, CD1a-, langerhine- phenotype, with rare images of emperipolesis. These aspects finally suggested the diagnosis of Rosai-Dorfman-Destombes disease, then confirmed by a cervical lymph node biopsy showing characteristic histological features. Simultaneously, NGS analysis of the laryngeal lesion showed a mutation in the MAP2K1 gene, in accordance with the diagnosis. The patient was treated with revlimid and dexamethasone for 6 months, with complete remission, and is currently undergoing maintenance treatment with revlimid.

[Impact of algorithms proposed by the Cutaneous Lymphoma French Study Group for diagnosis of cutaneous lymphoproliferations]. / Impact des algorithmes du groupe français d'étude des lymphomes cutanés (GFELC) sur le diagnostic anatomopathologique des lymphoproliférations cutanées.

After a first diagnosis proposition, management of cutaneous lymphomas requires a systematic review by an expert pathologist and each case is presented to a multidisciplinary meeting in the setting of the French Study Group of Cutaneous Lymphomas to propose an adequate treatment. A retrospective study of the 2760 cutaneous lymphoproliferations retrieved between 2010 and 2011 were analyzed and demonstrated the interest of diagnostic algorithms we built with the group. The objective of our study was to compare two cohorts from 2010-2011 and 2015-2017 regarding the proportion of cases sent for validation or expertise, the concordance and mismatch rates and potential diagnostic issues using our diagnostic algorithms. Between 2015-2017, 5640 skin lymphoproliferation cases were examined. It appeared that Pathologists were more confident and effective in finding the right diagnosis. Indeed, the rate of concordant diagnosis increased from 57% to 67%. Moreover, in comparison with the 2010-2011 concordant cases sent for expertise, 73.5% of concordant cases were sent for validation in 2015-2017. 14% of cases remained discordant, mainly sent for expertise. Furthermore, half of questionable cases (26.3%) were resolved after expertise, and 12.1% cases remained unsolved. These priority cases are important to be presented at multidisciplinary meeting. The analysis of discordant and doubtful cases unveiled recurrent diagnostic problems for which we proposed appropriate diagnostic algorithms including large B cell lymphomas, CD4+ T cell lymphoproliferations, epidermotropic CD8+ T-cell lymphoproliferations and the differential diagnosis of mycosis fongoïdes/Sezary syndrome versus inflammatory dermatitis.

Cutaneous Adenosquamous Carcinoma of the Scalp With Intestinal Phenotype.

Cutaneous adenosquamous carcinoma is a mixed, squamous and glandular, rare malignant tumor of the skin characterized by a mixed, squamous, and glandular differentiation. Few cases of this tumor have been so far reported, and even fewer have been thoroughly studied by immunohistochemistry. We report here an exceptional case of cutaneous adenosquamous carcinoma which showed immunohistochemically features of intestinal differentiation, namely because of the expression of keratin 20 and CDX2, a marker of gastrointestinal tumors.

Proliferating Onychomatricoma. Clinical, Dermoscopical, and Pathologic Features of Onychomatricoma New Variant Resembling Onycholemmal/Squamous Cell Carcinoma.

Proliferating onychomatricoma is a new challenging variant of onychomatricoma that can clinically and histologically mimic squamous cell carcinoma/onycholemmal carcinoma. This is a retrospective case series study of the clinicopathologic and dermoscopic features of 6 patients with a pathologic diagnosis of proliferating onychomatricoma, which was conducted in the dermatology and dermatopathology departments of 2 university hospitals and a private nail's dermatology consultation. The clinical, histological, and immunohistochemical features and follow-up of 6 patients with proliferating onychomatricoma were analyzed; we compare our finding with 6 cases of conventional onychomatricoma. The female-to-male ratio was 1:1 with involvement of fingers in 4 and toe in 2. Among the symptoms were verrucous lesion simulating squamous cell carcinoma, nail thickening, periungual erythema, and pain; symptom duration ranged from 5 to 8 years. Clinical, dermoscopical en face free-margin view, and nail-clipping histologic findings reveal a nail wall-like pattern with pitting. Intraoperative, noncontact, polarizing, light dermoscopy was available in 1 case and showed the typical signs of onychomatricoma (OM). Histologically, all cases showed a well-differentiated, infiltrative, squamous, proliferative lesion exhibiting a lobulated and cystic pattern of growth in the dermis. Abrupt keratinization reminiscent of trichilemmal keratinization, but corresponding in fact to keratogenous spheres, was noted as well as a dysmaturative epithelial pattern. No atypical cytomorphological changes were found. Proliferating onychomatricoma is a new variant of onychomatricoma, which can be misdiagnosed as squamous cell carcinoma/onycholemmal carcinoma; its proper recognition may minimize morbidity associated with inappropriate treatment. Proliferating OM can be differentiated from conventional OM clinically by a free-edge wall-like pattern and on histology of nail clipping by the relatively small size of the cavities. Dermoscopic and nail clipping attributes as free-edge honeycomb-like cavities associated with conventional OM are well established and permit a diagnosis of OM without an invasive nail biopsy. The free-edge wall-like pattern is a distinct new dermoscopic and nail-clipping pattern that should raise for the others onychogenic neoplasms and prompt the clinician to obtain a biopsy specimen. In addition to proliferating OM, the differential diagnosis includes a micropapilliferum variant of OM, onychocytic matricoma, and onychocytic carcinoma.

Lipofibromatosis-Like Neural Tumor: A Case Report and Review of the Literature.

Lipofibromatosis-like neural tumors (LPF-NT) are soft tissue tumors characterized by a lipofibromatosis-like pattern, CD34/PS100 positivity, and recurrent NTRK1 gene rearrangement. It occurs mainly in pediatric patients or young adults. We report here, the first case of LPF-NT in a middle-aged adult initially misdiagnosed as a myoepithelial tumor. LPF-NT may have a locally aggressive course but no recurrence was seen after complete surgeries, whereas metastatic diseases remain exceptional.

Primary cutaneous large B-cell lymphomas: relevance of the 2017 World Health Organization classification: clinicopathological and molecular analyses of 64 cases.

AIMS: We applied the 2017 World Health Organization (WHO) classification criteria to categorise a series of 64 primary cutaneous large B-cell lymphomas (PCLBCLs), containing a majority (≥80%) of large cells and a proliferative rate of ≥40%, raising the problem of the differential diagnosis between PCLBCL, leg type (PCLBCL-LT) and primary cutaneous follicle centre lymphoma, large cell (PCFCL-LC). The aims were to determine the reproducibility and prognostic relevance of the 2017 WHO criteria. METHODS AND RESULTS: Morphology and phenotype identified 32 PCLBCLs-LT and 25 PCFCLs-LC; seven cases (11%) remained unclassified. Morphology was less reproducible than immunophenotype. Pertinent markers for the differential diagnosis were MUM1, FOXP1, CD10, and IgM. bcl-2 and bcl-6 were expressed by both PCFCLs-LC and PCLBCLs-LT at substantial levels. Neither Ki67 expression nor p63 expression was of diagnostic value. MYD88 was found to be mutated only in PCLBCLs-LT (n = 22, 69%). According to Hans/Hans modified algorithms, 23 of 25 PCFCLs-LC had germinal centre (GC) status, and the 32 PCLBCLs-LT had non-GC status. Overall survival was poorer for PCLBCLs-LT than PCFCLs-LC (P = 0.0002). Non-GC cases had poorer overall survival than GC cases (P = 0.0007). In PCLBCLs-LT, MYC expression was associated with cutaneous relapses (P = 0.014). When GC/non-GC status was applied to unclassified cases, only a single case remained discordant. CONCLUSIONS: Our results support the 2017 WHO classification criteria for PCLBCL diagnosis. The Hans modified algorithm using CD10 and MUM1 distinguished PCFCLs-LC from PCLBCLs-LT with optimal diagnostic value without requiring bcl-6 immunolabelling (poorly reproducible). Rare unclassified cases may constitute a provisionally heterogeneous subgroup for which GC/non-GC status (relevant for prognosis) may guide therapeutic decisions.

Association of subungual melanoma and subungual squamous cell carcinoma: A case series.

BACKGROUND: Subungual squamous cell carcinoma (SSCC) and subungual melanoma (SUM) are rare tumors. Several case reports of association of SSCC with SUM (SSCC-SUM) have been published. OBJECTIVE: We sought to document the clinical, dermoscopic, and histologic features in a case series of SSCC-SUMs and describe their relative frequency compared with those of SSCC and SUM. METHODS: All patients who underwent surgical exploration of the nail apparatus with a dermatopathologic examination from 2012 to 2015 were reviewed retrospectively to identify all cases of SSCC, SUM, and SSCC-SUM. For patients with SSCC-SUM, clinical characteristics were obtained from electronic medical records. All histologic specimens were reviewed by 3 dermatopathologists. RESULTS: The medical records of 456 patients were reviewed. SSCC was diagnosed in 78 (17%), SUM was diagnosed in 63 (14%), and SSCC-SUM was diagnosed in 9. Patients with SSCC-SUM accounted for 11% of those with a diagnosis of SSCC (9 of 78) and 14% of those with a diagnosis of SUM (9 of 63). LIMITATIONS: This was a single-institution retrospective study. CONCLUSION: The association of SSCC and SUM is relatively frequent in patients with SUM and warrants further consideration to understand the underlying mechanisms involved.

[The key role of the pathologist in the diagnosis of syphilis: A case report]. / L'apport du pathologiste dans le diagnostic de syphilis : à propos d'un cas.

Syphilis is a resurging sexually transmitted infection linked to Treponema Pallidum. Syphilitic lymphadenitis can be present during the 3 stages of the disease. Its histological diagnosis remains challenging for the pathologist given its possible misleading aspect and its ability to mimic as well as reactional as tumoral conditions. We report the case of an HIV-infected young patient referred for suspicion of an aggressive lymphoma. Histological and immunohistochemical analysis of cervical lymphadenopathy revealed secondary syphilis.