Pulmonary Inflammatory Myofibroblastic Tumor: A Case Report.

ALK1 and p80 Expression and Chromosomal Rearrangements Involving 2p23 in Inflammatory Myofibroblastic Tumor

Inflammatory myofibroblastic tumor in children: clinical review with anaplastic lymphoma kinase, Epstein-Barr virus, and human herpesvirus 8 detection analysis

The uncommon and mysterious pulmonary inflammatory myofibroblastic tumor (PIMT) primarily affects children and young people. PIMT is characterized by the proliferation of myofibroblastic spindle cells mixed with inflammatory cells. It can resemble both benign and malignant disorders, both radiographically and clinically. PIMT typically manifests as a solitary lung tumor. The genesis of the tumor is linked to genetic anomalies, including those related to the ALK gene (anaplastic lymphoma kinase); nonetheless, some cases are not ALK-positive, indicating genetic variability. Clinically, patients may have non-specific symptoms such as cough, chest pain, or hemoptysis, or they may not exhibit any symptoms at all. In these cases, imaging tests may unintentionally reveal unrelated conditions. From a histopathological perspective, PIMT is characterized by a heterogeneous cellular makeup, encompassing lymphocytes, myofibroblasts, plasma cells, and histiocytes, which generally exhibit a fascicular or storiform pattern. The diagnosis is verified using immunohistochemical labeling, molecular research, and histological examination. The cornerstone of treatment is still surgical resection, which has a good prognosis and a low recurrence rate. On the other hand, specific treatments, such as ALK inhibitors, have shown promise for incurable or recurring instances. Even though PIMT usually has a benign history, it is important to comprehend its biological behavior and molecular foundations for precise diagnosis and efficient management. This underscores the need for additional study into the pathophysiology and potential treatments of PIMT. This report presents a case of a 53-year-old female who presented with complaints of breathlessness and chest pain and was diagnosed with the condition accidentally.

10024 Background: Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate malignancy, predominantly seen in children and young adults. Given its rarity, data are limited. We describe the largest cohort of patients with IMT to date, with an aim to further characterize this poorly understood tumor. Methods: A multi-institutional review was performed at 18 North American hospitals participating in the Pediatric Surgical Oncology Research Collaborative to identify IMT patients ≤39 years, diagnosed from 2000-2018. Descriptive statistics are described as median and interquartile range. Multivariable analysis was used to identify predictors of event free survival (EFS). Results: 182 patients were identified with a median age of 11 years (5-17); 52% were female. 33% of tumors were thoracic, 26% abdominal/pelvic, 20% head/neck, and 14% genitourinary. Common presenting symptoms included pain (29%), respiratory symptoms (24%), weight loss (12%), and a palpable mass (10%). Median tumor size was 3.9 cm (1.9-6.5). Anaplastic lymphoma kinase (ALK) overexpression was identified via immunohistochemistry in 53% of patients tested. One third of patients had abnormal cytogenetics, with 12% of the entire cohort having an ALK mutation. 7% of patients had distant disease at diagnosis. 13% of patients received neoadjuvant therapy including chemotherapy (3%), ALK inhibitor (4%), radiation (0.5%), non-steroidal anti-inflammatories (NSAIDs) (7%), or steroids (2%). Of those who underwent resection with known margin status (n = 158), 66% had complete resection, 20% had microscopic positive margins, and 14% had gross residual disease. Just over 40% of patients had an en bloc resection of involved organs, most commonly lung (26%). 21% of patients received adjuvant therapy, including chemotherapy (3%), ALK inhibitor (9%), radiation (0.5%), NSAIDs (8%), or steroids (5%). 12% of all patients received an ALK inhibitor: 24% neoadjuvant, 62% adjuvant, and 14% without surgery. Median follow-up time was 36 months (14-69). Overall 5-year survival (OS) was 95% and 5-year EFS was 80%. Predictors of recurrence included respiratory symptoms, larger tumor size, or distant disease at diagnosis. Gender, race, age and primary site were not predictive of EFS. Likewise, there was no association of ALK overexpression or ALK mutation with EFS. The presence of gross or microscopic margins following resection was not associated with recurrence. Conclusions: IMT is a rare tumor with favorable OS. Five year recurrence rate was 20%. Presenting with respiratory symptoms, larger tumor size, or metastatic disease was associated with recurrence, while ALK positivity was not. Notably, a positive margin after resection was not associated with increased recurrence, indicating that aggressive attempts at surgical resection that would compromise form or function may not be warranted.

5′-(RACE) Identification of Rare ALK Fusion Partner in Anaplastic Large Cell Lymphoma

Inflammatory myofibroblastic tumor (IMT) is an indolent spindle cell proliferation that can histologically resemble various malignant mesenchymal neoplasms; however, it generally behaves as a benign or locally recurrent tumor. Most IMTs involve the lung, mesentery, omentum, or retroperitoneum. We report the clinical and pathologic features of six IMTs of the uterus, one of which was included in a previous report, and emphasize the histologic and immunohistochemical features that distinguish IMTs from uterine spindle cell neoplasms that require aggressive treatment. Recently, translocations of the anaplastic lymphoma kinase (ALK) gene and immunohistochemical expression of ALK have been reported in IMTs of various anatomic sites. We compared ALK expression in uterine IMTs with that in uterine mesenchymal neoplasms with which it may be confused. Patients with IMT were between 6 and 46 years of age. None had a history of abdominal surgery; three were multiparous. The IMTs ranged from 1 to 12 cm in maximum dimension. Three grew as polypoid masses that arose in the lower uterine segment, and two of these prolapsed through the cervical os. The three other tumors grew as bulky myometrial masses with focally irregular borders and infiltrated the endometrium, parametrium, or cervical stroma. There were three main microscopic patterns: a hypocellular pattern, a fascicular pattern, and a hyalinized pattern. A lymphoplasmacytic infiltrate was present in all of the tumors, and most had a myxoid background. Mitotic activity ranged from 0 to 2 mitotic figures per 10 high power fields (HPF) except in one tumor that focally had up to 8 mitotic figures per 10 HPF. No nuclear atypia or necrosis was present. Immunohistochemical expression of ALK was present in a cytoplasmic pattern in all IMTs tested. No ALK expression was identified in uterine leiomyoma (n = 7), leiomyosarcoma (n = 6), carcinosarcoma (n = 4), endometrial stromal sarcoma (n = 4), or normal uterine tissues. Follow-up ranging from 1.5 years to 5 years in 4 patients with uterine IMTs revealed no recurrence or metastasis. IMTs should be differentiated from aggressive uterine mesenchymal tumors because they can be treated conservatively and have a more favorable prognosis. ALK expression appears to be of diagnostic value in conjunction with other immunohistochemical stains.

Pulmonary inflammatory myofibroblastic tumor (IMT) has been considered as a synonym for inflammatory pseudotumor (IPT) for a long time. Recent studies have indicated that IMT and IgG4-related IPT are distinct diseases. However, no consensus criteria have been recommended. Here we propose a set of criteria for the differential diagnosis. Twenty-six archived IMT and IgG4-related IPT samples were examined for histological characteristics and the expression of IgG, IgG4, SMA and ALK-1. Based on our proposed criteria, we reclassified the cases into either IMT or IgG4-related IPT group and compared the clinicopathological features, laboratory findings, overall survivals (OS) and disease-free survivals between groups to validate the effectiveness and dependability of the diagnostic criteria. The average age of IgG4-related IPT group was higher than IMTs (48.82 vs. 39.22 years, P=0.031). In IMT group, tumors were characterized by bigger tumor sizes (3.47 vs. 2.22 cm, P=0.007), diffuse and total destroyed alveoli (88.89% vs. 17.65%, P=0.002), fewer lymphoid follicles (1.6/HPF vs. 3.0/HPF, P=0.045) and lower expression of IgG (74.7/HPF vs. 149.1/HPF; P<0.001). As an exclusion criterion of IgG4-related IPT, ALK-positivity was correlated with the higher cytological atypia (mean 3.7/HPF, P<0.001) and lesser lymphoid follicles (mean 1.2/HPF, P=0.021). And it's the first study to show the liner positive correlation between the lymphocytes + plasma cells count and IgG4-positive plasma cells count in these lesions (r=0.914, P<0.001). The negative correlation between the IgG4-positive plasma cells count and the expression of ALK-1 are reported for the first time as well (rs=-0.632, P=0.001). However, despite two patients with recurrence or metastasis were divided into IMT group, only borderline values were detected in the survival analysis (OS 88.89% vs. 100%, P=0.197, DFS 77.78% vs. 100.00%; P=0.056). The significant differences of clinicopathological characteristics between the IMTs and IgG4-related IPTs indicated that a combination of lymphocytes + plasma cells count, cytological atypia, IgG4 and ALK-1 staining will be helpful in differential diagnosis.

Targeted therapy has dramatically altered the treatment paradigm for some patients with inflammatory myofibroblastic tumor (IMT) that possesses specific molecular aberrations. IMT is an exceedingly rare type of sarcoma, with about 50% of cases featuring anaplastic lymphoma kinase (ALK) gene rearrangements. The treatment of IMT with ALK fusions using ALK tyrosine kinase inhibitors (TKIs) has become increasingly common. However, until now, there is a lack of evidence supporting the efficacy of third-generation ALK-TKIs in this disease category. Here, we report the first case of a patient with advanced IMT harboring the EML4-ALK fusion gene along with two rare ALK fusion genes: PLB1-ALK, which has only been reported in two cases of lung adenocarcinoma and large cell neuroendocrine carcinoma, and unreported ALMS1-ALK. The patient achieved partial response (PR) following first-line treatment with lorlatinib and subsequently underwent successful surgical intervention. This is the inaugural case of a third-generation ALK-TKI achieving therapeutic success in advanced IMT with complex ALK rearrangements, including rare and previously uncharacterized fusion subtypes. Although the biological functions of these two rare ALK fusions still need to be confirmed, this case underscores the dependency of ALK-rearranged IMT on ALK-mediated signaling, suggesting that third-generation ALK-TKIs may offer an optimal targeted therapeutic strategy for ALK-dependent mesenchymal tumor subtypes.

Inflammatory myofibroblastic tumor of bone harboring an ALK gene amplification

Epithelioid inflammatory myofibroblastic sarcoma – A rare case report

Inflammatory myofibroblastic tumor (IMT) of the lung is a rare malignancy with few cases reported in the literature. Histologically, it is composed by spindle cells and an infiltrate of inflammatory cells. Children and young, non-smoking adults constitute the majority of cases, the clinical behavior ranges from a benign entity to a malignant process with rapid recurrence and metastatic progression. We present a case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) of the pleura, a malignant variant of IMT, which was initially treated with debulking surgical resection followed by systemic chemotherapy. The tumor was found to have an anaplastic lymphoma kinase (ALK) gene rearrangement. An ALK directed tyrosine kinase inhibitor was used with an impressive response, the patient remains in remission nearly 1 year after presentation. The pathogenesis, pathologic findings, clinical behavior and imaging of pulmonary EIMS are discussed.

Inflammatory myofibroblastic tumor (IMT), also known as inflammatory pseudotumor, is a rare and benign process with myofibroblastic spindle cell proliferation. IMT usually displays an indolent course but its radiologic appearance can mimic malignancy. Although it can occur in any organ, the lung is the most commonly involved (1). Pulmonary IMT typically manifests as a single, peripheral, and sharply circumscribed mass with lower lobe predominance (2). Here, we present a case of pulmonary IMT with atypical radiologic and clinical manifestations which was treated successfully with prednisone. To our knowledge, there has not been a case report on multifocal pulmonary IMT rapidly progressing into masses in young adults. CASE REPORT

Copy number alterations and expression profiles of candidate genes in a pulmonary inflammatory myofibroblastic tumor

7504 Background: Patients with anaplastic lymphoma kinase (ALK) gene fusions derive significant clinical benefit from crizotinib, an ALK inhibitor; moreover, next generation ALK kinase inhibitors are in development. Unfortunately, drug resistance develops after initial benefit (acquired) or occurs in patients who never derive a benefit (intrinsic). This study aimed to define molecular mechanisms of resistance to ALK kinase inhibitors in ALK+ non-small cell lung cancer (NSCLC) patients. Methods: 30 ALK+ crizotinib-treated NSCLC patients experienced radiologic disease progression, of whom 7 progressed only in the CNS. Of the 23 patients with extra-CNS progression, a biopsy was attempted on 19. One of the patients without tissue post-crizotinib then proceeded to a second generation ALK inhibitor and tissue was obtained post progression on this drug. We performed molecular analysis and initiated cell lines from tumor tissue for these 19 patients. Results: 15 patients had material evaluable for molecular analysis. Six patients (40%) developed secondary mutations in the kinase domain of ALK. Two novel mutations were identified in samples from ALK+ NSCLC patients, F1174C and D1203N. Two patients each demonstrated G1269A or L1196M mutations. Two patients each, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). Four patients demonstrated the presence of another oncogenic driver (1 with EGFR mutation; 3 with KRAS mutation) with or without a persistent ALK gene rearrangement. One patient lacked an ALK gene fusion on progression biopsy, but had no identifiable alternate oncogene alteration. 3 patients retained ALK positivity with no identifiable resistance mechanism. Data on additional patients and an in vitro model of copy number gain will be presented. Conclusions: ALK kinase inhibitor resistance in ALK+ NSCLC occurs through a diverse array of kinase domain mutations, ALK gene fusion CNG, and emergence of second (same cell) or separate (different cell) oncogenic drivers. In order to overcome resistance it will be important to differentiate patients that preserve ALK dominance (secondary mutations and CNG) versus those that have diminished ALK dominance (separate or second oncogenic drivers).

Pulmonary inflammatory myofibroblastic tumor is a rare disease. Computed tomography in a 54-year-old woman showed a mass compressing the segmental bronchus of the left lung. Bronchoscopy indicated a mesenchymal tumor, hamartoma, or inflammatory myofibroblastic tumor. Because an inflammatory myofibroblastic tumor can potentially clog the segmental bronchus, we performed a left upper division segmentectomy. Pathologic examination revealed an inflammatory myofibroblastic tumor. In most cases, preoperative diagnosis is difficult because of the varied radiologic manifestations, and it can also be difficult to distinguish from malignancy in small tissue samples.