Inflammatory myofibroblastic tumors: A short series with an emphasis on the diagnostic and therapeutic challenges.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are a distinct entity of mesenchymal tumors. We present the challenges in their diagnosis and management. MATERIALS AND METHODS: A retrospective study with detailed clinical, radiological, and histopathological (HPE) features along with management and outcome of 10 biopsy-proven patients with IMT, between 2001 and 2020. RESULTS: The location included intracranial (5), orbital (4), and spinal (1) with M : F = 7 : 3. The mean age of onset was in the third decade. The commonest symptom was headache, while proptosis and blurred vision occurred in orbital IMTs. HPE revealed diffuse infiltration of mixed inflammatory cells over proliferating myofibroblasts. Smooth muscle antigen immunoreactivity was noted in fibroblastic spindle cells of all IMTs. However, we did not find anaplastic lymphoma kinase expression in any of our cases, as this is only found in ~ 50% of all IMTs. Tumor infiltration into adjacent tissue was noted in 4 patients. Surgical excision was limited to orbital IMTs, as most central nervous system (CNS) tumors were not amenable for resection. Steroid administration showed moderate improvement in the IMT-CNS patients but also required additional immunomodulation. Four patients had a median long-term follow-up of 7 years. Two patients had recurrent lesions demonstrated by imaging after 2 years of initial presentation. CONCLUSION: IMTs are rare and ambiguous tumors of unknown etiology that can occur anywhere in the body. Clinical and radiological features may not be specific to determine the diagnosis, but it should be considered as a differential diagnosis. Extensive thorough workup with histopathology along with the help of immunohistochemistry is conducive to better clinical outcomes. Surgical biopsy with extensive and total resection of these tumors along with steroid and radiotherapy may enhance the survival outcomes.

Inflammatory pseudotumor and myofibroblastic inflammatory tumor. Diagnostic criteria and prognostic differences.

INTRODUCTION: Inflammatory pseudotumor (IPT) and inflammatory myofibroblastic tumor (IMT) are two very rare entities that were formerly included in the same category; however, today they are considered two different diseases due to the neoplastic origin of the IMT. Our objective is to share our experience in the management of these two types of tumors that we must take into account in the differential diagnosis of pulmonary masses or nodules. METHODS: Thirteen patients with a pathological diagnosis of IPT and IMT who underwent surgery between 2008 and 2019 were retrospectively studied. We recorded the pre and postoperative information of each one, as well as the survival analysis. RESULTS: Of the 13 patients, 8 were men and 5 women. The mean age of presentation was 53,5 years. An atypical segmentectomy was performed in 6 patients; a lobectomy was necessary in 6 and a pneumonectomy in 1 case. In all cases a complete resection was achieved. Diagnosis was possible thanks to histology, immunohistochemical (IHQ) and fluorescent in situ hybridization (FISH) techniques determining the expression of IgG4 and the rearrangement of ALK, respectively. After a median follow up of 49 months, we didn't find any loco-regional or distant recurrence in the patients studied. CONCLUSION: IPT and IMT are rare tumors with a very good prognostic. The diagnosis of both entities is based mainly on specific anatomopathological techniques. Surgery has, in most cases, both a diagnostic and therapeutic role.

Diagnosis of cutaneous mycobacterial spindle cell pseudotumor in the absence of typical inflammatory cells: A case report.

Mycobacterial spindle cell pseudotumor (MSP) is a non-neoplastic condition that is characterized by spindle-shaped histiocytes colonized by mycobacteria. MSP is most commonly diagnosed in the immunocompromised and, while MSP can occur throughout the body, the most common sites of MSP involvement are the lymph nodes and the skin. To diagnose MSP, histopathological analysis typically demonstrates the presence of inflammatory cells, in addition to spindle cells and the unequivocal mycobacteria, which guides the diagnosis away from potential neoplasms. If properly diagnosed and treated with appropriate antibiotic therapy, patients tend to experience almost complete resolution of their symptoms. MSP is a rare condition; to our knowledge, there have only been 11 documented cases of cutaneous MSP, including the one introduced in this report. Here, we present a unique case of a 50-year-old female on chronic immunosuppressive therapy diagnosed with cutaneous MSP in the absence of inflammatory cells on pathology.

Collision Tumor Composed of an Inflammatory Myofibroblastic Tumor and Adenocarcinoma of the Colon: a Rare Entity.

This report presents the case of an 83-year old man with a collision tumor consisting of an inflammatory myofibroblastic tumor (IMT) and adenocarcinoma of the left colon. As the clinical and radiologic features of IMT are non-specific, only the accurate histopathological examination from the left hemicolectomy specimen was diagnostic. Although the prognosis of a colorectal IMT seemed more favorable than in other sites, four months after surgery the patient developed a tumor relapse. Therefore, malignant behavior of IMT could not be totally excluded. Recent studies have demonstrated that a chromosomal rearrangement involving 2p23, the site of the anaplastic lymphoma kinase (ALK) gene, is present in a subset of these tumors. In our patient, tumor cells did not present ALK-1 perinuclear positivity and it could have indicated a less favorable prognosis. The collision of these different entities is extremely rare and this is the first case reported in literature. Further cases of collision tumors with clinical information including their treatment and prognosis are needed.

Over expression of CDK4 and MDM2 in a patient with recurrent ALK-negative mediastinal inflammatory myofibroblastic tumor: A case report.

RATIONALE: The diagnosis of anaplastic lymphoma kinase (ALK)-negative inflammatory myofibroblastic tumors (IMT) remains challenging because of their morphological resemblance with spindle cell sarcoma with myofibroblastic characteristics. PATIENT CONCERNS: A 69-year-old female patient presented with loco-regional recurrent IMT several times within 8 years after primary treatment and neck lymph node metastasis 3.5 years after last recurrence. DIAGNOSIS: The primary, recurrence, and lymph node metastasis lesions were diagnosed as ALK-negative IMTs based on the histopathological features. INTERVENTIONS: Biopsy samples were obtained during repeated surgeries and evaluated for genomic alterations during first and recurrent presentations. The evaluation was done using pathway-driven massive parallel sequencing, and genomic alterations between primary and recurrent tumors were compared. OUTCOMES: Copy number gains and overexpression of mouse double minute 2 homolog (MDM2) and cyclin dependent kinase 4 (CDK4) were observed in the primary lesion, and additional gene amplification of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), Succinate Dehydrogenase Complex II subunit C (SDHC), and thyroid stimulating hormone receptor (TSHR) Q720H were found in the recurrent tumors. Metastases to the neck lymph node were observed 3.5 years after recurrence. LESSONS: Our results indicated genetic evolution in a microscopically benign condition and highlighted the importance of molecular characterization of fibro-inflammatory lesions of uncertain malignant potential.

Paratesticular Fibrous Pseudotumor: A New Entity of IgG4-Related Disease?

INTRODUCTION: Paratesticular fibrous pseudotumor (PFP) represents a benign tumor-like lesion confined to intrascrotal, paratesticular areas. Due to its rarity, only less than 200 cases have been reported to date, of which both pathogenesis and clinical management are little understood. Recently, PFP has been postulated to be among the spectrum of so-called immunoglobulin G4-related diseases (IgG4-RD). Here we describe a case of PFP focusing on the clinical, morphological features and the utility of immunohistochemistry to support the theory that PFP might be a potential member of IgG4-RD family. CASE PRESENTATION: A 41-year-old man presented with a slowly growing, right intrascrotal mass An MRI scan revealed a diffuse-proliferative nodular mass around the paratesticular area. The patient underwent right orchiectomy and a diffuse multinodular tumor with testicular compression was discovered without intratesticular infiltration. Postoperatively, the patient has been well for 2 years up to the recent follow up. On histological examination, the lesion consisted of hyalinized fibrotic tissue with storiform patterns. There were scattered germinal centers; lymphocytic vasculitis was also noted. The immunoglobulin G4 staining showed infiltration of positive plasma cells with highest count 52 per high-power field, whereas the mixed Kappa and Lambda immunoglobulin light chain expression indicated the polyclonality of the plasma cell population. CONCLUSIONS: The morphological and immunohistochemical features in our case support the theory of PFP being part of IgG4-RD. Familiarity to this tumor-like lesion is crucial, since it may respond to corticosteroid therapy, which may save patients from more aggressive surgical procedures.

Inflammatory Myofibroblastic Tumors of the Female Genital Tract Are Under-recognized: A Low Threshold for ALK Immunohistochemistry Is Required.

Inflammatory myofibroblastic tumor (IMT) of the female genital tract is under-recognized. We investigated the prevalence of ALK-positive IMT in lesions previously diagnosed as gynecologic smooth muscle tumors. Immunohistochemistry (IHC) for ALK was performed on tissue microarrays of unselected tumors resected from 2009 to 2013. Three of 1176 (0.26%) "leiomyomas" and 1 of 44 (2.3%) "leiomyosarcomas" were ALK IHC positive, confirmed translocated by fluorescence in situ hybridization (FISH) and therefore more appropriately classified as IMT. On review significant areas of all 4 tumors closely mimicked smooth muscle tumors morphologically, but all showed at least subtle/focal features suggesting IMT. Recognizing that the distinction between IMT and leiomyoma/leiomyosarcoma can be subtle, we then reviewed 1 hematoxylin and eosin slide from each patient undergoing surgery for "leiomyoma" from 2014 to 2017 and selected cases for ALK IHC with a low threshold. Of these, 30 of 571 (5.3%) underwent IHC. Two were confirmed to be IHC positive and FISH rearranged. Of the 6 IMTs, only 1 tumor with a previous diagnosis of leiomyosarcoma, an infiltrative margin and equivocal necrosis, metastasized. Of note it demonstrated a less aggressive clinical course compared with most metastatic leiomyosarcomas (alive with disease at 6 y). The patient was subsequently offered crizotinib to which she responded rapidly. In conclusion, IMTs may closely mimic gynecologic smooth muscle tumors. IMTs account for at least 5 of 1747 (0.3%) tumors previously diagnosed as leiomyoma and 1 of 44 (2.3%) as leiomyosarcoma. These tumors may be recognized prospectively with awareness of subtle/focal histologic clues, coupled with a low threshold for ALK IHC.

ALK-positive inflammatory myofibroblastic tumor harboring ALK gene rearrangement, occurring after allogeneic stem cell transplant in an adult male.

Inflammatory myofibroblastic tumor arose as a defined neoplasm from the disparate group of tumors (both neoplastic and inflammatory) originally described as inflammatory pseudotumors. The morphologic features are well described, and 50-60% of cases are associated with fusions of the anaplastic lymphoma kinase (ALK) gene. We describe an inflammatory myofibroblastic tumor in the lower abdominal wall of an adult male, which occurred 88days after he received an allogeneic stem cell transplant for T-lymphoblastic lymphoma, and which was positive for ALK immunohistochemistry and showed ALK gene rearrangement by fluorescence in situ hybridization. Two other cases are reported in the post-stem cell transplant setting, but both occurred in children and did not have molecular analysis performed. The etiology remains unclear, but may be due to immune dysregulation caused by any combination of prior chemotherapy, radiotherapy and immune suppression. These neoplasms should be considered as a rare consequence of allogeneic stem cell transplantation and referral to a specialist sarcoma center for further management may be required.

Inflammatory pseudotumor of kidney masquerading as renal carcinoma.

Inflammatory pseudotumor also known as inflammatory fibroblastic tumor is a rare benign tumor, which commonly affects the lung. It is very rarely seen in the genitourinary tract. As the preoperative diagnosis, clinically and radiologically is inconclusive, it is imperative to surgically remove and confirm it on histopathologic examination. We report a case of inflammatory pseudotumor in a 51-year-old male who presented with flank pain and was treated with nephrectomy.

Hepatic inflammatory pseudotumor presenting in an 8-year-old boy: A case report and review of literature.

Hepatic inflammatory pseudotumors are uncommon benign lesions. Accurately diagnosing hepatic inflammatory pseudotumor can be very challenging because the clinical presentation and radiological appearances are nonspecific and cannot be certainly distinguished from malignant neoplastic processes. Herein, we present a case of hepatic IPT in an 8-year-old boy who presented to clinic with a 3-mo history of a tender hepatic mass, fever of unknown origin, and 9-kg weight loss. The physical examination was notable for tender hepatomegaly. Laboratory investigations were notable for a normal hepatic profile and elevated erythrocyte sedimentation rate and C-reactive protein. A T2-attenuated magnetic resonance imaging scan of the abdomen showed a 4.7 cm × 4.7 cm × 6.6 cm, contrast-enhancing, hyper-intense, well-defined lesion involving the right hepatic lobe. In view of the unremitting symptoms, tender hepatomegaly, thrombosed right hepatic vein, nonspecific radiological findings, and high suspicion of a deep-seated underlying infection or malignancy, a right hepatic lobectomy was recommended. Microscopically, the hepatic lesion exhibited a mixture of inflammatory cells (histiocytes, plasma cells, mature lymphocytes, and occasional multinucleated giant cells) in a background of dense fibrous tissue. Immunohistochemically, the cells stained negative for SMA, ALK-1, CD-21 and CD-23, diffusely positive for CD-68, and focally positive for IgG4. The final histopathological diagnosis was consistent with hepatic IPT. At the postoperative 4-mo follow-up, the patient was asymptomatic without radiological evidence of recurrence.

Mesothelial/monocytic incidental cardiac excrescences of the heart - a report of three cases.

Mesothelial/monocytic incidental cardiac excrescences (MICE) are uncommon pseudotumours and may histologically mimic metastatic adenocarcinoma. They consist of nonneoplastic proliferations of mesothelial cells intermingled with foamy macrophages enmeshed in fibrin. There are only around 40 cases reported in literature, and it is important that the pathologists should be aware of this lesion especially while dealing with cardiac surgery specimens. We report a series of three cases of MICE that were incidentally discovered during valve replacement surgeries.

FN1: a novel fusion partner of ALK in an inflammatory myofibroblastic tumor.

Inflammatory myofibroblastic tumors (IMTs) are rare tumors characterized as low-to-intermediate grade sarcomas. Rearrangements of the anaplastic lymphoma kinase (ALK) gene have been reported in IMT. Here, we describe a novel fusion gene in an IMT tumor specimen. A 12-year-old male was admitted to our hospital with a bladder tumor. We identified the fibronectin 1 gene (FN1) as a fusion partner of ALK using 5'RACE. This novel fusion, FN1-ALK, resulted in ALK overexpression in the IMT. This finding should clarify the causes of IMT and facilitate development of novel therapeutics.

Inflammatory myofibroblastic tumours of the urinary bladder: multi-centre 18-year experience.

OBJECTIVE: To review a series of inflammatory myofibroblastic tumours (IMTs) of the urinary bladder in 10 hospitals in Hong Kong. METHODS: A database search in the pathology archives of 10 hospitals in Hong Kong from 1995 to 2013 was performed using the key words 'inflammatory myofibroblastic tumour', 'inflammatory pseudotumour' and 'spindle cell lesion'. Patient characteristics, clinical features, histological features, immunohistochemical staining results and treatment outcomes were reviewed. RESULTS: Nine cases of IMT of the urinary bladder were retrieved. The mean age was 45.4 ± 22.8 years (range 11-78). Eight patients (88.9%) presented with haematuria and 5 patients (55.6%) had anaemia with a mean haemoglobin level of 6.8 ± 1.3 g/dl. Histologically, the majority of patients (77.8%) had a compact spindle cell pattern. Anaplastic lymphoma kinase staining was positive in 75% of cases. During a mean follow-up period of 43.4 months (range 8-94), none of them developed any local recurrence or distant metastasis. CONCLUSIONS: A high index of suspicion of IMT should be maintained for young patients presenting with bleeding bladder tumours and significant anaemia. IMTs of the urinary bladder run a benign disease course, and good prognosis can be achieved after surgical resection.

Clinicopathologic characteristics of inflammatory pseudotumor-like follicular dendritic cell sarcoma.

Inflammatory pseudotumor (IPT)-like follicular dendritic cell (FDC) sarcoma is a recently described rare tumor and considered a unique entity, with different histologic appearances and behavior from those of the classical FDC sarcoma. This study analyzed the clinical and pathological findings of two such cases that the authors encountered and 36 previously reported cases identified in the literature. Assessment of all 38 cases showed a slight female predominance (2.2:1) with a median age of 56.5 years. Seventeen patients complained of abdominal discomfort or pain, while fifteen patients had no clinical symptom. Almost all cases occurred in liver (n=20) or spleen (n=17). Except in one case, all patients underwent surgical resection of the tumor alone. Histologic features showed a mixture of chronic inflammatory cells and variable amounts of spindle cells with vesicular nuclei and distinct nucleoli. The tumor cells expressed conventional FDC markers such as CD21 (75%), CD35 (92%), CD23 (62%), clusterin (75%), and CNA.42 (100%). EBV was detected in thirty-five cases (92.1%) by Epstein-Barr virus (EBV)-encoded RNA in situ hybridization, and EBV-latent membrane protein-1 was expressed in 90% of the cases. With a median follow-up of 21 months, 29 patients (85.3%) were alive and well, 4 (11.8%) were alive with disease, one patient (2.9%) died of disease. Only four patients with hepatic tumors underwent recurrence or metastasis after initial treatment. Epstein-Barr virus is thought to play a role in the development of the tumor; however, the pathogenesis of the disease and the origin of tumor cells remain unclear.

Inflammatory pseudotumor in head and neck.

BACKGROUND: Inflammatory pseudotumor (IPT) is a tumefactive lesion characterized by fibroblastic proliferations and a prominent inflammatory component. It behaves as a locally benign or aggressive lesion, clinically and radiologically mimicking a neoplastic process. Numerous entities can be diagnosed as IPT, from reactive lesions to true neoplasms. The diagnosis of IPT requires further elaboration, and IPT should be distinguished from other similar entities such as inflammatory myofibroblastic tumor and IgG4-related sclerosing disease. CASE SUMMARY: We report two cases of IPT arising from the head and neck region. One occurred at the orbit and the other at the parapharyngeal space. Histologically, they showed aggregates of myofibroblasts and inflammatory cells. Immunohistochemically, the number of IgG4-positive cells was less than 40% of the number of IgG positive cells, and the myofibroblastic cells were negative for anaplastic lymphoma kinase. The diagnosis was IPT/not otherwise specified. One patient was treated by systemic administration of corticosteroid and had good response. The other, who was treated by local administration of corticosteroid, partially responded and is currently stable with limited disease. DISCUSSION: IPT has been reported to occur in various anatomical sites, most commonly in the lungs. The incidence in the head and neck area is extremely rare. Treatment of IPT is controversial and may involve corticosteroids or surgical resection, or both. Other chemotherapeutic agents and radiotherapy may be considered in steroid-resistant patients. The pathological subtype, safety of resection, and safety of corticosteroid use must be included in the decision-making process for treatment.

[Expression and significance of IgG4 in inflammatory disease of nasal cavity and paranasal sinuses].

OBJECTIVE: To study the prevalence of IgG4-positive plasma cells in inflammatory disease of nasal cavity and paranasal sinuses and its association with IgG4-related sclerosing disease (IgG4-SD). METHODS: The expression of IgG4 and IgG in plasma cells of 103 cases diagnosed as inflammatory disease of nasal cavity and paranasal sinuses with dense lymphoplasmacytic infiltrate was studied by immunohistochemistry (EnVision) and quantitatively analyzed by medical image analysis system. RESULTS: Immunohistochemical study showed marked infiltration by IgG4-positive plasma cells (>50 per high-power field) in 28 cases, moderate infiltration (30 to 50 per high-power field) in 23 cases, mild (10 to 29 per high-power field) in 30 cases and negative (<10 per high-power field) in 22 cases (P < 0.05). Twenty-two cases studied fulfilled the diagnostic criteria of IgG4-SD (>50 IgG4-positive plasma cells per high-power field and IgG4-to-IgG ratio > 40%), including 3 cases of chronic sinusitis (3/20), 3 cases of nasal polyps (3/18), 3 cases of inflammatory pseudotumor (3/17), 4 cases of fungal sinusitis (4/20), 1 case of rhinoscleroma (1/12), 7 cases of Wegener's granulomatosis (7/11) and 1 case of Rosai-Dorfman disease (1/2). CONCLUSION: Inflammatory disease of nasal cavity and paranasal sinuses fulfilling the diagnostic criteria IgG4-SD is not uncommon. Definitive diagnosis of IgG4-SD requires correlation with other clinical and laboratory findings. Some cases of unexplained inflammatory disease of nasal cavity and paranasal sinus may represent a member of the IgG4-SD spectrum. IgG4 carries diagnostic value in differential diagnosis of inflammatory disease occurring in nasal cavity and paranasal sinuses.

ALK-1 positive orbital inflammatory myofibroblastic tumour (IMT) associated with prominent numbers of IgG4 plasma cells - a case report.

A 14-year-old boy presented with a 2-year history of a supraorbital mass, associated with loss of vision and phthisis. A lack of response to systemic steroids led to an incisional biopsy. This showed a spindle cell lesion with a prominent inflammatory component, with numerous plasma cells. The spindle cells were positive for anaplastic lymphoma kinase (ALK-1). Over 90% of the plasma cells were surprisingly positive for IgG4. The presence of ALK-1 positivity within the spindle cells, coupled with the prominent inflammation indicated a diagnosis of ALK-1 positive inflammatory myofibroblastic tumour (IMT-the neoplastic member of the so called inflammatory pseudotumours). However, the level of IgG4 positivity within the plasma cell population would have otherwise lead to a diagnosis of IgG4 related disease, if the ALK-1 positive spindle cells population was not represented. Recent literature from systemic IMT has alluded to the presence of IgG4 plasma cell positivity in IMT and argues that in the absence of other supporting histological features of IgG4 disease (phlebitis and lymphoid aggregates), as in this case, the presence of IgG4 plasma cells, even in high numbers should not lead to a kneejerk diagnosis of co-existing IgG4 disease. This case report is the first to make this association in the orbit and argues that in the presence of IMT, the IgG4 plasma cells are not necessarily pathogenic.

Inflammatory myofibroblastic tumor: a rapidly growing soft tissue mass in the posterior mandible.

The term inflammatory myofibroblastic tumor (IMT) encompasses a diverse group of spindle cell entities that traverses a clinical and histologic spectrum, extending from reactive to benign neoplastic to highly aggressive with malignant inclinations. Head and neck IMTs are rarely seen and comprise less than 5 % of tumors. Here we report a case of a 30 year old male who presented with a rapidly enlarging and extremely painful growth in the right posterior mandible, post extraction. Histopathological examination revealed a highly cellular connective tissue stroma comprised of spindle shaped cells arranged in fascicles, admixed with inflammatory cells, predominantly plasma cells. Apart from routine hematological investigations, serum protein electrophoresis was also performed. The final diagnosis was confirmed by a panel of immunomarkers consisting of MPO, CD34, CD20, CD3, CD23, CD138, SMA and ALK. To the best of our knowledge, this is the third case of oral IMT arising from an extraction socket.