Search

We present the case of a 70-year-old woman with a history of seronegative arthritis, recurrent pleural effusion and weight loss. A prior lung biopsy had revealed non-caseating epithelioid cell granulomas without evidence for microbial organisms on special stains. Intestinal biopsy findings where suspicious for Whipple’s disease, which was confirmed by PCR testing, both on the intestinal and retrospectively on the lung tissue. Treatment with ceftriaxone resulted in clinical deterioration with fever, arthritis and recurrent pleuritis consistent with immune reconstitution inflammatory syndrome. Dose increase of glucocorticoids and therapy rotation to doxycycline and hydroxychloroquine resulted in rapid clinical improvement.

Uterine perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm that occasionally shares morphologic and immunohistochemical overlap with low- and high-grade endometrial stromal sarcoma (LGESS and HGESS). In this study, we sought to characterize the clinical, morphologic, genetic, and epigenetic features of five uterine sarcomas that display histologic features of LGESS, HGESS, and PEComa. All tumors demonstrated epithelioid cells often associated with a low-grade spindled component resembling LGESS, with both regions expressing CD10, ER, PR, variable HMB45, and Melan-A immunoreactivity, and strong cathepsin K and pS6 expression. Targeted massively parallel sequencing analysis revealed the presence of somatic TSC2 mutations in all five cases, of which four harbored concurrent or consecutive JAZF1-SUZ12 gene fusions. Unsupervised hierarchical clustering analysis of methylation profiles of TSC2-mutant uterine sarcomas (n = 4), LGESS (n = 10), and HGESS (n = 12) demonstrated two clusters consisting of (1) all LGESS and TSC2-mutant uterine sarcomas and (2) all HGESS. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, calcium, and Rap1 signaling. TSC2-mutant uterine sarcomas were responsive to hormone suppression, and mTOR inhibition demonstrated clinical benefit in four patients with these neoplasms. Our results suggest that these tumors represent histologically distinctive LGESS with TSC2 mutations. TSC2 mutations and JAZF1-SUZ12 fusion may help diagnose these tumors and possibly direct effective treatment.

This case report aims to present clinicopathological features of an extremely rare case of multifocal pseudomyogenic hemangioendothelioma (PMHE) in the scalp. A 21-year-old male developed multiple, focally ulcerated, nodules over the root of his nose and scalp. One of the skin lesions was sampled at another dermatology clinic, where this was diagnosed as a sarcoma. A review of biopsy sections showed well-circumscribed dermal lesions, comprising plump spindle and epithelioid cells, mimicking rhabdomyoblasts. Immunohistochemically, tumor cells were positive for AE1/AE3, CD31, FLI-1 and ERG. INI-1 was retained. A diagnosis of PMHE was offered. Subsequently, the patient underwent wide excision and has been asymptomatic for 8 months, post-surgery. PMHE is rarely reported in the head and neck region, where it can constitute a diagnostic pitfall. Awareness of this tumor and appropriate immunohistochemical stains are necessary for its timely diagnosis, in order to avoid radical treatments. A review of similar, previously documented cases is presented.

Composite hemangioendothelioma (CHE) displaying neuroendocrine differentiation is a rare histologic variant that is often mistaken for angiosarcoma, having a predilection for visceral locations and being associated with an aggressive clinical course. Their pathogenesis is still evolving, with only 2 cases to date from separate studies reporting a recurrent PTBP1-MAML2 fusion. Herein, we report two new cases of neuroendocrine CHE harboring PTBP1-MAML2 fusions occurring in two elderly patients (70-year-old male and 71-year-old female), both involving neck lymph nodes. The first case presented with multifocal cervical lymphadenopathy, while the second case occurred unifocally in an enlarged neck lymph node. Histologically, the tumors displayed heterogenous architectural patterns with areas reminiscent of benign cavernous hemangioma, retiform hemangioendothelioma, epithelioid hemangioendothelioma, and angiosarcoma. Cytologically, the cells were monotonous with round to ovoid nuclei, open to fine chromatin, scant to moderate cytoplasm, and frequent vacuolization. In addition, the first case showed focal solid areas of large epithelioid cells with severe nuclear atypia, enlarged nuclei and prominent nucleoli, resembling epithelioid angiosarcoma. Tumor cells were diffusely positive for vascular markers and focally positive for synaptophysin. In both cases, a next-generation sequencing fusion panel confirmed an in-frame fusion between PTBP1 exon 10 and MAML2 exon 2. One case with clinical follow-up showed stable recurrent disease and metastatic lung deposits following treatment. Both patients were alive at 3 months and one year following initial diagnosis. Our findings lend further support to classifying CHE with PTBP1-MAML2 fusions as a distinct variant of CHE with unique clinicopathologic features, including neuroendocrine features. This article is protected by copyright. All rights reserved.

Sarcoidosis induced by anti-PD1 or anti-PDL1 agents such as atezolizumab has recently been reported. It has been suggested that the predilection of sarcoidosis to affect scars is due to the presence of antigens or foreign bodies that can serve as a stimulus for granuloma formation. However, to the best of our knowledge, sarcoidosis-specific skin lesions have not to date been reported involving xanthelasma. We report a patient who developed specific lesions of sarcoidosis infiltrating some xanthelasmata 6 months after starting treatment with atezolizumab. A 69-year-old woman was referred to the dermatology department for infiltration of xanthelasmata. The patient was being treated with atezolizumab for metastatic uterine carcinosarcoma. Cutaneous biopsy from an infiltrated xanthelasma and from still yellow, no infiltrated xanthelasma showed differing proportions of foamy histiocytes and sarcoid granulomas. On physical examination, erythemato-marronaceous papules clustered on both knees, and not previously detected by the patient, were observed. The biopsy showed sarcoid dermal granulomas with foreign bodies. A chest computerized tomography scan was consistent with intrathoracic involvement of sarcoidosis. Endobronchial ultrasound-guided transbronchial needle aspiration of a mediastinal lymphadenopathy showed epithelioid cell granulomas. Histopathologically, the foamy histiocytes of xanthelasma seem to be replaced by or evolve to epithelioid cells to form sarcoid granulomas. The possible pathogenic mechanism is discussed. Dermatologists and dermatopathologists should bear in mind that sarcoidosis can present as infiltration of pre-existing xanthelasmata.

Perivascular epithelioid cell tumours are a novel histological description of mesenchymal tumours consisting of perivascular and epithelioid cells. Angiomyolipomas are one of the commoner types of this tumour group. They are typically associated with the inherited condition tuberous sclerosis (TS). In TS they are often seen arising in the kidneys and brain, although much more rarely can be seen in the liver. While usually thought of as benign tumours there is little evidence to predict whether they will progress to malignancy. Currently, there is no recommended best management strategy between resection and surveillance. We report two patients with TS seen in our centre with these described PEComa liver lesions histologically, however only one required a resection. On review of the literature, features such as increased size, rapid growth and vascular invasion would be concerning for possible malignant potential and therefore merit resection, as well as significant symptoms.

Epithelioid hemangioma (EH) is a benign vascular lesion, typically consisting of small vascular channels lined by epithelioid endothelial cells and associated with a dense lymphocytic infiltrate with eosinophils. Here, we report a rare case of EH involving large arteries. The patient presented with a nine-month history of an asymptomatic nodule on the forehead, which was thought to be an epidermal inclusion cyst. Skin biopsy revealed large arteries with clusters of epithelioid cells in the vascular walls and lumen. Scattered eosinophils were noted in the walls. Adjacent areas showed groups of small-caliber vessels lined by prominent endothelial cells and associated with a dense lymphoid infiltrate with eosinophils. No significant cytologic atypia was noted. Given the presence of the classic small vessel involvement, along with CD31 reactivity for the epithelioid cells in the large vessels, the findings are classified as EH involving large arteries, which is an uncommon subtype. There have only been a handful of such cases reported in the literature. This article is protected by copyright. All rights reserved.

Composite hemangioendothelioma (CHE) is considered a borderline malignant vascular tumor defined by an admixture of distinct vascular neoplastic components. A 21-year-old female is presented herein with a 1 cm painless mandibular vestibular mass of less than a year duration. The infiltrating tumor was characterized by dilated vascular channels lined by endothelial cells with bland ovoid or round nuclei exhibiting, occasionally, hobnail/matchstick-like arrangement. Intravascular cell proliferations with hyaline globular deposits were also present. Additionally, lobular spindle and epithelioid cell aggregates, as well as slit-like spaces exhibiting a retiform or angiosarcomatous morphology were observed. Intracytoplasmic signet-ring or lipoblast-like vacuolization was also noted. Mitotic activity was exceptionally rare. Vascular spaces and the stroma featured lymphocytes and plasma cells. Neoplastic cells were positive for CD31, CD34, D2-40 and ERG, negative for CAMTA1 and synaptophysin, while type IV collagen highlighted the plasmalemma of most vessels and hyaline globules. Fluorescence in situ hybridization revealed gene rearrangements in both YAP1 and MAML2 genes, in keeping with a YAP1-MAML2 fusion. Whole exome sequencing (WES) identified three missense mutations FLT1 [p.R1016G], PIK3CA [p.H1047L], and C11orf42 [p.A304P] and a mitochondrial frameshift insertion MT-ND4 [c.1107_1108insC; p.P370fs]. These WES results suggest that FLT1 and/or PIK3CA variants may contribute to tumor growth/transformation while the MT-ND4 variant may relate to proliferation, angiogenesis and/or inhibition of apoptosis.

Epithelioid hemangioendothelioma (EHE) with YAP1-TFE3 fusion is a recently characterized distinctive variant of EHE that accounts for a small subset (

Epithelioid malignant peripheral nerve sheath tumor (MPNST) is a rare subtype of MPNST composed of epithelioid cells with abundant cytoplasm. Currently, strong and diffuse immunostaining for S100 protein and SOX10 is generally regarded as a characteristic feature of epithelioid MPNST. However, malignant tumors with epithelioid morphology that arise from a peripheral nerve or a pre-existing benign nerve sheath tumor should be regarded as epithelioid MPNSTs when they do not show characteristic features that definitively lead to other specific diagnoses. Here, we describe 3 cases of epithelioid MPNST in the peripheral nerve or schwannoma that was negative for S100 protein and SOX10 expression. Instead, these tumors were positive for EMA, GLUT1, claudin 1, and cytokeratin to varying degrees, while all of them retained SMARCB1 and H3K27me3 by immunohistochemistry. EMA, GLUT1, and claudin 1 are known markers of perineurial cell differentiation; thus, they could possibly represent epithelioid MPNST with perineurial cell differentiation.

AimsTo evaluate the prognostic value of clinical, histopathological and molecular features and to relate different treatment modalities to clinical outcome in conjunctival melanomas (CM).MethodsRetrospective review of clinical, histopathological and BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutation status and treatment modalities, correlated to recurrence and metastasis in 79 patients with CM, diagnosed between 1987 and 2015 in three tertiary referral centres in the Netherlands and Belgium.ResultsOut of 78 evaluable patients, recurrences occurred in 16 patients and metastasis in 12 patients (median follow-up time 35 months (0–260 months)). Tumour thickness >2 mm, pT status, the presence of epithelioid cells, ulceration and mitoses was significantly correlated with metastasis (p value 0.046, 0.01, 0.02, 0.001 and 0.003, respectively). Furthermore, CM frequently harbour BRAF V600E and TERT promoter mutations (29% and 43%, respectively). TERT promoter mutations were correlated to shorter metastasis-free survival (p value 0.002). No significant correlation was found for clinical parameters and metastatic disease. Palpebral, forniceal and caruncular melanomas were more prone to develop recurrences (p value: 0.03). Most CM were treated with excision with adjuvant therapy.ConclusionIn line with the recommendations in the Eighth Edition of the American Joint Committee on Cancer Staging for CM, the pathology report should include information about pT status, tumour thickness, presence of epithelioid cells, ulceration and mitoses. Furthermore, information about the presence of a TERT promoter mutation and BRAF V600E mutation is of interest for therapeutic decision making. The presence of a TERT promoter mutation is correlated to metastatic disease.

Mucoepidermoid carcinoma (MEC) of the lacrimal gland (LG) is a rare entity. A 47-year-old woman was aware of periorbital swelling for 3 months. At presentation, the patient showed periorbital swelling in the right eye. CT scan showed an isodense mass in the anterior superolateral part of the orbit. MRI delineated the mass as enhancing, extra-conal tumor appearing isointense on T1-weighted sequences, and to be of mixed intensity on T2-weighted sequences. The tumor was totally resected. Microscopically, the tumor tissue was comprised of squamous, epithelioid cells, and cells with plump and clear cytoplasm. Necrosis, neural invasion, or mitotic figures were not observed. Immunohistochemical examination revealed intense staining for cytokeratin 7. A subset of the cells was positively stained with periodic acid–Schiff and mucicarmine stains. Genetic analysis revealed the presence of the CRTC1-MAML2 fusion. The CRTC1-MAML2 fusion may be a useful indicator for the prognosis and planning of adjuvant therapy.

Desmoplastic small round cell tumor (DSRCT) is a high-grade round cell sarcoma that typically arises in the abdominopelvic cavity of young males, co-expresses keratins and desmin, and carries a pathognomonic EWSR1-WT1 gene fusion. The EWSR1-WT1 gene fusion is generally considered specific for DSRCT, although there are two reports of this fusion in tumors otherwise lacking features of DSRCT. We report three female genital tract tumors with EWSR1-WT1 fusions but showing morphologic and immunohistochemical features incompatible with DSRCT. The tumors occurred in the uterine cervix, uterine corpus/ovaries, and vagina, respectively, of 46, 30, and 20-year-old women. Two tumors consisted of a sheet-like to fascicular proliferation of relatively uniform spindled to occasionally more epithelioid cells arrayed about thick-walled, hyalinized, and capillary-sized vessels, with distinctive areas of pseudovascular change, and absence of desmoplastic stroma. The third tumor resembled a monomorphic spindle cell sarcoma with necrosis. All had diffuse desmin and variable but more limited keratin expression, two of three expressed smooth muscle actin, and all were negative for h-caldesmon, CD10, estrogen receptor, myogenin, N-terminus WT-1, and S100 protein. One patient received neoadjuvant chemotherapy and radiation therapy followed by resection and is disease-free 42 months after diagnosis. Another patient was managed by resection only and is disease-free 9 months after initial diagnosis. The remaining patient recently underwent resection of multifocal pelvic disease. Comprehensive differential gene expression analysis on two tumors compared to two classic DSRCTs with known EWSR1-WT1 fusions resulted in 1726 genes that were differentially expressed (log2 fold change >2 or < -2) and statistically significant (FDR < 5%). In combination with previous reports, our findings suggest pleiotropy of the EWSR1-WT1 fusion is possible and not limited to DSRCT. Subsets of non-DSRCT EWSR1-WT1 positive tumors may represent discrete entities, but further study is necessary.

Hypersensitivity pneumonitis (HP) is an inflammatory and/or fibrotic disease of the lung parenchyma and terminal bronchioles caused by an allergic reaction to inhaled antigens. The immune response following antigen exposure results in lymphocytic inflammation as well as granuloma formation.The typical histologic pattern of HP consists of cellular interstitial pneumonia, cellular bronchiolitis, and epithelioid cell granulomas. The additional presence of fibrosis has a significant impact on the course as well as the prognosis of the disease and represents a therapeutic approach. Therefore, a classification into a non-fibrotic and a fibrotic phenotype is proposed.The diagnosis of HP is made by high-resolution computed tomography (HRCT) of the lung, evaluation of possible antigen exposure, and bronchoscopy with bronchoalveolar lavage and, if necessary, forceps biopsy. If the diagnosis is inconclusive, transbronchial cryobiopsy or surgical lung biopsy may need to follow. A multidisciplinary board is critical in making the diagnosis.

Gene rearrangements involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase gene have been identified in various neoplasms, including inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma. We present an ALK-rearranged cutaneous soft tissue tumor with unique morphologic and immunophenotypic features that are not shared by other entities with ALK rearrangements. The six cases involved two females and four males, aged 18-84 (mean 51) years old. Three tumors were on the back and three on the lower extremities (thigh, knee, shin); ranging from 0.5 to 5.6 (mean 2.1) cm. Four were confined to the dermis; two involved the subcutis. All six cases were characterized by the presence of spindled to ovoid cells arranged in concentric whorls and cords against a myxoid to myxohyaline stroma and relatively cellular aggregates of plump ovoid to epithelioid cells. Four cases showed distinct hyalinized blood vessels. Both cases that involved the subcutis showed peripheral lipofibromatosis-like areas. Tumor-infiltrating lymphocytes were absent to moderate. Severe cytologic atypia or conspicuous mitotic activity was not identified. Immunohistochemically, all tumors diffusely expressed ALK (D5F3) and CD34. All but one tumor was diffusely positive for S100 protein. All tumors were negative for EMA, AE1/AE3, SMA, and SOX10. Next-generation sequencing revealed ALK fusions with FLNA (3 cases), MYH10 (2 cases), and HMBOX1 (1 case) as the partner genes. In all six cases, the breakpoints involved exon 20 of ALK, which preserves the receptor tyrosine kinase domains of ALK in the fusion product. Of the four cases with limited follow-up information (2-18 months), none recurred. In conclusion, we report an ALK-rearranged cutaneous soft tissue tumor characterized by the presence of myxoid spindle cell whorls and cords, and co-expression of ALK, CD34, and frequently S100 protein, we term "superficial ALK-rearranged myxoid spindle cell neoplasm".

ALK-positive histiocytosis is a rare malignancy which was first described in 2008 and recognized as a systemic histiocytic disorder that can affect multiple organs. Less than 20 cases were reported to date, and much fewer cases were presented as disseminated disease, especially with lung and central nervous system (CNS) involvement. The clinical presentation, cytologic and histologic features were diverse in prior reported cases. Diagnosis relied on clinical, pathological findings and might be determined by molecular identification of anaplastic lymphoma kinase (ALK) gene translocation. Exclusion of other tumors such as Erdheim-Chester disease, Langerhans cell histiocytosis (LCH) and histiocytic sarcoma are required. Because of their rarity and diverse features, no standard treatment was applied so far. Here we reported a 51-year-old Asian female patient documented as ALK-positive histiocytosis with lung, intracranial and lymph nodes involvement. Surgery for left frontal tumor resection was performed. Of note was the presence of foam-like histiocytes, epithelioid cells and Touten-like histiocytes scattered in the lesion, emperipolesis also could be observed. Histiocytes were positive immunostaining for CD68/PGM-1, CD163 and ALK1 in cytoplasmic pattern. Fluorescence in situ hybridization (FISH) analysis confirmed ALK gene translocation and next generation sequencing (NGS) revealed KIF5B-ALK fusion. The patient received treatment of second-generation ALK inhibitor-alectinib after diagnosed and showed durable remission. Therefore, our case highlights a new treatment option for this rare entity.

Background Perivascular epithelioid cell tumor (PEComa) is an uncommon tumor of mesenchymal origin. Cases of PEComa in the liver are extremely rare. Aim To analyze the clinicopathological features and treatment of hepatic PEComa and to evaluate the prognosis after different treatments. Methods Clinical and pathological data of 26 patients with hepatic PEComa were collected. All cases were analyzed by immunohistochemistry and clinical follow-up. Results This study included 17 females and 9 males, with a median age of 50 years. Lesions were located in the left hepatic lobe in 13 cases, in the right lobe in 11, and in the caudate lobe in 2. The median tumor diameter was 6.5 cm. Light microscopy revealed that the tumor cells were mainly composed of epithelioid cells. The cytoplasm contained heterogeneous eosinophilic granules. There were thick-walled blood vessels, around which tumor cells were radially arranged. Immunohistochemical analysis of pigment-derived and myogenic markers in PEComas revealed that 25 cases were HMB45 (+), 23 were Melan-A (+), and 22 SMA (+). TFE3 and Desmin were negative in all cases. All the fluorescence in situ hybridization samples were negative for TFE3 gene break-apart probe. Tumor tissues were collected by extended hepatic lobe resection or simple hepatic tumor resection as the main treatments. Median follow-up was 62.5 mo. None of the patients had metastasis or recurrence, and there were no deaths due to the disease. Conclusion Hepatic PEComa highly expresses melanin and smooth muscle markers, and generally exhibits an inert biological behavior. The prognosis after extended hepatic lobe resection and simple hepatic tumor resection is semblable.

A novel molecular subset of epithelioid leiomyosarcomas with rhabdoid features harboring PGR gene rearrangements has recently been documented. Herein, we present a unique case of PGR-rearranged smooth muscle tumor with both PGR-NR4A3 and UBR5-PGR gene fusions reported in a 30-year-old woman who had a mass in the broad ligament. The histological examination showed a round/polygonal to spindle cell tumor with abundant myxoid matrix and focal hyalinization, resulting in an epithelioid pattern. Immunohistochemical examination revealed that the tumor had variable staining for desmin, SMA, and h-caldesmon and diffuse nuclear staining of ER, PR, and WT1. Furthermore, targeted RNA sequencing analysis revealed PGR-NR4A3 and UBR5-PGR gene fusions. Our case in addition with the reported cases suggest that myxoid matrix with two types of tumor cells (round/polygonal epithelioid cells and spindle cells) may be significant for the diagnosis of PGR-NR4A3 fusion-positive leiomyosarcoma. UBR5-PGR gene fusion is a novel finding in epithelioid leiomyosarcoma.

NUTM1 gene rearrangements were originally identified in NUT carcinoma. Recently, NUTM1 has been discovered to rearrange with a variety of gene partners in malignancies of diverse location and type. Only one NUTM1-rearranged tumor occurring in the colon has been reported. Herein we report five such tumors. The five tumors occurred in four females and one male, ranging from 38 to 67 years of age (median 51 years). The masses occurred in the colon (cecum, descending, sigmoid) and ileocecal valve region, measuring 2.5-20 cm in size (median 7 cm). Four patients had metastases at presentation (liver, n = 4; lymph nodes, n = 3). Histologically, the lesions arose in the submucosa, infiltrating into the mucosa and muscularis propria, and grew in fibrosarcoma-like fascicles and sheets of epithelioid or rhabdoid cells, with foci of hyalinized to vaguely osteoid-like matrix. The tumors were composed of relatively monomorphic, spindled to epithelioid cells with focal rhabdoid morphology, hyperchromatic nuclei, and small nucleoli. Mitotic activity was usually low (range 1-14/10 HPF; median 5/10 HPF); necrosis was present in two cases. Variable keratin expression and uniform nuclear NUT expression was present; KIT/DOG1 were negative and SMARCB1/SMARCA4 were retained. Next-generation sequencing identified MXD4-NUTM1 rearrangement in all cases (breakpoints: MXD4 exon 5, NUTM1 exons 2 or 3). Follow-up showed one of the four patients who presented with metastases to be dead of disease at 30 months; the other three patients were alive with metastatic disease. The final patient is disease-free, 5 months after diagnosis. NUTM1-rearranged colorectal sarcomas have characteristic morphologic, immunohistochemical, and molecular genetic features, suggesting that they represent a distinct entity within the family of NUTM1-rearranged neoplasia. A NUTM1-rearranged tumor should be considered for any difficult-to-classify submucosal spindle cell neoplasm of the gastrointestinal tract, in particular keratin-positive tumors showing an unusual combination of fibrosarcomatous, epithelioid to rhabdoid and hyalinized morphologies. Recognition of MXD4-NUTM1 rearranged sarcomas may be therapeutically important, even though best treatment is currently elusive/unknown.

International audience; Cutaneous melanomas are exceptional in children and represent a variety of clinical situations, each with a different prognosis. In congenital nevi, the risk of transformation is correlated with the size of the nevus. The most frequent type is lateral transformation, extremely rare before puberty, reminiscent of a superficial spreading melanoma (SSM) ex-nevus. Deep nodular transformation is much rarer, can occur before puberty, and must be distinguished from benign proliferative nodules. Superficial spreading melanoma can also arise within small nevi, which were not visible at birth, usually after puberty, and can reveal a cancer predisposition syndrome (CDKN2A or CDK4 germline mutations). Prognosis is correlated with classical histoprognostic features (mainly Breslow thickness). Spitz tumors are frequent in adolescents and encompass benign (Spitz nevus), intermediate (atypical Spitz tumor), and malignant forms (malignant Spitz tumor). The whole spectrum is characterized by specific morphology with spindled and epithelioid cells, genetic features, and an overall favorable outcome even if a regional lymph node is involved. Nevoid melanomas are rare and difficult to diagnose clinically and histologically. They can arise in late adolescence. Their prognosis is currently not very well ascertained. A small group of melanomas remains unclassified after histological and molecular assessment.

We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 (median 39) years and the tumors from 4.5 to 25.5 (median 11) cm. Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median 9 per 10 high-power fields). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2–40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphological, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome.

Extra-axial chordomas in the pediatric population are extremely rare and diagnostically challenging; only four cases have been previously reported with ages ranging from 13 to 20 years. We report a primary extra-axial chordoma involving the soft tissue directly dorsal and ulnar to proximal phalanx in the right thumb of a 12-year-old girl who presented with worsening right thumb pain for 1.5 years. The diagnosis was confirmed by excisional biopsy demonstrating proliferation of large, polygonal epithelioid cells with diffuse expression of pan-cytokeratin and brachyury. The patient required repeat excision for local recurrence seven months later. Since then, she has remained disease free through 15 months surveillance. Extra-axial chordomas share the same histopathological and immunohistochemical characteristics with their axial counterparts and should be considered in the differential diagnosis for any extra-axial bone or soft tissue mass with epithelioid morphology.

The experience with uterine inflammatory myofibroblastic neoplasms with an unfavorable outcome is limited. We present the clinicopathologic features of 9 such cases, including 8 inflammatory myofibroblastic tumors (IMTs) and 1 epithelioid inflammatory myofibroblastic sarcoma (EIMS). Median patient age for the IMT group was 50.5 years; the patient with EIMS was 43 years old. Patients presented with abnormal uterine bleeding, presumed fibroids, pelvic pain, arthralgia and low-grade fever, as well as an incidental finding. Median tumor size for the IMTs was 8.5 cm. The borders were either infiltrative or well-circumscribed. Histologically, IMTs were purely fascicular or myxoid or showed predominance of one or the other pattern. Seven tumors were spindled, and 1 was both spindled and epithelioid. Tumors had variable nuclear atypia, ranging from grade 1 to 3. All tumors had an inflammatory infiltrate-predominantly lymphocytic, majority had necrosis (62.5%) and none had lymphovascular invasion. 7/8 (87.5%) tumors were positive for ALK-1 by immunohistochemistry (IHC). One tumor was negative for ALK-1 by IHC but was positive for ALK fusion by fluorescence in situ hybridization and had TNS1-ALK fusion by next-generation sequencing (NGS). Three other tumors with NGS testing showed one of the following ALK-fusion partners: FN1, DCTN1, and IGFBP5. The EIMS had infiltrative borders, myxoid and hyalinized patterns, epithelioid cells, and no lymphovascular invasion. This tumor was ALK-1 positive by IHC, had ALK rearrangement by fluorescence in situ hybridization and RANBP2-ALK fusion by NGS. Extrauterine disease at time of diagnosis was noted in 2/8 (25%) of IMTs, and in the single case of EIMS. Seven patients had surgery as primary treatment, 1 patient had neoadjuvant chemotherapy and 1 patient declined treatment. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, radiotherapy or hormonal therapy. Most patients (71.4%) recurred within 24 months (mos). Two thirds of patients were alive with disease at last follow up (mean 43.6 mos). The patient with EIMS was alive with disease at 22 mos. IMT referral cases were initially diagnosed as smooth muscle tumors in 87.5% of cases; while the EIMS was diagnosed as high-grade endometrial stromal sarcoma. Lack of consideration of IMT in the differential diagnosis of smooth muscle tumors with myxoid features can result in misdiagnosis and under-utilization of targeted therapy in these patients.

A 6-year-old girl presented with a 1-week history of progressive upper and lower extremity weakness and bilateral upper extremity dysesthesia. Imaging demonstrated a 4.7 × 1.2-cm enhancing intramedullary lesion in the cervical spine from level C2 to C5 with associated cystic components and syringomyelia. The patient underwent a C2-C5 laminoplasty, with gross total resection of the intramedullary lesion. Histological analysis showed small to medium-sized epithelioid cells, with predominantly a solid architecture focally infiltrating into the adjacent spinal cord tissue. Focal papillary differentiation was present along with peri-vascular pseudorosettes, mucin microcysts, and globules of dense collagen. Focal anaplasia was noted with mitosis (5/10 HPF), focal necrosis, and elevated Ki67 10-15%. These findings were consistent with a myxopapillary ependymoma with anaplastic features. CSF cytology was negative for tumor cells. MYCN amplification was not present. She was treated with targeted proton-beam radiation therapy. This is the fourth case of an intramedullary anaplastic myxopapillary ependymoma to date, and the first case in the cervical spine reported in the literature.