John R. Priest

Extrapulmonary Inflammatory Myofibroblastic Tumor (inflammatory Pseudotumor) A Clinicopathologic and Immunohistochemical Study of 84 Cases

Inflammatory myofibroblastic tumor (IMT) or inflammatory pseudotumor is a spindle cell proliferation of disputed nosology, with a distinctive fibroinflammatory and even pseudosarcomatous appearance. Although the lung is the best known and most common site, inflammatory myofibroblastic tumor occurs in diverse extrapulmonary locations. We report our experience with 84 cases occurring in the soft tissues and viscera of 48 female patients and 36 male patients between the ages of 3 months and 46 years (mean, 9.7 years; median, 9 years). A mass, fever, weight loss, pain, and site-specific symptoms were the presenting complaints. Laboratory abnormalities included anemia, thrombocytosis, polyclonal hypergamma-globulinemia, and elevated erythrocyte sedimentation rate. Sites of involvement included abdomen, retroperitoneum, or pelvis (61 cases); head and neck, including upper respiratory tract (12 cases); trunk (8 cases); and extremities (3 cases). The lesions ranged in size from 1 to 17 cm (mean, 6.4; median, 6.0). Excision was performed in 69 cases. Eight had biopsy only. Five patients received chemotherapy or radiation in addition to undergoing biopsy or resection as initial treatment. Sixteen patients had multinodular masses involving one region. Clinical follow-up in 53 cases revealed that 44 patients were alive with no evidence of disease, four were alive with IMT, and five were dead. Thirteen patients had one or more recurrences at intervals of 1–24 months (mean, 6 months; median, 10 months). No distant metastases were documented. The five patients who died had complications either due to the location of the lesion (heart, peritoneum, retroperitoneum, or mesentery) or related to treatment (lymphoproliferative disorder following hepatic transplantation; sepsis following wound infection). The abdominal masses were the largest. All tumors were firm and white with infiltrative borders and focal myxoid change. Three basic histologic patterns were recognized: (a) myxoid, vascular, and inflammatory areas resembling nodular fasciitis; (b) compact spindle cells with intermingled inflammatory cells (lymphocytes, plasma cells, and eosinophils) resembling fibrous histiocytoma; and (c) dense plate-like collagen resembling a desmoid or scar. Immunohistochemistry demonstrated positivity for vimentin, muscle-specific actin, smooth muscle actin, and cytokeratin consistent with myofibroblasts. Based on this series, inflammatory myofibroblastic tumor is a benign, nonmetastasizing proliferation of myofibroblasts with a potential for recurrence and persistent local growth, similar in some respects to the fibromatoses.

DICER1 Mutations in Familial Pleuropulmonary Blastoma

A rare form of lung cancer in children is associated with mutational disruption of an enzyme that generates small noncoding RNAs. Pleuropulmonary blastoma (PPB) is a rare pediatric lung tumor that is often part of an inherited cancer syndrome. PPBs consist of mesenchymal cells that are susceptible to malignant transformation and cysts lined by epithelial cells. In a subset of patients, overgrowth of the cysts by mesenchymal cells leads to sarcoma formation. Here, we show that 11 multiplex PPB families harbor heterozygous germline mutations in DICER1, a gene encoding an endoribonuclease critical to the generation of small noncoding regulatory RNAs. Expression of DICER1 protein was undetectable in the epithelial component of PPB tumors but was retained in the malignant mesenchyme (sarcoma). We hypothesize that loss of DICER1 in the epithelium of the developing lung alters the regulation of diffusible factors that promote mesenchymal proliferation.

Pleuropulmonary blastoma the so-called pulmonary blastoma of childhood

The authors studied 11 pediatric intrathoracic neoplasms that share clinicopathologic features and constitute a specific tumor in children. These neoplasms were intrapulmonary, mediastinal, or pleural‐based masses. A common histologic feature was the presence of small, primitive cells with blastematous qualities separated by an uncommitted stroma. Focal rhabdomyosarcomatous, chondrosarcomatous, and liposarcomatous differentiation was observed. Epithelial components had bland cytologic features and probably represented entrapped benign epithelium and/or mesothelium. The prognosis for these patients was grave; seven patients died of their disease 5 months to 2 years after diagnosis. Two patients have survived diseasefree for 10 and 12 years after diagnosis. Two recent cases are alive 14 and 32 months after diagnosis. This neoplasm constitutes a distinct entity which has been reported in the literature as pulmonary blastoma in children. It differs from pulmonary blastema in adults because of its variable anatomic location, primitive embryonic‐like blastema and stroma, absence of a carcinomatous component, and potential for sarcomatous differentiation. The designation of pleuropulmonary blastoma is suggested by the authors for these intrathoracic neoplasms of childhood rather than pulmonary blastoma for histogenetic and anatomic reasons. The clinicopathologic features, immunophenotypic and ultrastructural characteristics, possible histogenesis, and differential diagnosis of these neoplasms from other thoracopulmonary tumors in children serve as the basis for this report.

DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome

Background Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). Aim To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. Methods and results The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli–Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli–Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli–Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. Conclusion Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli–Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition ‘DICER1 syndrome’. Accession numbers The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2.

DICER1 Mutations in Familial Multinodular Goiter With and Without Ovarian Sertoli-Leydig Cell Tumors

CONTEXT Nontoxic multinodular goiter (MNG) is frequently observed in the general population, but little is known about the underlying genetic susceptibility to this disease. Familial cases of MNG have been reported, and published reports describe 5 families that also contain at least 1 individual with a Sertoli-Leydig cell tumor of the ovary (SLCT). Germline mutations in DICER1, a gene that codes for an RNase III endoribonuclease, have been identified in families affected by pleuropulmonary blastoma (PPB), some of whom include cases of MNG and gonadal tumors such as SLCTs. OBJECTIVE To determine whether familial MNG with or without SLCT in the absence of PPB was associated with mutations in DICER1. DESIGN, SETTING, AND PATIENTS From September 2009 to September 2010, we screened 53 individuals from 2 MNG and 3 MNG/SLCT families at McGill University for mutations in DICER1. We investigated blood lymphocytes and MNG and SLCT tissue from family members for loss of the wild-type DICER1 allele (loss of heterozygosity), DICER1 expression, and microRNA (miRNA) dysregulation. MAIN OUTCOME MEASURE Detection of germline DICER1 gene mutations in familial MNG with and without SLCT. RESULTS We identified and characterized germline DICER1 mutations in 37 individuals from 5 families. Two mutations were predicted to be protein truncating, 2 resulted in in-frame deletions, and 1 was a missense mutation. Molecular analysis of the 3 SLCTs showed no loss of heterozygosity of DICER1, and immunohistochemical analysis in 2 samples showed strong expression of DICER1 in Sertoli cells but weak staining of Leydig cells. miRNA profiling of RNA from lymphoblastoid cell lines from both affected and unaffected members of the familial MNG cases revealed miRNA perturbations in DICER1 mutation carriers. CONCLUSIONS DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns.

DICER1: mutations, microRNAs and mechanisms

Dicer is central to microRNA-mediated silencing and several other RNA interference phenomena that are profoundly embedded in cancer gene networks. Most recently, both germline and somatic mutations in DICER1 have been identified in diverse types of cancer. Although some of the mutations clearly reduce the dosage of this key enzyme, others dictate surprisingly specific changes in select classes of small RNAs. This Review reflects on the molecular properties of the Dicer enzymes in small RNA silencing pathways, and rationalizes the newly discovered mutations on the basis of the activities and functions of its determinants.

Pulmonary cysts in early childhood and the risk of malignancy.

Surgery for congenital and early childhood lung cysts is often dictated by symptoms such as respiratory distress, infection or pneumothorax. Asymptomatic cysts present a therapeutic dilemma: surgical intervention and “conservative” observation have advocates. The risk of malignancy in such cysts is considered by some an indication for surgical intervention and is reviewed in this paper. Pleuropulmonary blastoma (PPB) is the most frequent malignancy associated with childhood lung cysts. Although rare, PPB occurs predictably in certain clinical and familial situations. This unique biology of PPB can inform the cyst management decision. The earliest manifestation of PPB is a malignant lung cyst in young children, clinically and radiographically indistinguishable from benign congenital lung cysts. Histopathologic examination differentiates cystic PPB from the benign cystic variants. Surgical excision of cystic PPB (with or without chemotherapy) cures approximately 85–90% of children. If not excised, cystic PPB evolves to cystic/solid or solid high‐grade sarcoma (cure rate 45–60%) by age 2–6 years. Numerous reports of “malignancy in a congenital lung cyst” are now understood as the characteristic progression of cystic PPB. PPB is genetically determined in many cases. Detailed family history may reveal the hallmarks of PPB in the patient or young relatives: a unique constellation of diseases including lung cysts, cystic nephroma, childhood cancers, stromal sex‐chord ovarian tumors, seminomas or dysgerminomas, intestinal polyps, thyroid hyperplasias, and hamartomas. Pneumothorax and multifocal/bilateral lung cysts also characterize PPB. These diagnoses predict that a lung cyst is more likely PPB than a benign congenital cyst. Patients fitting this pattern deserve histologic diagnosis. The genetic basis for this heritable syndrome is unknown but is being actively investigated. Pediatr Pulmonol. 2009; 44:14–30.

Pleuropulmonary blastoma : a marker for familial disease

OBJECTIVE To catalog and evaluate patterns of disease in families of children with pleuropulmonary blastoma (PPB). METHODS Data have been collected since 1988 on 45 children with PPB and their families. All pathologic materials were centrally reviewed. Preliminary molecular genetic analyses were performed when possible. RESULTS In 12 of 45 patients, an association was found between PPB and other dysplasias, neoplasias, or malignancies in the patients with or in their young relatives. The diseases found to be associated with PPB include other cases of PPB, pulmonary cysts, cystic nephromas, sarcomas, medulloblastomas, thyroid dysplasias and neoplasias, malignant germ cell tumors, Hodgkin disease, leukemia, and Langerhans cell histiocytosis. Abnormalities of the p53 tumor suppressor gene, Wilms tumor suppressor gene (WT1), and the putative second genetic locus for Wilms tumor (WT2) were not found in preliminary investigations. CONCLUSIONS The occurrence of PPB appears to herald a constitutional and heritable predisposition to dysplastic or neoplastic disease in approximately 25% of cases. All patients with PPB and their families should be investigated carefully. Further research of this new family cancer syndrome may provide insight into the genetic basis of these diseases.

A syndrome of thrombosis and hemorrhage complicating l-asparaginase therapy for childhood acute lymphoblastic leukemia**

L-Asparaginase therapy for childhood acute lymphoblastic leukemia causes deficiencies of plasma hemostatic proteins, especially antithrombin, plasminogen, and fibrinogen. Severe thromboses and hemorrhages occurred in 18 children receiving vincristine, prednisone, and asparaginase therapy for ALL. Thirteen children had intracranial thrombosis or hemorrhage, four had extremity thrombosis, and one had both an intracranial hemorrhage and an extremity thrombosis. These events occur characteristically in the third and fourth weeks of therapy during or just after a three-week course of L-asparaginase. Symptoms of headache, obtundation, hemiparesis, and seizure were common for the intracranial events: local pain, swelling, and discoloration were common for the extremity thromboses. These complications have been recognized in 1 to 2% of children undergoing induction therapy which includes asparaginase.

Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry.

Pleuropulmonary blastoma (PPB) is a malignant neoplasm of the lung that presents in early childhood. The early form of the disease, cystic type I PPB, can be clinically and pathologically deceptive because of its resemblance to some developmental lung cysts. This study reviews 51 cases of type I PPB and 6 lung cysts from relatives of children with PPB. Type I PPB is a delicate multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface. Rhabdomyoblasts and cartilage nodules are seen in 49% and 40% of cases, respectively. Tumors in the youngest subset of patients, from birth to 2 months of age, are more uniform in composition and cellularity compared with those in older groups. Early tumors have a subtle transition between normal developing lung and tumor, showing bland interstitial mesenchymal cells uniformly expanding the alveolar septa. Presumed regressive changes including cyst wall necrosis are common. This phenomenon may explain the variable and sometimes sparse tumor cellularity seen in some type I PPBs. On a biologic level, this process supports the concept that not all type I PPBs are fated to progress to a type II or III PPB. Factors that control the balance between progression and regression may be important in predicting tumor behavior and determining which patients will benefit from adjuvant chemotherapy. In the meantime, recognition of this lesion as a neoplasm with malignant potential rather than a developmental cystic malformation is vital so the child can receive complete excision and appropriate follow-up care.