Alyaa Al-Ibraheemi

TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis

Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS‐F). Expression of TP53 was evaluated in BM core biopsy specimens using dual‐colour CD34/TP53 immunohistochemistry with computer‐assisted image analysis. Mutation analysis was performed using next‐generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 + in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high‐ and very‐high risk IPSS‐R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = <0·001). Expression of TP53 by CD34‐positive cells was associated with shorter OS and leukaemia‐free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS‐F.

Histologic Spectrum of Giant Cell Tumor (GCT) of Bone in Patients 18 Years of Age and Below: A Study of 63 Patients.

Although the majority of giant cell tumors (GCTs) of the bone occur in adult patients, occasionally they arise in the pediatric population. In this setting they may be mistaken for tumors more commonly seen in this age group, including osteosarcoma, aneurysmal bone cyst, and chondroblastoma. All cases of primary GCT of the bone arising in patients 18 years and below were retrieved from our institutional archives and examined with emphasis on the evaluation of various morphologic patterns. Clinical/radiologic records were reviewed when available. Analysis for H3F3A/H3F3B mutations was performed in a subset of cases. Sixty-three (of 710) patients treated at our institution for GCT were 18 years of age and below. The following morphologic patterns were identified: fibrosis (31 cases, 49%), reactive-appearing bone (26, 41%), cystic change (7, 11%), foamy histiocytes (6, 10%), secondary aneurysmal bone cyst (3, 5%), and cartilage (2, 3%). Infarct-like necrosis was present in 17 tumors (27%), and the mitotic rate ranged from 0 to 35 mitoses/10 high-power fields (median 5 mitoses/10 high-power field). Follow-up information (n=55; 6 mo to 69.6 y; median, 11.6 y) showed 21 patients with local recurrence (38%) and 2 patients with lung metastasis (4%). Polymerase chain reaction with sequencing showed that 5 of 5 tested cases harbored H3F3A mutations. In summary, GCT arising in the pediatric population is rare, representing 9% of GCTs seen at our institution. The morphologic spectrum of these tumors is broad and similar to that seen in patients above 18 years of age. It is important to recognize that matrix formation may be observed in GCT, including reactive-appearing bone and cartilage, as well as areas of fibrosis mimicking osteoid production, to avoid misclassification as osteosarcoma or other giant cell–rich lesions common in children.

Fibrous hamartoma of infancy: a clinicopathologic study of 145 cases, including 2 with sarcomatous features.

Fibrous hamartoma of infancy is a rare soft tissue lesion of infants and young children with characteristic triphasic morphology, which typically occurs in the axilla and less commonly in other locations. We reviewed 145 cases of fibrous hamartoma of infancy from our consultation archives. Cases occurred in 106 males and 39 females (mean age—15 months; range—birth to 14 years), and involved both typical sites (eg, axilla/back/upper arm) (n=69) and unusual locations (n=76). Six were congenital. The tumors presented as subcutaneous masses and ranged from 0.4 to 17 cm (mean 3 cm). All displayed triphasic morphology, but varied widely in the relative percentages of fat, fibroblastic fascicles, and primitive mesenchyme. Hyalinized zones with cracking artifact, mimicking giant cell fibroblastoma, were present in a 44 (30%) of cases; however FISH for PDGFB gene rearrangement was negative in five tested cases. In addition to classical fibrous hamartoma of infancy, two lesions contained large sarcomatous-appearing foci with high cellularity, high nuclear grade, and brisk mitotic activity. One occurred in a 10-month-old female as a new mass in a congenital fibrous hamartoma of infancy; the other occurred as a leg mass in a 6-year-old male. ETV6 gene rearrangement was negative in the tumor from the 10-month-old female. Genomic microarray (OncoScan) showed normal molecular karyotype in eight tested cases, whereas the two tumors with sarcomatous features showed a hyperdiploid/near tetraploid molecular karyotype with copy neutral loss of heterozygosity of chromosomes 1p and 11p, and loss of 10p, chromosome 14, and a large portion of chromosome 22q (22q11.23q13.33), respectively. Follow-up (52 patients; range: 1–208 months, median: 8 months) showed only two local recurrences and no metastases. Extensive local disease in the 10-month-old female with sarcomatous-appearing fibrous hamartoma of infancy necessitated forequarter amputation. In summary, our study confirms the classic clinicopathologic features, including the triphasic morphologic appearance of most cases. In contrast to earlier studies, our series illustrates a broader histologic spectrum than previously appreciated, including its close resemblance to giant cell fibroblastoma in one quarter of cases and the rare presence of ‘sarcomatous’ areas, the latter providing evidence that these are complex neoplasms rather than hamartomas.

Comparison between 1-needle technique versus 2-needle technique for bone marrow aspiration and biopsy procedures.

CONTEXT Bone marrow examination is essential for diagnosis and staging of hematologic disorders. Traditionally, the bone marrow biopsy and aspirate are obtained with 2 needles at 2 separate sites. This approach is associated with significant discomfort, procedural time, and occasionally, morbidity. Although previous observations had suggested that a single-needle technique at one site is a simpler and less-painful procedure, there had been concern that the 1-needle technique may yield a suboptimal biopsy for diagnosis. OBJECTIVE To conduct a systematic comparison of multiple parameters of bone marrow biopsy specimens obtained by the traditional 2-needle technique versus the 1-needle technique for bone marrow collection. DESIGN We retrospectively evaluated 20 biopsy specimens obtained by each of the 2 mentioned techniques by comparing the morphologic quality of the biopsy, biopsy length, and biopsy cellularity. RESULTS We found that the 1-needle technique yielded an adequate biopsy for diagnosis. The measured parameters of the samples obtained by the 1-needle versus 2-needle techniques were similar. CONCLUSION This study suggests that the 1-needle technique may be preferred for bone marrow aspirate and biopsy.

PPP6R3-USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis

Nodular fasciitis (NF) is a clonal self‐limited neoplastic proliferation characterized by rearrangements of the USP6 locus in most examples. To our knowledge well‐documented malignant behavior has never been previously observed in NF. In this report we present an unusual case of NF with classical histologic features that showed a protracted clinical course characterized by multiple recurrences and eventual metastatic behavior over a period of 10 years. Molecular analyses revealed the presence and amplification of the novel PPPR6‐USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of NF.

Phenotypic evolution in a case of peripheral T-cell lymphoma suggests the presence of tumor heterogeneity

Peripheral T‐cell lymphoma (PTCL), not otherwise specified (NOS), represents a heterogeneous group of nodal and extranodal lymphomas that express a variety of T‐cell antigens indicative of mature T‐cell lineage. Most cases of PTCL express CD4 and lack CD8 expression and have a T‐helper immunophenotype. Although the immunophenotype of PTCL is usually stable over time, immunophenotypic switch or evolution from T‐helper to T‐suppressor or vice versa has been rarely reported. Herein, we report a patient who presented with nasal PTCL, NOS, that was CD8+ and negative for Epstein–Barr virus, with concurrent skin lesions that had a CD8+/TIA‐1+ T‐cell immunophenotype. Patient received multi‐agent chemotherapy and matched unrelated donor stem cell transplant, and subsequently suffered a cutaneous relapse with a CD4+/TIA‐1(−) immunophenotype. Molecular analysis of the neoplasm biopsied at presentation showed one monoclonal T‐cell receptor gamma gene rearrangement, and a second oligoclonal peak. At the time of CD4‐positive recurrence, the oligoclonal peak was rather prominent, suggesting that the emergence of this peak is related with the phenotypic evolution from CD8+ to CD4+ predominant. These results highlight the utility of sequential immunophenotypic and molecular analysis of PTCL cases at the time of relapse to better understand the mechanisms of disease.

PTEN hamartoma of the soft tissue: the initial manifestation of an underlying PTEN hamartoma tumor syndrome in a 4-year-old female

A 4-year-old female was referred to pediatric orthopedic surgery for left leg pain and limping for 3 months following a motor vehicle collision. Recently, the patient’s mother had noted left knee swelling and dragging of the left leg when walking. Past medical history was significant for hip dysplasia with slight leg length discrepancy. The patient was otherwise healthy. Physical examination was remarkable for left pre-patellar soft tissue fullness with normal range of motion. There was no warmth or tenderness. Subsequent ultrasound revealed a heterogeneous soft tissue mass superior and medial to the patella with a moderate degree of internal vascularity. MR exhibited a heterogeneous soft tissue mass with heterogeneous signal on both T1- and T2-weighted images centered within the vastus medialis obliquus muscle infiltrating the quadriceps tendon. Excisional biopsy was performed with a histopathologic diagnosis of fibroadipose tissue with anomalous vessels, suggestive of phosphatase and tensin homolog (PTEN) hamartoma of the soft tissue (PHOST). The patient was found to be positive for the PTEN gene mutation on genetic testing. The child was also determined to be macrocephalic, a major criterion for PTEN hamartoma tumor syndrome (PHTS). The geneticist advised the patient to undergo yearly physical examinations and early, routine surveillance for several malignancies occurring with PHTS. This case report presents the ultrasound and MRI appearance of a rare benign tumor typically appearing in pediatric patients. The strong association between PHOST and other soft tissue malignancies and the resulting need for life-long surveillance make PHOST an important pathology to recognize.

Voluntary Second Opinions in Pediatric Bone and Soft Tissue Pathology A Retrospective Review of 1601 Cases From a Single Mesenchymal Tumor Consultation Service

The diagnosis of bone and soft tissue tumors in children is challenging. These lesions are especially difficult for general pathologists. We reviewed our experience with pediatric mesenchymal tumors sent in consultation to our service, with the goal of identifying issues that most often prompted second-opinion referral. Roughly 16 000 cases were seen in toto, of which 1601 occurred in children. These included 491 bone cases and 1110 soft tissue cases. The cases were referred by private practices/nonacademic medical centers (85%), academic medical centers (8%), and pediatric hospitals (7%). Reasons for referral were (a) self-perceived lack of experience with pediatric mesenchymal tumors (n = 930), (b) second opinion requested by the clinician or patient (n = 132), and (c) perceived or real need for ancillary studies not available at the referring institution (n = 116). The referring pathologists suggested a diagnosis for 670 cases; of these, 476 (71%) were in essential agreement with our final diagnosis. Of the remaining, 139 (21%) were considered “minor disagreements” and 55 (8%) “major disagreements.” The “major disagreement” cases could be divided into (a) malignant tumors submitted with benign diagnoses (58%), (b) benign tumors submitted with malignant diagnoses (25%), (c) nonneoplastic conditions submitted as representing neoplasms (11%), and (d) neoplasm submitted as representing nonneoplastic conditions (6%). Pediatric mesenchymal tumors comprised 10% of cases sent to our mesenchymal tumor consultation practice. The rates of diagnostic disagreement found in this study are roughly in accordance with prior studies of mandatory and voluntary second opinion in adult soft tissue tumors. Given the rarity of these tumors, expert second opinion may be of value.

Selected Diagnostically Challenging Pediatric Soft Tissue Tumors.

Many benign and malignant soft tissue tumors in children are challenging and their diagnosis requires knowledge of their vast diversity, histopathological complexity, and immunohistochemical, cytogenetic, and molecular characteristics. The importance of clinical and imaging features cannot be overstated. Soft tissue sarcomas account for 15% of all pediatric malignancies after leukemia/lymphoma, central nervous system tumors, neuroblastoma and Wilms tumor. This article discusses selected challenging pediatric soft tissue tumors with an update on recently described entities.

Superficial Solitary Fibrous Tumor

While superficial (cutaneous/subcutaneous) solitary fibrous tumor (SFT) have been described, definitive diagnosis is difficult due to overlapping features with other tumors. We describe the largest series to date of superficial SFT. For inclusion, SFT had to arise in dermis or subcutis. Twenty-six cases were identified. Patients ranged from 16 to 80 years (mean, 47 y) with a marked female predominance (19 F; 7 M). Tumors involved the head (11), thigh (7), back (3), shoulder (2), upper arm (1), ankle (1), and great toe (1). Mean size was 2.9 cm (range, 1.0 to 7.0 cm). The majority (n=19) had typical histologic features (cellular SFT) with irregular fascicles of spindled cells, staghorn-like blood vessels, and variable amounts of collagen. Necrosis was evident in 3 cases (all <25%). Mitotic activity ranged from 0 to 10 mitotic figures/10 high-power fields (mean, 2 mitotic figures/10 high-power fields). Seventeen of the 18 were positive for STAT6, whereas 21/22 expressed CD34. All were low risk (23/23) by proposed criteria (Demicco and colleagues), including 2 cases with malignant histology. Three could not be risk stratified due to lack of information on tumor size. Follow-up, available on 7 cases, showed no recurrence/metastasis (mean follow-up, 100 mo; range, 2 to 241 mo). Cutaneous SFT are more common in women and most often involve the head. They are usually low risk by proposed criteria and appear to behave in an indolent manner, though larger studies are needed to confirm this. Recognition that SFT may present as a superficial mass will avoid misclassification as other CD34-positive neoplasms that frequently arise in the skin and subcutaneous tissue.