Molecular Alterations in Pediatric Fibroblastic/Myofibroblastic Tumors: An Appraisal of a Next Generation Sequencing Assay in a Retrospective Single Centre Study.

BACKGROUND: Pediatric fibroblastic/myofibroblastic tumors (PFMTs) can be challenging to definitively classify. Large case series or diagnostic updates have not been recently published despite identification of molecular alterations that could improve diagnostic accuracy. Our review of the literature found that over two-thirds of the more than 30 types of PFMTs harbor recurrent molecular alterations. We performed an institutional review of PFMTs to highlight limitations of a predominantly morphological classification, and evaluated the utility of a next-generation sequencing assay to aid diagnosis. METHODS: PFMTs identified over a period of 12 years were reviewed, categorized per the new WHO classification, and tested using the Oncomine Childhood Cancer Research Assay. RESULTS: Eighty-seven specimens from 58 patients were reviewed; 50 were chosen for molecular analysis, 16 (32%) lacking definitive classification. We identified alterations, some novel, in 33% of assayed cases. Expected alterations were identified for most known diagnoses and mutations were identified in 6 of 16 tumors (38%) that were initially unclassified. CONCLUSION: We confirmed a significant subset of PFMTs remain difficult to classify using current criteria, and that a combined DNA/RNA assay can identify alterations in many of these cases, improving diagnostic certainty and suggesting a clinical utility for challenging cases.

Regenerative hepatic pseudotumor: a new pseudotumor of the liver.

Cases of new pseudotumors of the liver were collected from multiple medical centers. Four resection and 4 biopsy specimens were collected, including 4 women and 4 men at an average age of 48 ± 15 years (range: 28-73 years). The lesions were visible on imaging but were either ill-defined or had indeterminate features for characterization. They ranged in size from 2 to 9 cm and were multiple in five cases. The resection specimens showed lesions that had vague borders but were visible in juxtaposition to the normal liver on gross examination. Histologically, the lesions also had ill-defined borders and were composed of benign reactive liver parenchyma. Central vein thrombi were seen in 5 cases, and portal vein thrombi, in 2 cases. These vascular changes were associated reactive parenchymal changes including sinusoidal dilation, patchy bile ductular proliferation, and portal vein abnormalities. All lesions lacked the histological findings of hepatic adenomas, focal nodular hyperplasia, or other known tumors and pseudotumors of the liver. In summary, this study provides a detailed description of a new pseudotumor of the liver: a reactive, hyperplastic mass-like lesion that forms in association with localized vascular thrombi, for which we propose the term regenerative hepatic pseudotumor. This lesion can closely mimic other benign or malignant hepatic tumors on imaging and histology.

Selected pseudoneoplastic lesions of the skin.

CONTEXT: Pseudoneoplastic cutaneous lesions are diverse, not only morphologically but also with respect to their causes and cellular lineages. They include proliferations of epithelial, as well as mesenchymal, elements. OBJECTIVE: This review aims to consider selected lesions in the aforementioned groups, contrasting them with histologically similar neoplasms of the skin in a differential diagnostic setting. DATA SOURCES: Information used in assembling this discussion was drawn from the published literature on cutaneous pseudoneoplasms, using an Internet-based search engine. The authors' collective experience was also used in writing this review. CONCLUSIONS: Sufficient clinical and morphologic differences exist in virtually all instances to separate pseudoneoplastic cutaneous proliferations from the tumors that they imitate.

Pseudoneoplasms of the gastrointestinal tract.

CONTEXT: The pathologist plays the leading role in distinguishing pseudoneoplasms from truly neoplastic lesions in the gastrointestinal tract. OBJECTIVE: This review was conducted to heighten awareness of pseudoneoplasms, to help differentiate among the various types of pseudoneoplasms, and to help distinguish pseudoneoplasms from malignancies. DATA SOURCES: This review is based on the medical literature on pseudoneoplasms in MEDLINE and the authors' own experiences. Reference lists of retrieved articles were also reviewed to identify additional articles. CONCLUSIONS: A classification of pseudoneoplasms, according to the mechanism of injury to the gastrointestinal tract, morphologic patterns, and heterotopia, may be useful in providing a diagnostic framework in which ancillary techniques often have a diagnostic role. Several pseudoneoplasms may be closely associated with true neoplasms (eg, malakoplakia, prolapsetype lesions) because of the nonspecific nature of the response of the intestine to injury.

Pseudoneoplastic lesions of the female genital tract.

CONTEXT: Numerous benign, proliferative, or reactive processes, often related to hormone stimulation or inflammation, occur throughout the female genital tract and may mimic benign or malignant tumors. Several of the more common pseudoneoplastic lesions are discussed in this article, including microglandular hyperplasia of the cervix mimicking well-differentiated endometrial adenocarcinoma, reactive epithelial changes in the fallopian tubes mimicking adenocarcinoma or carcinoma in situ, and pregnancy changes in the ovary including pregnancy luteoma and large solitary luteinized follicular cyst of pregnancy and puerperium that may mimic ovarian neoplasms. OBJECTIVES: To discuss and illustrate several common lesions of the female genital tract that mimic neoplasms. DATA SOURCES: Material derived from consultation cases and review of the literature. CONCLUSIONS: Many benign hyperplastic or reactive processes that occur in the female genital tract may be mistaken for neoplasms both clinically and pathologically. Awareness of the features of such lesions will aid in their correct diagnosis and prevent overtreatment of benign processes.

Pseudoneoplasms of the nervous system.

CONTEXT: Pseudoneoplasms of the nervous system vary greatly in nature. Ranging from inflammatory to autoimmune, infectious, malformative, reactive, degenerative, and radiation induced, they all mimic true tumors. Thus, they have the potential to mislead clinicians, radiologists, and pathologists alike. Their clinical and/or neuroimaging and histologic features are readily misinterpreted as tumor. Knowledge of the pitfalls is essential to avoid mismanagement, specifically overtreatment. In such instances, pathologists must take the entire clinical picture into consideration, acquainting themselves with presenting symptoms, physical findings, and neuroimaging. OBJECTIVE: To present 10 examples of pseudoneoplasms of the nervous system, analyze the basis for their mimicry, and discuss their differential diagnosis. DATA SOURCES: Review of the pertinent literature related to pseudoneoplasms of the nervous system and review of the consultation files of one of the authors (B.W.S.). CONCLUSIONS: The identification of tumor mimics may be difficult under the best of circumstances, and maintaining a broad differential diagnosis as well as application of a variety of immunocytochemical and occasionally ultrastructural and/or molecular genetic methods is essential to arrive at a correct diagnosis.

Pulmonary pseudoneoplasms.

CONTEXT: Not uncommonly, a surgical pathologist will be requested to review excised material, with a clinical diagnosis of cancer, in which no malignancy can be identified. Often, sampling may be the issue. However, different nonneoplastic processes may mimic cancer clinically and not be recognized histologically. These are commonly referred to as pseudoneoplasms and can involve the lung, pleura, and mediastinum. OBJECTIVE: To review the most commonly encountered pseudoneoplasms of the thoracic cavity in surgical pathology and discuss the main differential diagnosis. DATA SOURCES: Literature and personal review of cases with focus on inflammatory pseudotumors of the lung, organizing pneumonia, nodular lymphoid hyperplasia, apical cap, round atelectasis, and sclerosing mediastinitis with its pulmonary counterpart, hyalinizing granuloma. CONCLUSIONS: When reviewing specimens that appear nondiagnostic for malignancy, it is important to consider one of these pseudoneoplasms in the differential diagnosis as they may explain the clinical and radiologic information.

Pseudoneoplastic mimics of prostate and bladder carcinomas.

CONTEXT: The differential diagnoses of prostatic carcinoma and bladder epithelial neoplasms include several histologic mimics that should be known to avoid misdiagnosis. OBJECTIVE: To discuss pseudoneoplastic lesions of the prostate and bladder that could potentially be confused with prostatic carcinoma and bladder epithelial neoplasms, respectively, with specific focus on their distinguishing histopathologic features. DATA SOURCES: Relevant published literature and authors' experience. CONCLUSIONS: Pseudoneoplastic lesions in the prostate include those of prostatic epithelial origin, the most common being atrophy, adenosis (atypical adenomatous hyperplasia), basal cell hyperplasia, and crowded benign glands, as well as those of nonprostatic origin, such as seminal vesicle epithelium. Such lesions often mimic lower-grade prostatic adenocarcinoma, whereas others, such as clear cell cribriform hyperplasia and granulomatous prostatitis, for example, are in the differential diagnosis of Gleason adenocarcinoma, Gleason grade 4 or 5. Pseudoneoplastic lesions of the urinary bladder include lesions that could potentially be confused with urothelial carcinoma in situ, such as reactive urothelial atypia, and others, such as polypoid/papillary cystitis, where papillary urothelial neoplasms are the main differential diagnostic concern. Several lesions can mimic invasive urothelial carcinoma, including pseudocarcinomatous hyperplasia, von Brunn nests, and nephrogenic adenoma. Diagnostic awareness of the salient histomorphologic and relevant immunohistochemical features of these prostatic and urinary bladder pseudoneoplasms is critical to avoid rendering false-positive diagnoses of malignancy.

Inflammatory myofibroblastic tumor of the central nervous system and its relationship to inflammatory pseudotumor.

Inflammatory myofibroblastic tumor (IMT) is a distinctive spindle cell lesion and occurs primarily in soft tissue. Recent evidence suggests a neoplastic nature, although historically, both neoplastic and nonneoplastic processes were combined in this category. Originally described as a nonneoplastic process, the term inflammatory pseudotumor (IP) has been used synonymously with IMT. IMTs have been linked to ALK gene (2p23) rearrangements, and some have suggested an association with the human herpesvirus 8 (HHV-8). IMT in the central nervous system (CNS) is rare, its characteristics are poorly defined, and its relation to similar tumors at other sites is unclear. To better characterize IMT within the CNS, we studied clinicopathologic features of 6 IMTs and compared them with 18 nonneoplastic lesions originally classified as IP. The IMT group consisted of 2 male and 4 female patients with a median age of 29 years. Of the six IMTs, 5 occurred within the cerebral hemispheres, and one was in the posterior fossa. All tumors were composed of neoplastic spindle cells and a variable amount of inflammatory infiltrate. Eighteen IPs included in this study consisted of predominantly inflammatory masses occasionally seen in the setting of systemic diseases. Only 1 IMT and none of the IPs recurred during the follow-up period. Four IMTs had either ALK protein overexpression or 2p23 rearrangement, and 1 case demonstrated both. None of the IPs were positive for ALK. Neither IMT nor IP cases demonstrated HHV-8 expression. We suggest that IMT in the CNS is distinct from the nonneoplastic IP, and distinguishing IMT from nonneoplastic lesions should enable better decisions for patient management.

Pathological classification of hepatic inflammatory pseudotumor with respect to IgG4-related disease.

Recently, much attention has focused on IgG4-related disease, which is characterized by abundant IgG4-positive plasma cell infiltration and high serum IgG4 levels. IgG4-related disease sometimes manifests as tumorous lesions, and its relationship to inflammatory pseudotumor has been suggested. In this study, we examined clinicopathological features of a total of 16 cases of hepatic inflammatory pseudotumor (11 men and 5 women with an average age of 67 years) with respect to IgG4-related disease. The tumors could be pathologically classified into two types: fibrohistiocytic (10 cases) and lymphoplasmacytic (6 cases). Fibrohistiocytic inflammatory pseudotumors were characterized by xanthogranulomatous inflammation, multinucleated giant cells, and neutrophilic infiltration, and mostly occurred in the peripheral hepatic parenchyma as mass-forming lesions. In contrast, lymphoplasmacytic inflammatory pseudotumors showed diffuse lymphoplasmacytic infiltration and prominent eosinophilic infiltration, and were all found around the hepatic hilum. In addition, venous occlusion with little inflammation and cholangitis without periductal fibrosis were frequently observed in the fibrohistiocytic type, whereas obliterative phlebitis and cholangitis with periductal fibrosis were common features of the lymphoplasmacytic type. Interestingly, IgG4-positive plasma cells were significantly more numerous in the lymphoplasmacytic than fibrohistiocytic type. However, two of the fibrohistiocytic inflammatory pseudotumors had relatively many IgG4-positive plasma cells. In conclusion, hepatic inflammatory pseudotumor could be classified into two types based on clinicopathological characteristics. The lymphoplasmacytic type is unique, and could belong to the so-called IgG4-related diseases. In contrast, the fibrohistiocytic type might still be a heterogeneous group of disorders. This latter type seems pathologically different from IgG4-related disease, although cases with relatively abundant IgG4-positive plasma cells should be differentiated from IgG4-related disease with secondary histopathologic modifications.

Pseudo-tumoral lesions of the cervix.

Pseudo-tumoral lesions of the cervix implies some reactive, non-neoplastic changes (metaplasia, hyperplasia, inflammation) that, occasionally, are wrong interpreted as precancerous or malign lesions. Even some can present architectural or cytological abnormal aspects, these are different from the one noted in carcinomas or the precursor lesions of carcinomas. Them recognition is indispensable in order to avoid the diagnose errors and the super evaluation of these benign lesions.

Hepatic inflammatory pseudotumor: case report, review of the literature, and a proposal for morphologic classification.

Inflammatory pseudotumors (IPT) are uncommon mass lesions arising most typically in the lungs of young adults. These tumors are so named because of the difficulty in distinguishing them preoperatively from malignant lesions. IPT are characterized histologically by localized fibrous proliferations with infiltration by mononuclear leukocytes, particularly plasma cells. Seventeen previous cases of IPT involving the liver and biliary tree have been reported in children. In this location, IPT may lead to biliary obstruction, portal hypertension, cirrhosis and eventually hepatic failure. We describe the youngest patient ever reported with hepatic IPT (HIPT) and biliary obstruction, who was successfully managed with a left hepatic lobectomy and Kasai portoenterostomy. Based on all previous cases of HIPT in both adults and children (74 cases), we propose a morphologic classification of these lesions based on the presence of single versus multiple lesions, with individualized management. Type 1 lesions are large, solitary lesions, often with central necrosis, giving a characteristic radiographic appearance. Type 2 lesions are multiple smaller, solid nodules indistinguishable from metastatic malignancy.

ALK probe rearrangement in a t(2;11;2)(p23;p15;q31) translocation found in a prenatal myofibroblastic fibrous lesion: toward a molecular definition of an inflammatory myofibroblastic tumor family?

A prenatal tumor located in the lumbar paravertebral area was discovered during a routine ultrasound examination at 32 weeks of pregnancy and surgically removed at 4 months of life. The histopathological diagnosis was first suggested to be an infantile desmoid fibromatosis. The tumor karyotype showed a three-way translocation involving both chromosomes 2 and a chromosome 11, t(2;11;2)(p23;p15;q31). Fluorescence in situ hybridization with a probe flanking the ALK gene at 2p23 demonstrated a rearrangement, as previously described in inflammatory myofibroblastic tumors (IMTs). In light of the genetic analysis, the histopathological diagnosis was revised to IMT, although inflammatory cells were scarce. IMTs are pseudosarcomatous inflammatory lesions that primarily occur in the soft tissue and viscera of children and young adults. Our report describes for the first time the occurrence of IMT during prenatal life. The ALK rearrangement may represent the molecular definition of a subgroup of mesenchymal tumors, not always with complete morphological features of IMT, similar to the model of EWS rearrangement in the Ewing sarcoma family of tumors.

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 hypergammaglobulinemia, 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.