Publications by authors named "Andrew L Folpe"

213 Publications

Rapidly fatal SMARCA4-deficient undifferentiated sarcoma originating from hybrid hemosiderotic fibrolipomatous tumor/pleomorphic hyalinizing angiectatic tumor of the foot.

Virchows Arch 2021 Aug 14. Epub 2021 Aug 14.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft parts and hemosiderotic fibrolipomatous tumor (HFLT) are two rare low-grade locally recurring neoplasms with predilection for the foot/ankle. Recent studies support a close link between the two entities, and origin of PHAT from HFLT and occurrence of hybrid HFLT/PHAT have been documented. Both lesions often harbor TGFBR3 or MGEA5 rearrangements. Rare sarcomas originating from HFLT/PHAT have been reported, typically resembling myxofibrosarcoma or myxoinflammatory fibroblastic sarcoma. We describe a novel SMARCA4-deficient undifferentiated sarcoma with rhabdoid features originating from hybrid HFLT/PHAT in the foot of a 54-year-old male. The tumor pursued a highly aggressive course with rapid regrowth after resection and multiple metastases resulting in patient's death within 5 months, despite systemic chemotherapy. Immunohistochemistry revealed SMARCA4 loss in the undifferentiated sarcoma, but not in the HFLT/PHAT. Molecular testing confirmed TGFBR3/MGEA5 rearrangements. This report expands the phenotypes of sarcomas developing from pre-existing PHAT/HFLT.
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http://dx.doi.org/10.1007/s00428-021-03167-6DOI Listing
August 2021

Eccrine angiomatous hamartoma: First case in the cytology literature.

Ann Diagn Pathol 2021 Oct 17;54:151796. Epub 2021 Jul 17.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA. Electronic address:

A 34-year-old male presented with a swelling on the volar surface of the third digit of his right hand. This swelling was associated with pain and erythema. Ultrasound-guided needle biopsy was performed. Cytologic and histologic preparations together confirmed the diagnosis of a rarely encountered mixed epithelial and mesenchymal proliferation, an eccrine angiomatous hamartoma. To our knowledge, this case is the first to illustrate the cytomorphologic features of this rare lesion.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151796DOI Listing
October 2021

PRRX1-NCOA1-rearranged fibroblastic tumour: a clinicopathological, immunohistochemical and molecular genetic study of six cases of a potentially under-recognised, distinctive mesenchymal tumour.

Histopathology 2021 Jul 17. Epub 2021 Jul 17.

Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

Aims: PRRX1-NCOA1-rearranged fibroblastic tumour is a recently described, rare mesenchymal tumour. Only four cases have been previously reported. The aim of this article is to report six additional cases of this unusual mesenchymal neoplasm, with an emphasis on its differential diagnosis.

Methods And Results: The six cases were from three females and three males (age, 20-49 years; median, 42 years). Three tumours were located on the abdominal wall; two from the shoulder/axillary areas, and one on the lateral hip. All presented as slow-growing subcutaneous nodules, ranging from 26 to 55 mm (median, 40 mm). The tumours consisted of circumscribed, variably cellular nodules composed of relatively bland plump spindled to epithelioid cells arranged singly, in cords, and occasionally in nests, embedded in hyalinised and collagenous stroma. Small hypocellular myxoid zones with ropey collagen fibres were present, as were irregularly dilated, gaping, crescent-shaped or staghorn-like thin-walled vessels, best appreciated at the periphery. Immunohistochemistry for CD34, S100, MUC4 and STAT6 was consistently negative. RNA-sequencing revealed PRRX1-NCOA1 fusions in all cases. Of the four cases with limited follow-up (1.5-4 months), none recurred following local surgical excision.

Conclusions: The morphological features of PRRX1-NCOA1-rearranged fibroblastic tumour overlap with those of RB1-deficient soft-tissue tumours, solitary fibrous tumour, and low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. This differential diagnosis can be resolved with a combination of careful morphological study and the application of a panel of immunostains, although molecular genetic study is most definitive. The natural history of PRRX1-NCOA1-rearranged fibroblastic tumour appears to be quite favourable, although longer-term study of a larger number of cases is warranted.
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http://dx.doi.org/10.1111/his.14454DOI Listing
July 2021

Myxoid pleomorphic liposarcoma-a clinicopathologic, immunohistochemical, molecular genetic and epigenetic study of 12 cases, suggesting a possible relationship with conventional pleomorphic liposarcoma.

Mod Pathol 2021 Jun 24. Epub 2021 Jun 24.

Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.

Myxoid pleomorphic liposarcoma is a recently defined subtype of liposarcoma, which preferentially involves the mediastinum of young patients and shows mixed histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma. While myxoid pleomorphic liposarcoma is known to lack the EWSR1/FUS-DDIT3 fusions characteristic of the former, additional genetic data are limited. To further understand this tumor type, we extensively examined a series of myxoid pleomorphic liposarcomas by fluorescence in situ hybridization (FISH), shallow whole genome sequencing (sWGS) and genome-wide DNA methylation profiling. The 12 tumors occurred in 6 females and 6 males, ranging from 17 to 58 years of age (mean 33 years, median 35 years), and were located in the mediastinum (n = 5), back, neck, cheek and leg, including thigh. Histologically, all cases consisted of relatively, bland, abundantly myxoid areas with a prominent capillary vasculature, admixed with much more cellular and less myxoid foci containing markedly pleomorphic spindled cells, numerous pleomorphic lipoblasts and elevated mitotic activity. Using sWGS, myxoid pleomorphic liposarcomas were found to have complex chromosomal alterations, including recurrent large chromosomal gains involving chromosomes 1, 6-8, 18-21 and losses involving chromosomes 13, 16 and 17. Losses in chromosome 13, in particular loss in 13q14 (including RB1, RCTB2, DLEU1, and ITM2B genes), were observed in 4 out of 8 cases analyzed. Additional FISH analyses confirmed the presence of a monoallelic RB1 deletion in 8/12 cases. Moreover, nuclear Rb expression was deficient in all studied cases. None showed DDIT3 gene rearrangement or MDM2 gene amplification. Using genome-wide DNA methylation profiling, myxoid pleomorphic liposarcomas and conventional pleomorphic liposarcomas formed a common methylation cluster, which segregated from conventional myxoid liposarcomas. While the morphologic, genetic and epigenetic characteristics of myxoid pleomorphic liposarcoma suggest a link with conventional pleomorphic liposarcoma, its distinctive clinical features support continued separate classification for the time being.
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http://dx.doi.org/10.1038/s41379-021-00862-2DOI Listing
June 2021

EWSR1-WT1 gene fusions in neoplasms other than desmoplastic small round cell tumor: a report of three unusual tumors involving the female genital tract and review of the literature.

Mod Pathol 2021 Oct 7;34(10):1912-1920. Epub 2021 Jun 7.

Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.

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.
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http://dx.doi.org/10.1038/s41379-021-00843-5DOI Listing
October 2021

RNAscope CSF1 chromogenic in situ hybridization: a potentially useful tool in the differential diagnosis of tenosynovial giant cell tumors.

Hum Pathol 2021 Sep 28;115:1-9. Epub 2021 May 28.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. Electronic address:

Colony stimulating factor-1 (CSF1) upregulation and CSF1/colony-stimulating factor 1 receptor (CSF1R) signaling pathway is central to the tumorigenesis of tenosynovial giant cell tumors (TGCT) of both localized (LTGCT) and diffuse (DTGCT) types, and has been demonstrated in a small number of malignant tumors (MTGCT) as well. In situ hybridization for CSF1 mRNA has been shown to be potentially useful in the diagnosis of TGCT, although only a relatively small number of cases have been studied. We studied CSF1 mRNA expression using RNAscope chromogenic in situ hybridization (CISH) in standard tissue sections from 31 TGCT and 26 non-TGCT, and in tumor microarray slides (Pantomics normal MN0341, Pantomics tumor MTU391, Pantomics melanoma MEL961). Among normal tissues, CSF1 mRNA expression was invariably present in synovium (10/10, 100%) and absent in all other normal tissues. All LTGCT and DTGCT were positive (24/24, 100%), exclusively in large, eosinophilic synoviocytes. MTGCT contained large clusters of CSF1-positive malignant synoviocytes (8/8, 100%); malignant spindled cells were also positive. Among non-TGCT, CSF1 CISH was less often positive with high specificity (90%). CSF1-positive cases included leiomyosarcoma, giant cell tumor of bone and of soft parts, pulmonary carcinoma and others. The sensitivity and specificity of RNAscope CSF1 mRNA CISH for the diagnosis of TGCT were 100% and 90%, respectively. We conclude that RNAscope CSF1 CISH may be a valuable adjunct for the diagnosis of TGCT of all types, especially those with atypical or malignant morphologic features. Detection of CSF1 mRNA expression may also have predictive significance in cases where use of the CSF1 inhibitor pexidartinib is considered.
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http://dx.doi.org/10.1016/j.humpath.2021.05.010DOI Listing
September 2021

Response to Lee et al: Toward a unifying entity that encompasses most, but perhaps not all, inflammatory leiomyosarcomas and histiocyte-rich rhabdomyoblastic tumors.

Authors:
Andrew L Folpe

Mod Pathol 2021 07 11;34(7):1439. Epub 2021 May 11.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1038/s41379-021-00819-5DOI Listing
July 2021

Inflammatory rhabdomyoblastic tumor with progression to high-grade rhabdomyosarcoma.

Mod Pathol 2021 05 23;34(5):1035-1036. Epub 2021 Mar 23.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1038/s41379-021-00791-0DOI Listing
May 2021

Recurrent novel HMGA2-NCOR2 fusions characterize a subset of keratin-positive giant cell-rich soft tissue tumors.

Mod Pathol 2021 08 19;34(8):1507-1520. Epub 2021 Mar 19.

Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Giant cell tumors of soft tissue (GCT-ST) are rare low-grade neoplasms that were at one time thought to represent the soft tissue counterparts of GCT of bone (GCT-B) but are now known to lack the H3F3 mutations characteristic of osseous GCT. We present six distinctive giant cell-rich soft tissue neoplasms that expressed keratins and carried a recurrent HMGA2-NCOR2 gene fusion. Patients were five females and one male aged 14-60 years (median, 29). All presented with superficial (subcutaneous) masses that were removed by conservative marginal (3) or wide (2) local excision. The tumors originated in the upper extremity (2), lower extremity (2), head/neck (1), and trunk (1). Five patients with follow-up (median, 21 months; range, 14-168) remained disease-free. Grossly, all tumors were well-demarcated but not encapsulated with variable lobulation. Histologically, they were composed of bland plump epithelioid or ovoid to spindled mononuclear cells admixed with evenly distributed multinucleated osteoclast-type giant cells. Foci of stromal hemorrhage and hemosiderin were seen in all cases. The mitotic activity ranged from 2 to 14/10 high power fields (median: 10). Foci of necrosis and vascular invasion were seen in one case each. The mononuclear cells were immunoreactive with the AE1/AE3 keratin cocktail and less frequently/less diffusely for K7 and K19 but lacked expression of other lineage-associated markers. RNA-based next-generation sequencing revealed an HMGA2-NCOR2 fusion in all tumors. None of the keratin-negative conventional GCT-ST showed the HMGA2-NCOR2 fusion (0/7). Metaplastic bone (4/9) and SATB2 expression (3/4) were frequent in keratin-negative conventional GCT-ST but were lacking in keratin-positive HMGA2-NCOR2 fusion-positive tumors. The distinctive immunophenotype and genotype of these tumors strongly suggest that they represent a discrete entity, differing from conventional GCT-ST and other osteoclast-rich morphologic mimics. Their natural history appears favorable, although a study of additional cases and longer follow-up are warranted.
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http://dx.doi.org/10.1038/s41379-021-00789-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295036PMC
August 2021

NUTM1-rearranged colorectal sarcoma: a clinicopathologically and genetically distinctive malignant neoplasm with a poor prognosis.

Mod Pathol 2021 08 13;34(8):1547-1557. Epub 2021 Mar 13.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

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.
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http://dx.doi.org/10.1038/s41379-021-00792-zDOI Listing
August 2021

Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.

Bone Rep 2021 Jun 24;14:100744. Epub 2020 Dec 24.

Program for Metabolic Bone Disorders at Vanderbilt, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, 8210 Medical Center East, 1215 21st Avenue South, Nashville, TN 37232-8148, United States of America.

Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH ( gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker -, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
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http://dx.doi.org/10.1016/j.bonr.2020.100744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804981PMC
June 2021

CD10 (neprilysin) expression: a potential adjunct in the distinction of hibernoma from morphologic mimics.

Hum Pathol 2021 04 3;110:12-19. Epub 2021 Jan 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. Electronic address:

Although the morphologic diagnosis of hibernoma is usually straightforward, some hibernomas have atypical morphologic features, mimicking atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDLs). In addition, the multivacuolated brown fat cells may be mistaken for lipoblasts by pathologists, especially those without significant soft tissue tumor exposure. Thus, we continue to receive in consultation cases of hibernoma sent for MDM2 fluorescence in situ hybridization testing to exclude ALT/WDL. Testing hibernomas for MDM2 amplification, however, adds cost and delays the final diagnosis. Recently, we have noted expression of neprilysin (CD10, CALLA), a zinc-dependent metalloproteinase involved in the inactivation of various peptide hormones, in brown fat cells, and wished to explore the potential utility of this widely available, inexpensive ancillary test in the differential diagnosis of hibernoma. Formalin-fixed, paraffin-embedded tissue sections from well-characterized cases of hibernoma (n = 48), brown fat (n = 21), ALTs/WDLs (n = 17), pleomorphic liposarcomas (PLPSs) (n = 6), lipomas (n = 5), and fat necrosis (n = 5) were immunostained for CD10, using a commercially available antibody and routine laboratory protocols. CD10 expression was evaluated in both adipocytes and in surrounding stromal cells. The hibernomas occurred in 28 men and 20 women, ranging from 11 to 76 years of age and involved the extremities (n = 25), pelvis (n = 7), abdomen/pelvis/retroperitoneum (n = 7), head and neck region (n = 6), back (n = 2), and chest (n = 1). All showed diffuse, strong CD10 expression in multivacuolated brown fat cells and in the majority of adjacent univacuolated fat cells. Brown adipose tissue from various anatomic structures showed an identical pattern of immunoreactivity. In contrast, CD10 expression was present in the adipocytes of only 3 of 17 (18%) ALTs/WDLs and was absent in lipomas and fat necrosis. Lipoblasts expressed CD10 in 3 PLPSs. Expression of CD10 by surrounding fibroblastic stromal cells was more widespread, present in 13 hibernomas, 10 ALTs/WDLs, 1 instance of fat necrosis, 6 PLPSs, and 4 examples of brown fat. We conclude that immunohistochemistry for CD10 may represent a useful, rapid and inexpensive ancillary test in the differential diagnosis of hibernoma from potential morphologic mimics, especially when morphologic features favor hibernoma. CD10 expression in adipocytes, however, should be rigorously distinguished from fibroblastic stromal cell CD10 expression, a nonspecific finding.
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http://dx.doi.org/10.1016/j.humpath.2020.12.012DOI Listing
April 2021

Glomangiomatosis of the Upper Extremity.

J Hand Surg Am 2021 08 17;46(8):716.e1-716.e3. Epub 2020 Dec 17.

Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, FL. Electronic address:

We describe a 43-year-old woman with a 23-year history of recurrent extradigital glomus tumors (glomangiomatosis) of the hand and forearm. She presented with a typical presentation of pain, tenderness to palpation, and hypersensitivity of the affected regions. After surgical resection, she continued to present with new locations of tumor burden and progressively malignant features of the tumors. This exceedingly rare presentation highlights the importance of vigilantly monitoring patients for recurrence with glomangiomatosis.
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http://dx.doi.org/10.1016/j.jhsa.2020.10.006DOI Listing
August 2021

"Inflammatory Leiomyosarcoma" and "Histiocyte-rich Rhabdomyoblastic Tumor": a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as "Inflammatory Rhabdomyoblastic Tumor".

Mod Pathol 2021 04 22;34(4):758-769. Epub 2020 Oct 22.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Inflammatory leiomyosarcoma (ILMS), defined as "a malignant neoplasm showing smooth muscle differentiation, a prominent inflammatory infiltrate, and near-haploidization", is a very rare soft tissue tumor with a generally favorable prognosis. The morphologic features of "histiocyte-rich rhabdomyoblastic tumor" (HRRMT) are similar to those of ILMS, although this lesion shows by definition a skeletal muscle phenotype. Recent gene expression profiling and immunohistochemical studies have also suggested that ILMS and HRRMT may be related. We studied the clinicopathologic, immunohistochemical and genetic features of four cases previously classified as ILMS and nine classified as HRRMT. Tumors from both groups tended to occur in the deep soft tissues of the extremities of young to middle-aged males and exhibited indolent behavior. Morphologically, all were well-circumscribed, often encapsulated, and showed a striking histiocyte-rich inflammatory infiltrate admixed with variably pleomorphic tumor cells showing spindled and epithelioid to rhabdoid morphology, eosinophilic cytoplasm, and prominent nucleoli, but few, if any, mitotic figures. Immunohistochemically, the tumor cells expressed desmin, alpha-smooth muscle actin, and the rhabdomyoblastic markers PAX7, MyoD1, and myogenin. H-caldesmon expression was absent in all cases, using the specific h-CD antibody. Karyotypic study (1 HRRMT) and genome-wide copy number analysis (7 HRRMT, OncoScan SNP assay), revealed near-haploidization in four cases, with subsequent genome doubling in one, an identical phenotype to that seen in ILMS. We propose reclassification of ILMS and HRRMT as "inflammatory rhabdomyoblastic tumor", a name which accurately describes the salient morphologic and immunohistochemical features of this distinctive tumor, as well as its intermediate (rarely metastasizing) clinical behavior.
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http://dx.doi.org/10.1038/s41379-020-00703-8DOI Listing
April 2021

Update on SWI/SNF-related gynecologic mesenchymal neoplasms: SMARCA4-deficient uterine sarcoma and SMARCB1-deficient vulvar neoplasms.

Genes Chromosomes Cancer 2021 Mar 14;60(3):190-209. Epub 2020 Dec 14.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Our knowledge regarding the role of genes encoding the chromatin remodeling switch/sucrose non-fermenting (SWI/SNF) complex in the initiation and progression of gynecologic malignancies continues to evolve. This review focuses on gynecologic tumors in which the sole or primary genetic alteration is in SMARCA4 or SMARCB1, two members of the SWI/SNF chromatin remodeling complex. In this review, we present a brief overview of the classical example of such tumors, ovarian small cell carcinoma of hypercalcemic type, and then a detailed review and update of SMARCB1-deficient and SMARCA4-deficient tumors of the uterus and vulva.
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http://dx.doi.org/10.1002/gcc.22922DOI Listing
March 2021

Lipoblastomas presenting in older children and adults: analysis of 22 cases with identification of novel PLAG1 fusion partners.

Mod Pathol 2021 03 23;34(3):584-591. Epub 2020 Oct 23.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Lipoblastomas are benign neoplasms of embryonal white fat that typically present in the first 3 years of life and show a lobular arrangement of maturing adipocytes with variable degrees of myxoid change. We systematically studied the clinicopathologic and genetic features of lipoblastomas arising in older children and adults. Cases with a diagnosis of lipoblastoma or maturing lipoblastoma in patients >3 years of age were retrieved from our archives. Immunostaining for CD34 and desmin and molecular studies (FISH, RNA sequencing) were performed. Twenty-two cases (8F; 14M) were identified in patients ranging from 4 to 44 years of age (median 10 years). Sites included extremity (n = 15), head and neck (n = 4), and trunk (n = 3) with tumor sizes varying from 1.6 to 17.5 cm (median 5). Only three tumors had histologic features of "conventional" lipoblastoma. The majority of tumors (n = 14) were composed of variably sized lobules of mature adipose tissue partitioned by thin fibrous septa ("maturing"). The remaining five cases consisted predominantly of bland spindled to plump ovoid cells embedded in a fibrous stroma, with a vaguely plexiform arrangement of small myxoid and adipocytic nodules ("fibroblastic"). CD34 was diffusely positive in all cases tested (21/21), while desmin immunoreactivity was identified in 12 of 21 cases (diffuse = 7, focal = 5). PLAG1 rearrangements were identified in 13 tumors in the entire cohort (59%), including all 5 fibroblastic tumors. RNA sequencing detected eight PLAG1 fusion partners, of which two were known (CHCHD7 and COL3A1) and six were novel (SRSF3, HNRNPC, PCMTD1, YWHAZ, CTDSP2, and PPP2R2A). Twelve cases had follow-up (1-107 months; median 21 months), and no recurrences were reported. Lipoblastomas may occur in older children and adults and may be difficult to recognize due to their predominantly adipocytic or fibrous appearance. Awareness that lipoblastomas may occur in older patients, careful evaluation for foci showing more typical morphologic features, ancillary immunohistochemistry for CD34 and desmin, and molecular genetic studies to identify PLAG1 rearrangements are the keys to recognizing these tumors.
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http://dx.doi.org/10.1038/s41379-020-00696-4DOI Listing
March 2021

Treatment outcome of superficial leiomyosarcoma.

J Surg Oncol 2021 Jan 15;123(1):127-132. Epub 2020 Oct 15.

Clinic Department of Orthopedic Surgery, Rochester, Minnesota, USA.

Background: Nonuterine leiomyosarcomas (LMS) are common extremity soft-tissue sarcomas. Deep LMS are at an increased risk for recurrence; however, few studies have focused on superficial LMS.

Methods: We reviewed the clinicopathological features of 82 patients with a primary superficial LMS. The mean age and follow-up were 57 ± 15 and 7 ± 5 years. Depth was classified as dermal (based in the skin; n = 35, 43%) and subcutaneous (based below the dermis, above the fascia; n = 47, 57%) on the final resection specimen. Dermal cases were treated with negative margin resection, while subcutaneous tumors were evaluated by a multidisciplinary team for consideration of possible adjuvant therapy.

Results: The 10-year disease-specific survival (DSS) for superficial LMS was 90% with no difference (p = .18) in the 10-year DSS between patients with dermal (100%) and subcutaneous (86%) LMS. All disease recurrences occurred in subcutaneous LMS (17% vs. 0%, p = .02) and subcutaneous tumors had a worse10-year metastatic free survival (81% vs. 100%, p = .03).

Conclusions: The results of this study suggest that dermal LMS can be managed with a negative margin resection alone. Although the prognosis for patients with subcutaneous LMS is quite favorable, there is some risk for local and distant recurrence, and such patients will benefit from multidisciplinary care.
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http://dx.doi.org/10.1002/jso.26262DOI Listing
January 2021

Primary intra-abdominal melanoma arising in association with extracutaneous blue naevus: a report of two cases.

Histopathology 2021 Jan 16;78(2):281-289. Epub 2020 Oct 16.

Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

Aims: Blue naevi are uncommon dermal melanocytic neoplasms characterised by GNAQ/GNA11 mutations, which very rarely progress to melanoma. Such melanomas also often have BAP1 mutations, and lack genetic events associated with conventional melanoma. Exceptionally, blue naevi arise in extracutaneous locations; one melanoma arising in this setting has been reported. We report the clinicopathological, immunohistochemical and molecular genetic features of two cases of melanoma arising in extracutaneous blue naevus.

Methods And Results: Both arose in males, aged 25 and 63 years, with no history of other melanocytic lesions, and presented as large, painful intra-abdominal masses. The tumours were dark-brown/black, multilobulated, involved small intestinal mesentery and consisted of a predominantly fascicular and spindled, but occasionally nested and epithelioid, proliferation of variably pigmented, relatively monotonous cells with pale cytoplasm and ovoid nuclei with mild to moderate atypia. Mitotic activity was variable but generally low. Both cases showed areas of conventional and cellular blue naevus. Recurrent tumour in one case showed predominantly epithelioid morphology and greater cytological atypia and mitotic activity. One case expressed Melan-A, SOX10 and CD117, with absent expression of S100 protein and DOG1; the other expressed Melan-A, HMB45 and S100 protein. Next-generation sequencing identified GNAQ and BAP1 mutations in one case and GNA11 mutation in the other. Both patients developed widespread metastatic disease.

Conclusion: Exceptionally rare, aggressive melanomas arising in extracutaneous blue naevi should be distinguished from metastatic melanoma, gastrointestinal stromal tumour and malignant melanotic nerve sheath tumour, especially given the significant therapeutic and prognostic differences between these different entities.
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http://dx.doi.org/10.1111/his.14219DOI Listing
January 2021

Paraspinal pseudoneoplasms: a series of 58 consultation cases emphasizing the importance of pathology-radiology correlation.

Hum Pathol 2020 09 15;103:14-24. Epub 2020 Jul 15.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 99505, USA. Electronic address:

A variety of non-neoplastic diseases of the spine, including herniated/sequestered intervertebral discs, synovial cysts, and degenerative or post-traumatic changes, may present as mass lesions. Over the past several years, we have seen a large number of such paraspinal pseudoneoplasms in consultation, referred out of concern for malignancy on the part of the clinician, pathologist, or both. Herein, we report our experience with these specimens, emphasizing the clinical, radiologic, and histopathological features that allow their confident distinction from various mesenchymal tumors. Fifty-eight cases were identified within our consultation archives, referred in consultation to exclude malignancy and diagnosed as non-neoplastic disease involving the intervertebral disc, ligamentum flavum, or paraspinal soft tissues (2006-2019). Available radiologic studies were reviewed by 2 musculoskeletal radiologists. The histologic features of all cases were re-evaluated. Available clinical records were reviewed. The masses occurred in adults (median age 62 years, range 20-86 years) with a male predominance (35 males and 23 females). Sites included lumbar spine (N = 33), thoracic spine (N = 15), cervical spine (N = 6), paraspinal region (N = 3), and sacral spine (N = 1). In 44 cases (76%), the referring pathologist regarded the specimen as representing a benign or malignant neoplasm, either primary or metastatic. Fifteen cases (26%) were sent for second opinion at the request of the treating clinician, following an initial malignant diagnosis. Advanced imaging studies were available for re-review in 37 cases (64%) and showed herniated/extruded disc (N = 17), compression fracture (N = 9), synovial cyst (N = 8), and degenerative joint disease (N = 7). Multiple radiologic findings were seen in 9 patients. Histologically, the specimens showed a spectrum of often florid reactive changes involving degenerating disc material, ligamentum flavum, and bone. Awareness that non-neoplastic spinal processes may form pseudoneoplastic mass lesions, and careful clinical-radiologic-pathologic correlation should allow their confident distinction from potential morphologic mimics.
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http://dx.doi.org/10.1016/j.humpath.2020.07.012DOI Listing
September 2020

Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements: a clinicopathological, immunophenotypic, and molecular study of eight cases, emphasizing their distinction from gastrointestinal stromal tumor (GIST).

Mod Pathol 2021 01 15;34(1):95-103. Epub 2020 Jul 15.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Mesenchymal tumors driven by NTRK fusions are clinically and morphologically heterogeneous. With an increasing number of clinicopathological entities being associated with NTRK fusions, the diagnostic and predictive value of the identification of NTRK fusions is uncertain. Recently, mesenchymal tumors in the gastrointestinal tract with NTRK fusions were described as gastrointestinal stromal tumors (GIST), but the nosology of such neoplasms remains controversial. We report eight mesenchymal tumors involving the gastrointestinal tract with NTRK1 or NTRK3 rearrangements. The tumors occurred in six children and two adults, five males and three females (age range 2 months-55 years; median 3.5 years), and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1), and mesentery (n = 1). Clinical outcomes were variable, ranging from relatively indolent (n = 2) to aggressive diseases (n = 2). Morphologically, the tumors were heterogeneous and could be classified in the following three groups: (1) infantile fibrosarcoma involving the gastrointestinal tract (n = 4), enriched for NTRK3 fusions; (2) low-grade CD34-positive, S100 protein-positive spindle-cell tumors, associated with NTRK1 fusions (n = 2); and (3) unclassified high-grade spindle-cell sarcomas, with NTRK1 fusions (n = 2). By immunohistochemistry, the tumors demonstrated diffuse pan-TRK expression, of variable intensity, and lacked a specific line of differentiation. Four cases expressed CD34, which was coexpressed with S100 protein in three cases. Expression of SOX10, KIT, and DOG1 was consistently absent. Molecular genetic testing identified TPM3-NTRK1 (n = 3), TPR-NTRK1, LMNA-NTRK1, and ETV6-NTRK3 (n = 2), and SPECC1L-NTRK3 in-frame gene fusions. We conclude that the evaluation of mesenchymal spindle-cell neoplasms of the gastrointestinal tract without a definitive line of differentiation should include interrogation of NTRK alterations, particularly in pediatric patients. Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements are clinically and morphologically heterogeneous, and few, if any, seem related to GIST.
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http://dx.doi.org/10.1038/s41379-020-0623-zDOI Listing
January 2021

Colonic Angiosarcoma Arising in Association with Amyloid Deposits.

Case Rep Gastrointest Med 2020 16;2020:3780763. Epub 2020 May 16.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Angiosarcoma of the colon is rare, as is colonic amyloidosis. To our knowledge, there have been no reported cases of angiosarcoma arising in association with amyloid deposition. Herein, we described a case of 77-year-old man who presented with hematochezia, and a sigmoid mass was found on colonoscopy. Histologic examination of the resected specimen showed extensive nodular deposition of AL-lambda amyloid material in the colonic wall, as well as high-grade angiosarcoma which was closely intermingled with the amyloid deposits. While the occurrence of both colonic amyloidosis and angiosarcoma in this patient may represent pure coincidence, given the intimate association of the angiosarcoma and the amyloid deposition and the rarity of both of these lesions, we hypothesize that angiosarcoma could be secondary to amyloid deposition.
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http://dx.doi.org/10.1155/2020/3780763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246417PMC
May 2020

Xanthogranulomatous epithelial tumor: report of 6 cases of a novel, potentially deceptive lesion with a predilection for young women.

Mod Pathol 2020 10 15;33(10):1889-1895. Epub 2020 May 15.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.

Epithelial marker expression and/or epithelial differentiation, as well as "anomalous" expression of keratins, are features of some soft tissue tumors. Recently, we have encountered an unusual mesenchymal tumor composed of bland, distinctly eosinophilic, keratin-positive epithelial cells, which were almost entirely obscured by xanthogranulomatous inflammation. Six cases were identified (5 F, 1 M; 16-62 years (median 21 years)) arising in soft tissue (n = 4) and bone (n = 2) and ranging in size from 2 to 7 cm. The tumors were generally circumscribed, with a fibrous capsule containing lymphoid aggregates, and consisted in large part of a sheet-like proliferation of foamy histiocytes, Touton-type and osteoclast-type giant cells, and chronic inflammatory cells. Closer inspection, however, disclosed a distinct population of uniform, cytologically bland mononuclear cells with brightly eosinophilic cytoplasm arranged singly and in small nests and cords. Overt squamous and/or glandular differentiation was absent. By immunohistochemistry, these cells were diffusely positive with the OSCAR and AE1/AE3 keratin antibodies, and focally positive for high-molecular weight keratins; endothelial and myoid markers were negative and SMARCB1 was retained. RNA-seq identified a PLEKHM1 variant of undetermined significance in one case, likely related to this patient's underlying osteopetrosis. Follow-up to date has been benign. In summary, we have identified a novel tumor of soft tissue and bone with a predilection for young females, provisionally termed "xanthogranulomatous epithelial tumor". These unusual lesions do not appear to arise from adnexa, or represent known keratin-positive soft tissue tumors, and the origin of their constituent epithelial cells is obscure. The natural history of this distinctive lesion appears indolent, although study of additional cases and longer term follow-up are needed.
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http://dx.doi.org/10.1038/s41379-020-0562-8DOI Listing
October 2020

MyoD1 expression in fibroepithelial stromal polyps.

Hum Pathol 2020 05 23;99:75-79. Epub 2020 Mar 23.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55902, USA. Electronic address:

Fibroepithelial stromal polyps (FESPs) are benign polypoid mesenchymal lesions thought to arise from desmin-positive specialized stromal cells of the female genital tract. Although most cases are easily diagnosed by morphology alone, the morphology of FESPs is variable and in some instances can contain hypercellular stroma with numerous atypical desmin-positive cells, simulating botryoid embryonal rhabdomyosarcoma (ERMS). Recently, we encountered a cellular FESP showing desmin expression as well as nuclear immunoreactivity for the skeletal muscle-associated transcription factor MyoD1. Although these lesions are widely known to express desmin, there are very few studies examining expression of the more specific markers of skeletal muscle differentiation, myogenin and MyoD1. The aim of our study was to examine desmin, MyoD1, and myogenin expression in a series of 25 FESPs. Of the 25 cases, desmin expression was present in 23 (92%), at least focal MyoD1 expression was present in 10 (40%), and all cases were negative for myogenin. Follow-up data were available for all 25 cases, and none recurred or behaved in a malignant fashion. Awareness of this potential immunohistochemical pitfall and careful morphologic evaluation should allow for the confident distinction of MyoD1-positive FESP from botyroid ERMS in almost all instances.
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http://dx.doi.org/10.1016/j.humpath.2020.03.006DOI Listing
May 2020

Juvenile Hyaline Fibromatosis.

Mayo Clin Proc 2020 02;95(2):328-329

Orange County Pathology Medical Group, St. Joseph Hospital, Orange, CA.

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http://dx.doi.org/10.1016/j.mayocp.2019.11.021DOI Listing
February 2020

Head and Neck Mesenchymal Neoplasms With GLI1 Gene Alterations: A Pathologic Entity With Distinct Histologic Features and Potential for Distant Metastasis.

Am J Surg Pathol 2020 06;44(6):729-737

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.

Soft tissue tumors with GLI1 gene fusions or amplifications have been recently described as a unique pathologic entity with an established risk of malignancy. We herein expand these findings by investigating a cohort of 11 head and neck lesions with GLI1 alterations, including 8 from the tongue, for their clinicopathologic and molecular features. The tumors commonly affected males in their 30s (male:female ratio 2.7:1; range: 1 to 65). Tumors showed a multinodular growth pattern, nested architecture separated by a delicate, arborizing vascular network, monotonous round to ovoid nuclei, and clear cytoplasm. Tumor protrusion into vascular spaces was common. Genetic alterations were investigated by fluorescence in situ hybridization and/or targeted RNA sequencing. Seven tumors harbored GLI1 fusions with the following partners: ACTB (n=4), PTCH1 (n=2), or MALAT1 (n=1). The remaining 4 cases showed coamplifications of GLI1 with CDK4 and MDM2 genes. Tumors were commonly positive for S100 protein and CD56. CDK4, MDM2, and STAT6 were positive in GLI1-amplified tumors. Two of 6 patients with available follow-up (1 each with GLI1 amplification and PTCH1-GLI1 fusion) developed distant metastases. Both tumors showed a high mitotic index and tumor necrosis. The head and neck region, particularly tongue, is a common location for GLI1-related mesenchymal tumors. Although a morphologic overlap was noted with the previously reported "pericytoma with t(7,12) translocation," often occurring in the tongue, our findings expand the original findings, to include a more variable immunophenotype, propensity for late distant metastases, and alternative mechanisms of GLI1 oncogenic activation, such as various GLI1 fusion partners or GLI1 coamplifications with MDM2 and CDK4 genes.
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http://dx.doi.org/10.1097/PAS.0000000000001439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225037PMC
June 2020

Contemporary approaches to soft tissue and bone pathology.

Virchows Arch 2020 01;476(1):1-2

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.

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http://dx.doi.org/10.1007/s00428-019-02731-5DOI Listing
January 2020

Ewing Sarcoma in Older Adults: A Clinicopathologic Study of 50 Cases Occurring in Patients Aged ≥40 Years, With Emphasis on Histologic Mimics.

Int J Surg Pathol 2020 Jun 17;28(4):352-360. Epub 2019 Dec 17.

Mayo Clinic, Rochester, MN, USA.

. We explore the clinicopathologic features of Ewing sarcoma (ES) presenting in older adulthood. . Cases of molecularly confirmed ES arising in patients aged ≥40 years were evaluated. . Fifty patients were identified (33 males/17 females; 41-86 years). The majority of tumors (41) arose at extraskeletal sites, while 9 were bone primaries. Twenty-eight cases showed nested architecture, while the remaining cases showed sheet-like growth. Tumor cytology was categorized as conventional (n = 39), crushed (n = 5), clear cell (n = 4), rhabdoid (n = 3), and epithelioid (n = 2). Fifty percent had necrosis, while rosettes were noted in 1 case. Immunostains performed ranged from 1 to 28 (median = 10). Follow-up (n = 43, 1-147 months) revealed 15 patients with metastasis. . Although rare, ES should be considered in the differential diagnosis for round cell malignancies in older adult patients. In this cohort, ES is most often extraskeletal, and may show unusual morphologic features, closely simulating more common neoplasms in this age group.
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http://dx.doi.org/10.1177/1066896919893073DOI Listing
June 2020

Frequent overexpression of klotho in fusion-negative phosphaturic mesenchymal tumors with tumorigenic implications.

Mod Pathol 2020 05 2;33(5):858-870. Epub 2019 Dec 2.

Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

Phosphaturic mesenchymal tumors (PMT) are tumors that cause hypophosphatemia/osteomalacia chiefly by secreting FGF23. We have identified FN1-FGFR1/FGF1 fusion genes in nearly half of PMT, suggesting a central role of FGFR1 pathways in the pathogenesis of PMT. Tumorigenic drivers are unknown for tumors where previous study detected neither fusion, including many in bone, where FISH failed because of tissue decalcification. To identify alternative fusions in PMT without known fusions, as well as to validate the positive FISH results and characterize the fusion junctions, 34 PMT were studied, including 12 with known FN1-FGFR1 fusion by FISH (Group A), 2 with FN1-FGF1 (B), 12 with neither fusion (C), and 8 with previous acid-based decalcification and hence unknown fusion status (D). In total, 23 archival samples were subjected to anchored multiplex PCR-based RNA-sequencing (AMP-seq) with primers targeting FN1, genes encoding the FGF/FGFR families, and KL (α-Klotho); five Group C cases were also studied with whole-transcriptomic and exome-captured RNA sequencing, respectively. The AMP-seq results were consistent with previous FISH and/or transcriptomic sequencing data, except in one old Group A sample. One case had a novel FGFR1 exon 9 breakpoint, confirmed by genomic DNA sequencing. One Group D bone tumor was found to harbor FN1-FGF1. All 3 RNA-sequencing platforms failed to identify convincing fusion genes in Group C (N = 10), which instead expressed significantly higher levels of either KL or KLB. This result was further confirmed with KL and KLB RNA CISH semi-quantification (RNAscope). Our results demonstrated the utility of AMP-seq, which was compromised by decalcification and prolonged archiving. Of potential importance, fusion-negative PMT frequently overexpressed α-Klotho (or instead β-Klotho less commonly), whose role as an obligatory co-receptor for FGF23-FGFR1 binding suggests its aberrant expression in osteocytes/osteoblasts might result in an FGF23-FGFR1 autocrine loop that in turn drives the overexpression of FGF23 and tumorigenesis through activated FGFR pathways.
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http://dx.doi.org/10.1038/s41379-019-0416-4DOI Listing
May 2020

Update on selected advances in the immunohistochemical and molecular genetic analysis of soft tissue tumors.

Virchows Arch 2020 Jan 7;476(1):3-15. Epub 2019 Nov 7.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.

Although traditional morphological evaluation remains the cornerstone for the diagnosis of soft tissue tumors, ancillary diagnostic modalities such as immunohistochemistry and molecular genetic analysis are of ever-increasing importance in this field. New insights into the molecular pathogenesis of soft tissue tumors, often obtained from high-throughput sequencing technologies, has enabled significant progress in the characterization and biologic stratification of mesenchymal neoplasms, expanding the spectrum of immunohistochemical tests (often aimed towards recently discovered genetic events) and molecular genetic assays (most often fluorescence in situ hybridization and reverse transcription-polymerase chain reaction). This review discusses selected novel molecular and immunohistochemical assays with diagnostic applicability in mesenchymal neoplasms, with emphasis on diagnosis, refinement of tumor classification, and treatment stratification.
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http://dx.doi.org/10.1007/s00428-019-02678-7DOI Listing
January 2020

Lymphatic-type "Angiosarcoma" With Prominent Lymphocytic Infiltrate.

Am J Surg Pathol 2020 02;44(2):271-279

Departments of Pathology and Laboratory Medicine.

We report 21 cases of a distinctive and unique vascular tumor which we propose to be a pure lymphatic-type angiosarcoma characterized by architectural and growth characteristics of angiosarcoma, cytologic, and immunohistochemical features of lymphatic differentiation, a prominent lymphocytic infiltrate, and variable nuclear grade. Patients included 12 males and 9 females with a median age of 65 years (range: 32 to 95 y). Tumors involved the head and neck (n=11), lower extremities (n=5), trunk (n=4), and upper extremity (n=1) and were located superficially in the dermis and/or subcutis. Tumors were designated "low grade" (n=10) when the nuclear grade was low, and vascular channel formation was evident throughout but with multilayering of endothelium within the vessels. Cases were designated "high grade" (n=11) when nuclei appeared higher grade with more rounded contours and prominent nucleoli and when solid areas predominated over vascular channel formation. A striking feature of both groups was the presence of a dense, lymphocytic infiltrate with occasional germinal center formation. All cases strongly and diffusely expressed at least 1 lymphatic marker (21/21) with podoplanin (17/19) and Prox-1 (11/11) more commonly expressed than LYVE-1 (5/10). No consistent molecular alteration was identified. Follow-up on 17 patients (median: 41 mo, mean: 54 mo) showed 10 patients were alive without disease, 5 were alive with disease, 1 died of other cause, and 1 died of disease. Local recurrence developed in 9 cases and metastasis in 2 cases, although neither correlated with grade as defined. On the basis of clinical follow-up to date, the natural history of lymphatic-type angiosarcoma appears to be more favorable than other forms of cutaneous angiosarcoma.
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http://dx.doi.org/10.1097/PAS.0000000000001398DOI Listing
February 2020
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