Publications by authors named "Shengmei Zhou"

78 Publications

Primary Adrenal Malignant Rhabdoid Tumor in a 14-Year-Old Female: A Case Report and Literature Review.

Int J Surg Pathol 2021 Jun 9:10668969211024331. Epub 2021 Jun 9.

Children's Hospital Los Angeles, Los Angeles, CA, USA.

Malignant rhabdoid tumor (MRT) is a rare, SWItch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 ()-deficient, aggressive tumor, occurring predominantly in children below 3 years of age. Primary adrenal MRT is extremely rare, with only 3 cases reported in the literature. A previously healthy 14-year-old female presented with left upper quadrant/epigastric abdominal pain. Imaging studies revealed an 8.0 × 8.0 × 6.5 cm, heterogeneous, partially enhancing mass along the superior margin of the left kidney encasing the adrenal gland. Surgical resection of the tumor revealed a hypercellular heterogeneous neoplasm arising from the adrenal gland. It was composed predominantly of primitive small round blue cells with focal true rosettes and areas of vague glandular epithelial differentiation and chondroid differentiation. Classic rhabdoid-type cytoplasmic inclusions were focally present. Mitoses, tumor necrosis, and hemorrhage were readily seen. Tumor cells showed complete loss of SMARCB1 (INI1) nuclear staining, demonstrated strong, and diffuse positivity for glypican 3, patchy positivity for CD99, cytokeratin, Sal-like protein 4, Lin-28 homolog A, epithelial membrane antigen, and S100. Molecular studies revealed biallelic frameshift mutations in the gene (c.673delG and c.683dupT) without pathogenic copy number aberrations. The histologic, immunohistochemical, and molecular findings support a diagnosis of MRT. The unusual age, location, and mutations of this case expand the clinicopathologic and molecular spectrum of MRT.
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http://dx.doi.org/10.1177/10668969211024331DOI Listing
June 2021

PD-L1 expression in angiomatoid fibrous histiocytoma.

Sci Rep 2021 Jan 26;11(1):2183. Epub 2021 Jan 26.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, MS 43, 4650 Sunset Boulevard, Los Angeles, CA, 90027, USA.

Angiomatoid fibrous histiocytoma (AFH) is a rare tumor of intermediate malignancy. Treatment options for unresectable and/or metastatic tumors are very limited. Immunotherapy with PD-1/PD-L1 inhibitors may be worth exploring. The aim of this study was to evaluate the expression of PD-L1 in AFHs. PD-L1 expression was assessed on 36 AFHs from 36 pediatric patients by immunohistochemical staining of PD-L1 (clone 22C3). Positivity was defined as membranous expression in ≥ 1% of either tumor or immune cells. The correlations between PD-L1 expression and clinicopathologic features were assessed. Two patients had lymph node metastasis. All patients underwent surgical resection; three of them also had systemic chemotherapy. Three patients had recurrence after initial resection; all patients were alive with a median follow-up of 2.5 years. Overall, twenty-two (61%) tumors were positively stained for PD-L1 and positivity was seen on both tumor and immune cells in eighteen of the 22 tumors. A positive correlation was found between tumor cell PD-L1 expression and CD8+ T-cell infiltration. There were no statistically significant differences between the status of PD-L1 expression and the clinicopathological features assessed. PD-L1 expression was identified in 61% of AFHs with a predominantly adaptive pattern. Our findings provide a rationale for future studies evaluating the potential of checkpoint immunotherapy for patients with unresectable and/or metastatic tumor.
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http://dx.doi.org/10.1038/s41598-021-81746-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838166PMC
January 2021

Primary Knee Intra-articular Synovial Sarcoma in Pediatric and Adolescent Patients.

Pediatr Dev Pathol 2021 Mar-Apr;24(2):159-163. Epub 2021 Jan 20.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California.

Synovial sarcoma (SS) arising within a knee joint is extremely rare, with 10 reported cases in pediatric and adolescent patients in English literature. Its rarity and nonspecific clinical and radiological features pose a diagnostic challenge. We present two cases of primary intra-articular SS of left knee to enhance awareness of this entity. One patient is a 17-year-old male complained of left knee pain and gait abnormality for 9 years. The other one is a 13-year-old female presented with left knee pain for one year. Both cases were clinically diagnosed as benign joint lesion and underwent biopsies. Histological examination, immunohistochemical staining and molecular study confirmed that both patients had primary intra-articular SS, monophasic spindle cell type. Intraarticular SS should be considered as a potential diagnosis with unexplained long-standing knee pain.
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http://dx.doi.org/10.1177/1093526620981368DOI Listing
January 2021

Clinicopathologic Characteristics of Late Acute Antibody-Mediated Rejection in Pediatric Liver Transplantation.

Transplantation 2020 Oct 7. Epub 2020 Oct 7.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.

Background: An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients.

Methods: We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients.

Results: Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6/7 patients; and arteritis was seen in 3/7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years.

Conclusions: Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.
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http://dx.doi.org/10.1097/TP.0000000000003469DOI Listing
October 2020

Phox2b Immunohistochemical Staining in Detecting Enteric Neural Crest Cells in Hirschsprung Disease.

Pediatr Dev Pathol 2021 Jan-Feb;24(1):19-26. Epub 2020 Sep 25.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.

Background: It can be challenging to recognize undifferentiated/immature ganglion cells, especially single forms. Ganglion cells and glia are derived from enteric neural crest cells (ENCCs), a group of autonomic nervous system (ANS)-lineage neural crest progenitors that regulates. Phox2b is an excellent marker for neoplastic and non-neoplastic ANS cells (eg, peripheral neuroblastic tumors [pNTs]). We hypothesized that Phox2b immunohistochemical staining (IHC) would also be useful for detecting ENCCs.

Methods: Hematoxylin and eosin, calretinin IHC, and Phox2b IHC were reviewed on 21 pull-through specimens and on a cohort of 12 rectal biopsies.

Results: Phox2b IHC demonstrated nuclear positivity in all of the ganglion cells across the different phases of differentiation without background staining. The Phox2b result correlated with the morphological findings, calretinin IHC results, and diagnoses based on the routine diagnostic method. The intensity was uniformly strong in the undifferentiated/immature forms and became variable in the mature forms; this pattern was similar to that seen in pNTs.

Conclusion: Phox2b IHC was highly sensitive and specific for detecting ganglion cells. It worked especially well for immature ganglion cells, seen in premature neonates, and scattered single forms in transition zones. In basic research settings, Phox2b can be a useful marker for early differentiation of ENCCs.
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http://dx.doi.org/10.1177/1093526620953372DOI Listing
September 2020

The Effect of Gross Total Resection on Patients with Pleuropulmonary Blastoma.

J Surg Res 2020 09 27;253:115-120. Epub 2020 Apr 27.

Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address:

Background: Pleuropulmonary blastoma (PPB) is the most common primary lung cancer in children. While rare, these tumors are highly aggressive. Tumor recurrence and overall survival are dependent on histologic grade and extent of surgical resection. We sought to examine our institutional experience with PPB to determine the effect of gross total resection (GTR) on recurrence and patient outcomes.

Materials And Methods: After IRB approval, a retrospective chart review from 1998 to 2018 was performed. Cases were confirmed by histology and Dehner Grade (I to III). Data collection included demographics, treatment, extent of surgical resection, and patient outcomes.

Results: Eight patients with nine procedures were identified. Histologically, three cases were type 1, 2 type 2, and four poor prognosis type 3. Three patients received neoadjuvant chemotherapy to facilitate surgical resection. The operative goal was to achieve GTR (>95%), and to this end, three partial lobectomies, five lobectomies, and one pneumonectomy were performed. All nine cases achieved GTR, of which eight had negative microscopic margins. Two patients with type III disease recurred (one locally, one distant) and died. One type 3 patient had a positive microscopic hilar margin not amenable to further resection. The patient recurred (distant) but is in remission. With respect to patient outcomes, the event-free survival was 2.3 y with an overall survival of 3.3 y.

Conclusions: From our experience, GTR of PPB is associated with minimal surgical morbidity and good overall survival. Multi-institutional studies are needed to determine if positive surgical margins affect outcomes given the morbidity of mediastinal dissection.
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http://dx.doi.org/10.1016/j.jss.2020.03.019DOI Listing
September 2020

Routine Surveillance Catheterization is Useful in Guiding Management of Stable Fontan Patients.

Pediatr Cardiol 2020 Mar 24;41(3):624-631. Epub 2020 Jan 24.

Division of Pediatric Cardiology, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, 4650 Sunset Blvd, Mailstop #34, Los Angeles, CA, 90027, USA.

We developed a Fontan surveillance catheterization protocol as part of routine assessment of stable patients 10 years after Fontan completion. The surveillance catherization includes hemodynamic assessment with inhaled nitric oxide, angiography, liver biopsy, and transcatheter intervention if indicated. We aimed to describe hemodynamic and liver biopsy findings, response to pulmonary vasoreactivity testing, rates of transcatheter intervention, and changes in medical therapy following surveillance catheterization in stable Fontan patients. A single-center retrospective review of Fontan patients undergoing surveillance catheterization between November 2014 and May 2019 was performed. Liver biopsies were independently scored by two pathologists. Sixty-three patients underwent surveillance catheterization (mean age 14.6 ± 3.0 years). The mean Fontan pressure was 11.8 ± 2.1 mmHg. The mean cardiac index was 2.9 ± 0.6 L/min/m. In the 51 patients who underwent pulmonary vasoreactivity testing, there was a significant decrease in median pulmonary vascular resistance (1.8 [range 0.8-4.1] vs 1.4 [range 0.7-3.0] Wood units × m; p < 0.001). The mean cardiac index increased (3.0 ± 0.6 vs 3.2 ± 0.7 L/min/m, p = 0.009). The Fontan pressure did not change significantly. Fifty-seven patients underwent liver biopsy, and all but one showed fibrosis. Nineteen patients (33.3%) demonstrated bridging fibrosis or cirrhosis. Twenty-five patients underwent 34 transcatheter interventions. Pulmonary artery or Fontan stent placement was performed in 19 patients. Phosphodiesterase type 5 inhibitors were initiated in nine patients following surveillance catheterization. Routine surveillance catheterization with liver biopsy in adolescent Fontan patients reveals information that can guide interventional and medical management. Further long-term follow-up and assessment are indicated to assess the benefit of these interventions.
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http://dx.doi.org/10.1007/s00246-020-02293-3DOI Listing
March 2020

Infective Endocarditis in a Pediatric Patient.

J Appl Lab Med 2019 01 30;3(4):720-723. Epub 2018 Nov 30.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA;

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http://dx.doi.org/10.1373/jalm.2018.027722DOI Listing
January 2019

Tumor Mutation Burden and Checkpoint Immunotherapy Markers in NUT Midline Carcinoma.

Appl Immunohistochem Mol Morphol 2020 08;28(7):495-500

Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.

NUT midline carcinoma (NMC) is a rare, aggressive poorly differentiated carcinoma genetically defined by NUTM1 gene rearrangement. The purpose of this study was to determine the tumor mutational burden (TMB) and the expression of immunohistochemical (IHC) markers in NMCs that are generally used to identify patients that might benefit from checkpoint immunotherapy. Three cases in a 39-year-old male (case 1) and two 13-year-old females (cases 2, 3) were identified from departmental files, with confirmation by NUT IHC and 15q14 rearrangement by fluorescent in situ hybridization. Normal-tumor paired whole exome sequencing (WES) was applied to determine TMB. IHC for DNA mismatch repair proteins, Programmed cell death ligand 1, programmed cell death 1 (PD1), and CD8 was also performed. WES yielded a TMB of 7.61 and 1.52 per Mbp in the primary and pulmonary metastasis in case 1, respectively, and a TMB of 1.04 per Mbp in the primary tumor of case 2. Programmed cell death ligand 1 tumor proportion score was 20%, 1%, and 0% and combined positive score was 25, 5, and 0 in cases 1, 2, and 3, respectively; PD1 stain counts were 25, 52, and 35 per high-power field and the PD1/CD8 ratio was 95%, 95%, and 99% in cases 1, 2, and 3, respectively. The CD8 count per high-power field was 15, 33, and 30 per high-power field in cases 1, 2, and 3, respectively. Mismatch repair IHCs showed retained staining. Although the number of cases is limited, this study is the first to investigate checkpoint immunotherapy markers in NMCs and the results demonstrate no clear biomarker association. However, the results suggest that, if checkpoint therapy is under consideration, a comprehensive workup utilizing WES and IHC is warranted.
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http://dx.doi.org/10.1097/PAI.0000000000000781DOI Listing
August 2020

Alteration of cystic airway mesenchyme in congenital pulmonary airway malformation.

Sci Rep 2019 03 28;9(1):5296. Epub 2019 Mar 28.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.

Congenital pulmonary airway malformation (CPAM) is the most common congenital lesion detected in the neonatal lung, which may lead to respiratory distress, infection, and pneumothorax. CPAM is thought to result from abnormal branching morphogenesis during fetal lung development, arising from different locations within the developing respiratory tract. However, the pathogenic mechanisms are unknown, and previous studies have focused on abnormalities in airway epithelial cells. We have analyzed 13 excised lung specimens from infants (age < 1 year) with a confirmed diagnosis of type 2 CPAM, which is supposed to be derived from abnormal growth of intrapulmonary distal airways. By examining the mesenchymal components including smooth muscle cells, laminin, and elastin in airway and cystic walls using immunofluorescence staining, we found that the thickness and area of the smooth muscle layer underlining the airway cysts in these CPAM tissue sections were significantly decreased compared with those in bronchiolar walls of normal controls. Extracellular elastin fibers were also visually reduced or absent in airway cystic walls. In particular, a layer of elastin fibers seen in normal lung between airway epithelia and underlying smooth muscle cells was missing in type 2 CPAM samples. Thus, our data demonstrate for the first time that airway cystic lesions in type 2 CPAM occur not only in airway epithelial cells, but also in adjacent mesenchymal tissues, including airway smooth muscle cells and their extracellular protein products. This provides a new direction to study the molecular and cellular mechanisms of CPAM pathogenesis in human.
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http://dx.doi.org/10.1038/s41598-019-41777-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439218PMC
March 2019

Embryonal rhabdomyosarcoma in a patient with a germline CBL pathogenic variant.

Cancer Genet 2019 02 30;231-232:62-66. Epub 2018 Dec 30.

Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Germline pathogenic variants in CBL are associated with an autosomal dominant RASopathy and an increased risk for malignancies, particularly juvenile myelomonocytic leukemia. Herein, we describe a patient with clinical features of a Noonan-spectrum disorder who developed embryonal rhabdomyosarcoma of the bladder at age two years. Tumor analysis using the OncoKids cancer panel revealed a CBL pathogenic variant: NM_005188.3:c.1100A>C (p.Gln367Pro). Sanger sequencing of peripheral blood DNA confirmed a de novo heterozygous germline variant. This is the first report of embryonal rhabdomyosarcoma in association with a germline CBL pathogenic variant, further broadening the CBL cancer predisposition spectrum.
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http://dx.doi.org/10.1016/j.cancergen.2018.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528629PMC
February 2019

A 10-Month-Old Infant Presenting With Signs of Precocious Puberty Secondary to a Sclerosing Stromal Tumor of the Ovary in the Absence of Hormonal Elevation.

Pediatr Dev Pathol 2019 Jul-Aug;22(4):375-379. Epub 2018 Dec 21.

1 Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California.

Precocious puberty in an infant is an alarming and infrequent finding, making the differential diagnosis difficult for practitioners. Precocious puberty secondary to a sclerosing stromal tumor (SST) of the ovary is rare. We present a case of a child that began precocious puberty at 3 months of age including development of breast buds, pubic hair, growth spurt, and menarche 5 days prior to presenting to pediatric endocrinology at 10 months. She underwent right salpingo-oophorectomy which demonstrated a soft tissue mass occupying almost the entire ovary with a tan-pink fleshy cut surface. Histological examination confirmed a variant of SST. This case represents an extremely young onset of precocious puberty secondary to a variant of SST without hormonal elevation.
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http://dx.doi.org/10.1177/1093526618819605DOI Listing
January 2020

Congenital Perirectal Dermoid Cyst: A Rare Cause of Complex, Recurrent Pediatric Fistula-in-ano.

Front Pediatr 2018 16;6:143. Epub 2018 May 16.

Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA, United States.

Perianal abscess and fistula-in-ano are well-described in the pediatric population. They are most common in infants less than 1 year of age and often resolve with oral antibiotics; occasionally they require drainage or fistulotomy. The etiology is commonly associated with cryptoglandular obstruction and subsequent infection, however alternative diagnoses should be considered in cases of recurrent abscesses and fistulae that are refractory to standard treatments. In this report, we present the case of an 8-year-old boy with a complex, recurrent fistula-in-ano that resulted from a rare congenital perirectal dermoid cyst.
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http://dx.doi.org/10.3389/fped.2018.00143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964207PMC
May 2018

A Multicenter Retrospective Review of Pediatric Leydig Cell Tumor of the Testis.

J Pediatr Hematol Oncol 2019 01;41(1):74-76

Rare Tumors Program, Texas Children's Cancer Center, Baylor College of Medicine.

Leydig cell tumors (LCTs) are rare tumors arising from testosterone-producing Leydig cells. Although LCTs are usually benign, malignancy has been reported in 10% of cases in adults, and local recurrence or metachronous tumors of the contralateral testis have been described. Radical orchiectomy is the current standard of care. We report on 12 children with LCT at 3 institutions between 2000 and 2016. Presenting symptoms included precocious puberty, palpable testicular mass, and scrotal swelling. Radical orchiectomy was performed in 9 patients. Three patients were treated with enucleation. All patients were alive at last follow-up without evidence of local recurrence or metastasis.
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http://dx.doi.org/10.1097/MPH.0000000000001124DOI Listing
January 2019

Melanotic Neuroectodermal Tumor of Infancy Presenting With Fast-Growing Scrotal Swelling: A Case Report and Literature Review.

Pediatr Dev Pathol 2017 Sep-Oct;20(5):411-415. Epub 2017 Jan 25.

1 Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA.

Testicular melanotic neuroectodermal tumor of infancy (MNTI) is extremely rare, with 2 cases reported in the literature. Its rarity and rapid and infiltrative growth pattern pose a diagnostic challenge. A previously healthy 3-month-old male, presented with a history of worsening left hemiscrotal swelling for 1 week. An outside ultrasound was suggestive of testicular torsion. Left orchiectomy demonstrated a mass occupying almost entire testicle with a variegated cut surface, with areas of pigmentation, necrosis, and hemorrhage. Histological examination confirmed MNTI of the testis and epididymis. MNTI should be included in differential diagnosis in infants presenting with fast-growing scrotal swelling.
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http://dx.doi.org/10.1177/1093526616686437DOI Listing
May 2019

Hepatocellular malignant neoplasm, NOS: a clinicopathological study of 11 cases from a single institution.

Histopathology 2017 Nov 15;71(5):813-822. Epub 2017 Sep 15.

Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Aims: The primary aim of this study is to characterize hepatocellular malignant neoplasm, NOS (HEMNOS), a new provisional entity describing a subset of paediatric hepatocellular tumours, which have histological features of neither typical hepatoblastoma (HB) nor hepatocellular carcinoma (HCC).

Methods And Results: The clinicopathological features of 11 patients with HEMNOS were analysed retrospectively. The median age and serum alpha-fetoprotein level at diagnosis was 7 years and 182 000 ng/ml, respectively. Ten patients presented with pretreatment extent of disease (PRETEXT) stages III/IV multifocal tumours, eight with major vascular involvement, three with lung metastases and three with extrahepatic extension. The original pathology diagnoses were: HB in seven patients, HCC in two and HEMNOS in two. Our pathology review of pre-chemotherapy specimens showed that six tumours had equivocal/overlapping histological features of HB and HCC, four had predominant HB histology along with focal HCC-like histology and one had HB histology. Seven of nine post-chemotherapy resection specimens showed predominant HCC-like histology. Beta-catenin, glypican 3 and spalt-like transcription factor 4 immunostaining showed that all the tumours had a mixed HB/HCC immunophenotype. Telomerase reverse transcriptase immunostaining showed nuclear staining in nine of the 11 tumours. All patients received chemotherapy and achieved gross total primary tumour resection. Nine of the 11 patients were treated with established HB chemotherapy regimens. After a median follow-up of 6.1 years (range: 1.2-11.8 years), all patients were in remission.

Conclusions: HEMNOS is a subtype of HB with focal HCC-like histology, a high-risk clinical profile but favourable outcome following chemotherapy and complete tumour resection.
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http://dx.doi.org/10.1111/his.13297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521842PMC
November 2017

A 5-year Old Immigrant Child With a Mediastinal Mass.

Pediatr Infect Dis J 2017 11;36(11):1109

From the *Pediatric Residency Program, Children's Hospital Los Angeles, Los Angeles, California; †Keck School of Medicine, University of Southern California, Los Angeles, California; ‡Pediatric Infectious Diseases and §Children's Center for Cancer and Blood Disease, Children's Hospital Los Angeles, Los Angeles, California; ¶Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; ‖Assistant Professor of Clinical Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; and **Department of Pathology and Laboratory Medicine and ††Department of General Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.

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http://dx.doi.org/10.1097/INF.0000000000001651DOI Listing
November 2017

Bronchial Mucoepidermoid Carcinoma With the Classic MAML2 Gene Rearrangement in a 2-year-old Boy.

Pediatr Dev Pathol 2018 Sep-Oct;21(5):480-485. Epub 2017 May 11.

1 Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California.

Pulmonary mucoepidermoid carcinoma (PMEC) is rare. To date, primary PMEC has not been reported in a child younger than 3 years of age. We report a case of a 2-year-old boy who presented with 3 episodes of wheezing, cough, and fever over a period of 1 month. Radiologic findings were consistent with foreign body aspiration with consequent bronchial obstruction. Bronchoscopy was performed and attempts to retrieve the foreign body resulted in a biopsy of a fleshy lesion. By histology, the lesion was an epithelial neoplasm comprising cells arranged in a nested pattern. The neoplastic cells were round with round nuclei and amphophilic, vacuolated cytoplasm. Our diagnosis was low-grade salivary gland-type carcinoma of the bronchus. The pneumonectomy specimen showed a well-circumscribed, polypoid intrabronchial mass measuring 2.1 cm in greatest dimension. Histologic examination of the tumor showed an admixture of intermediate cells which were predominant, a small number of mucus cells and rare foci of squamous cells. The final diagnosis rendered was a low-grade mucoepidermoid carcinoma of the bronchus. Accurate diagnosis of PMEC can be challenging on limited biopsy material as seen in the case reported here. The use of molecular studies such as MAML2 gene rearrangement may facilitate diagnosis in difficult cases. Increased awareness of this entity and further molecular studies are needed for a better understanding of the pathogenesis of PMEC. To date, the reported age range for primary bronchial mucoepidermoid carcinoma is between 3 years and 78 years. This case represents the youngest patient reported in the English literature.
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http://dx.doi.org/10.1177/1093526617707855DOI Listing
June 2019

Glypican 3 as a Serum Marker for Hepatoblastoma.

Sci Rep 2017 04 5;7:45932. Epub 2017 Apr 5.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Hepatoblastoma (HB) is the most common primary liver cancer in children. The conventional serum marker for HB, alpha-fetoprotein (AFP), has its limitations. Novel serum markers need to be explored. Glypican 3 (GPC3) has been reported to be an excellent histological immunomarker for HB. However, the clinical value of serum GPC3 in patients with HB is unknown. A total of 184 serum samples were tested for both GPC3 by ELISA, and AFP by immunometric assay. Of these, 134 were from 32 patients with HB at three treatment stages, 30 from age-matched patients with benign hepatobiliary disorders (BHD) and 20 from age-matched "normal controls"(NC). We found that the GPC3 levels in HB pretreatment group were significantly higher than those in NC group and HB remission group but not statistically different from those in BHD group and HB during treatment group. In contrast, AFP showed significant differences among different groups. The areas under the receiver operating curve (AUROC) value, sensitivity and specificity of GPC3 for HB pretreatment group versus all controls were all significantly lower than those of AFP. Serum GPC3 levels were not associated with prognostic parameters. We concluded that GPC3 is inferior to AFP as a serum marker for HB.
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http://dx.doi.org/10.1038/srep45932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381115PMC
April 2017

Mullerian-Type Ciliated Cyst of the Thigh with PAX-8 and WT1 Positivity: A Case Report and Review of the Literature.

Case Rep Med 2016 14;2016:2487820. Epub 2016 Dec 14.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA; Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Mullerian-type ciliated cysts are uncommon lesions usually found in the lower extremities and perineal region of young females. They have however been reported in males and in other anatomic sites. The cyst lining is typically positive for estrogen receptor (ER), progesterone receptor (PR), PAX-8, and WT1 immunohistochemical stains. This staining pattern has led to the notion that these cysts are of Müllerian origin. The vast majority of cases are located in the dermis where the preferred nomenclature is cutaneous ciliated cyst (CCC). We report a case of Müllerian-type ciliated cyst in the thigh of a 16-year-old girl. Unlike most of the cases reported in the English literature, this cyst was not centered in the dermis. Only a few other cases of Müllerian-type ciliated cysts with no cutaneous connection have been reported. We propose the term ectopic Müllerian cyst for this rare subset of lesions that are not skin based as is the current case.
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http://dx.doi.org/10.1155/2016/2487820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192324PMC
December 2016

Primary Epithelioid Sarcoma of the Zygomatic Bone.

Pediatr Dev Pathol 2019 May-Jun;22(3):252-257

1 Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California.

Primary epithelioid sarcoma (ES) of bone is extremely rare with only 2 reported cases in the English literature. A previously healthy 18-year-old man presented with a 6-month history of right facial numbness and tingling and right eye diplopia. A computerized tomography scan revealed an ill-defined mass with dense osseous matrix centered in the right zygomatic bone. An outside biopsy was read as osteosarcoma. The resection specimen revealed large epithelioid and spindle cells embedded in a prominent hyalinized matrix with focal metaplastic bone formation. The tumor cells were strongly and diffusely positive for AE1/AE3 and epithelial membrane antigen, but a definitive diagnosis of ES was not immediately reached due to the presence of dense hyalinized matrix and weak expression of SAT2B by tumor cells. Deficient INI1 protein expression by immunohistochemistry and homozygous loss of the SMARCB1 gene by chromosomal microarray analysis ultimately justified this tumor's designation as ES.
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http://dx.doi.org/10.2350/16-03-1798-CR.1DOI Listing
September 2019

The diagnostic and prognostic value of SALL4 in hepatoblastoma.

Histopathology 2016 Nov 25;69(5):822-830. Epub 2016 Jul 25.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Aims: To investigate the expression of spalt-like transcription factor 4 (SALL4), a regulator of embryonal development, in three epithelial components of hepatoblastoma (HB) and the relationship between SALL4 expression levels and patients' clinicopathological features.

Methods And Results: A total of 115 specimens from 79 patients with HB were selected for immunostaining of SALL4. Nuclear staining was semi-quantified using the immunoreactive score (IS; range: 0-12). SALL4 expression was seen in all embryonal components (mean IS = 8.58) and in 41% of fetal components (mean IS = 0.78). No SALL4 expression was seen in either small cell undifferentiated or mesenchymal components of HB. Neither chemotherapy nor metastasis altered SALL4 expression significantly. High SALL4 expression levels were associated significantly with decreased overall survival (OS) (P = 0.004), event-free survival (EFS) (P = 0.003) and the presence of metastasis (P = 0.049) on univariate analysis. Multivariate analysis identified SALL4 as an independent prognostic predictor for OS (P = 0.029).

Conclusions: SALL4 is useful for subtyping HB, and high SALL4 expression is associated with decreased survival in HB.
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http://dx.doi.org/10.1111/his.13005DOI Listing
November 2016

Renal Cell Carcinoma Occurring in Patients With Prior Neuroblastoma: A Heterogenous Group of Neoplasms.

Am J Surg Pathol 2016 07;40(7):989-97

*Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH ‡ Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN §Department of Pathology, Emory University School of Medicine, Atlanta, GA ∥Department of Pathology, Kaiser Permanente Panorama City Medical Center, Panorama City ¶Division of Pathology, Children's Hospital Los Angeles, Los Angeles, CA #Department of Pathology and Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI †Section of Pathological Anatomy, University of Ancona, Ancona, Italy.

Renal cell carcinoma (RCC) associated with neuroblastoma (NB) was included as a distinct entity in the 2004 World Health Organization classification of kidney tumors. A spectrum of RCC subtypes has been reported in NB survivors. We herein describe a series of 8 RCCs diagnosed in 7 patients with a history of NB. Microscopic evaluation, immunohistochemical staining for PAX8, cathepsin K, and succinate dehydrogenase subunit B (SDHB), and fluorescence in situ hybridization (FISH) for TFE3 and TFEB were performed. Four distinct morphologic subtypes were identified: 3 tumors were characterized by cells with abundant oncocytoid cytoplasm and irregular nuclei; 3 showed features of microphthalmia transcription factor family translocation RCC (MiTF-RCC); 1 had features of hybrid oncocytic-chromophobe tumor; 1 had papillary RCC histology. All RCCs expressed PAX8 and retained SDHB expression. Cathepsin K was positive in 2 MiTF-RCCs, 1 was TFEB FISH positive, and the other was indeterminate. Cathepsin K was negative in a third MiTF-RCC with TFE3 rearrangement. TFE3 FISH was negative in 4 and insufficient in 1 of the other 5 RCCs. While a subset of RCCs associated with NB is characterized by cells with prominent oncocytoid cytoplasm, other RCC subtypes also occur in post-NB patients. Renal neoplasms occurring in patients with a history of NB do not represent a single entity but a heterogenous group of RCCs. SDHB mutations do not explain the subset of nontranslocation RCCs with oncocytoid features; therefore, further studies are needed to clarify whether they may represent a distinct entity with unique molecular abnormalities or may belong to other emerging RCC subtypes.
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http://dx.doi.org/10.1097/PAS.0000000000000632DOI Listing
July 2016

Orthotopic liver transplant for multifocal lymphangioendotheliomatosis with thrombocytopenia.

Pediatr Transplant 2016 May 25;20(3):456-9. Epub 2016 Feb 25.

Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA.

An eight-yr-old female with a history of multifocal lymphangioendotheliomatosis and thrombocytopenia presented for MVT. The patient had multiple vascular lesions in the skin and stomach in infancy. Although her cutaneous lesions resolved with vincristine and methylprednisolone, her gastric lesions persisted. Eight yr later, she was diagnosed with portal hypertension and decompensating liver function despite therapy with bevacizumab, propranolol, furosemide, and spironolactone. Upon presentation, she was found to have a Kasabach-Merritt-like coagulopathy in association with multiple lesions in her GI tract and persistent gastric lesions. Although treatment with methylprednisolone and sirolimus normalized her coagulation factors and d-dimer levels, she never developed sustained improvement in her thrombocytopenia. Her liver function continued to deteriorate and she developed hepatorenal syndrome. Given better outcomes after OLT in comparison with MVT, she underwent OLT, with the plan to manage her GI lesions with APC post-transplant. Post-transplant, her liver function and coagulopathy normalized, and GI tract lesions disappeared upon screening with capsule endoscopy. The patient is doing well, without recurrence of either GI lesions or thrombocytopenia, at 18 months after transplantation.
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http://dx.doi.org/10.1111/petr.12696DOI Listing
May 2016

Refractory Kaposiform Hemangioendothelioma Associated with the Chromosomal Translocation t(13;16)(q14;p13.3).

Pediatr Dev Pathol 2016 Sep/Oct;19(5):417-420. Epub 2015 Nov 10.

4  Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.

We report a 7-year-old male with a history of recurrent kaposiform hemangioendothelioma (KHE) in the sacral area and multiple thoracic vertebral lesions. Tumor karyotyping revealed the balanced translocation t(13;16)(q14;p13.3). He had mildly decreased platelet counts but never experienced any episodes of Kasabach-Merritt phenomenon. He was treated with vincristine for 1 year but improvement was minor. Significant clinical improvement was seen with sirolimus therapy. To the best of our knowledge, this is the first report to demonstrate that KHE is associated with a clonal karyotypic abnormality.
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http://dx.doi.org/10.2350/15-09-1707-CR.1DOI Listing
June 2017

Castleman's Disease Presenting as a Parotid Mass in the Pediatric Population: A Report of 2 Cases.

Case Rep Otolaryngol 2015 5;2015:691701. Epub 2015 Oct 5.

Department of Otolaryngology-Head & Neck Surgery, Keck School of Medicine of USC, 1540 Alcazar Street, Suite 204, Los Angeles, CA 90033, USA.

Introduction. Angiofollicular lymph node hyperplasia (Castleman's disease) is a nonmalignant lymphoproliferative disorder that generally involves the lymph nodes of young adults, most commonly in the mediastinum. Rarely, Castleman's disease may present in the parotid gland. The disease can be further classified into unicentric or multicentric forms, with considerable differences in presentation, treatment, and prognosis. Case(s). We present cases of two pediatric patients, aged 7 and 11, who both presented with a slow-growing, painless parotid mass. In each case, the mass was excised via a superficial parotidectomy and the diagnosis made postoperatively upon further pathologic examination. At 6 months of follow-up, both had fully intact facial nerve function and no evidence of recurrence. Discussion. Castleman's disease presents a diagnostic challenge in the head and neck region, as radiographic characteristics and fine needle aspiration results are often inconclusive. Definitive diagnosis requires surgical excision for pathologic examination. The unicentric form generally presents as a painless mass and can be successfully treated with complete excision. The multicentric form is associated with constitutional symptoms and its treatment remains controversial. Conclusion. Although rare, clinicians should be aware of both forms of Castleman's disease when creating a differential diagnosis for parotid masses.
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http://dx.doi.org/10.1155/2015/691701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609787PMC
October 2015

Quantification of glypican 3, β-catenin and claudin-1 protein expression in hepatoblastoma and paediatric hepatocellular carcinoma by colour deconvolution.

Histopathology 2015 Dec 14;67(6):905-13. Epub 2015 Jul 14.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Aims: To identify an immunohistochemical panel for paediatric malignant epithelial liver tumours.

Methods And Results: Forty-five hepatoblastomas (HBs), 13 paediatric hepatocellular carcinomas (HCCs) and two hepatocellular malignant neoplasms not otherwise specified (NOS) were chosen for immunohistochemical staining of glypican 3 (GPC3), β-catenin, claudin-1, delta-like protein (DLK), and forkhead box protein G1 (FOXG1). Immunostaining was quantitatively analysed with NIH imagej software coupled with colour deconvolution. Different subtypes of HB and HCC showed distinct staining patterns of GPC3, β-catenin, and claudin-1. Moreover, GPC3, β-catenin and claudin-1 all showed higher expression in classic HCC and embryonal HB than in fetal HB; GPC3 showed complete negativity in small-cell undifferentiated (SCU) HB and fibrolamellar HCC (FLC); β-catenin showed the strongest expression in SCU HB but the weakest expression in FLC. A panel of these three immunomarkers was useful for the diagnosis of hepatocellular malignant neoplasms NOS. The expression of DLK and FOXG1 was inconstant among fetal and embryonal HB and classic HCC.

Conclusions: A panel of GPC3, β-catenin and claudin-1 is helpful for differentiating HB subtypes and distinguishing HB from HCC.
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http://dx.doi.org/10.1111/his.12730DOI Listing
December 2015

Inverted lymphoglandular polyp in descending colon.

Case Rep Pathol 2015 12;2015:646270. Epub 2015 Feb 12.

Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA ; Department of Pathology, LAC+USC Medical Center, Los Angeles, CA 90033, USA.

A 47-year-old male with a history of left colon cancer, status post left colon resection for 12 years, presented with rectal bleeding. Colonoscopic examination revealed an 8 mm sessile polyp in the proximal descending colon. Microscopic examination showed that the surface of this polyp was covered with a layer of normal colonic mucosa with focal surface erosion. In the submucosal layer, an intimate admixture of multiple cystically dilated glands and prominent lymphoid aggregates with germinal centers was seen. The glands were lined by columnar epithelium. Immunohistochemical staining showed the glands were positive for CK20 and CDX2 and negative for CK7, with a low proliferative index, mostly consistent with reactive colonic glands. The patient remained asymptomatic after one-year follow-up. A review of the literature shows very rare descriptions of similar lesions, but none fits exactly this pattern. We would designate this inverted lymphoglandular polyp and present this case to raise the awareness of recognizing this unusual histological entity.
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http://dx.doi.org/10.1155/2015/646270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342070PMC
March 2015

Small bowel dissemination of coccidioidomycosis.

Case Rep Pathol 2015 5;2015:403671. Epub 2015 Jan 5.

Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA ; Department of Pathology, LAC+USC Medical Center, Los Angeles, CA 90033, USA.

Gastrointestinal coccidioidomycosis is extremely rare, with less than 10 cases reported in the literature. We report a case of small bowel dissemination of coccidioidomycosis in a 21-year-old African American male with a history of living in San Joaquin Valley. The patient presented with one week of abdominal pain, nausea, shortness of breath, intermittent fever, and sweat, and one month of abdominal distention. A chest radiograph revealed complete effusion of left lung. A computed tomography scan of the abdomen showed diffuse small bowel thickening and enhancement, as well as omental and peritoneal nodules, and ascites. The coccidioidal complement fixation titer was 1 : 256. The duodenal biopsy revealed many spherules filled with round fungal endospores. Later, blood fungal culture showed positivity for Coccidioides immitis. The final diagnosis is disseminated coccidioidomycosis involving lungs, blood, and duodenum. Despite aggressive antifungal therapy, the patient's clinical situation deteriorated and he succumbed to multisystem organ failure one and half months later. A high index of suspicion for gastrointestinal coccidioidomycosis should be maintained in patients from an endemic area presenting as abdominal distention and pain.
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http://dx.doi.org/10.1155/2015/403671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313680PMC
February 2015