Case 4 -

Inflammatory Myofibroblastic Tumor of the Liver (Inflammatory Pseudotumor) David Owen Vancouver General Hospital Vancouver, BC, Canada

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Description of Slide Much of the slide consists of necrotic tissue. The surviving areas show spindle cell proliferation with heavy chronic inflammation. Plasma cells are particularly frequent but there are also smaller numbers of lymphocytes and histiocytes. Two patterns are present: a) compact areas with spindle shaped cells often with a storiform arrangement. b) myxoid and vascular areas with loosely arranged polygonal and stellate cells in an edematous background containing prominent vessels. Not present on this slide but noted in other areas of the tumor are hypocellular collagenous foci containing sparse spindle cells. Case 4 - Figure 1 - Low power view of lesion showing two different appearances: A densely cellular area and a sparsely cellular edematous area. Case 4 - Figure 2 - Medium power view of the densely cellular area. At this power it is apparent that there is a spindle cell component and an inflammatory component. Case 4 - Figure 3 - In this high power view the spindle cells are noted to be bland with little pleomorphism and no mitotic activity. The inflammatory cells consist of a mixture of lymphocytes, plasma cells and histiocytes. Case 4 - Figure 4 - The edematous area of the lesion also shows an inflammatory component and a vascular component. Dense spindle cell aggregations are not seen. Case 4 - Figure 5 - At this high power the bland nature of the spindle component is again demonstrated. The inflammatory cells are mixed and morphologically appear benign. All spindle cells are histologically bland and mitotic figures are sparse. Numerous special stains were performed. The spindle cells were strongly immunopositive for vimentin and patchily positive for smooth muscle actin. Negative staining was noted for EMA, various keratins, CD 21, CD34, p53, S100, PLAP, and AFP. The plasma cells showed a polyclonal staining pattern with both B and T lymphocytes were present. Immunostains for EBV were negative, but PCR analysis revealed a faint signal compatible with previous infection. Stains for amyloid and micro-organisms are negative. Patient Follow-up The patient recovered from surgery and remained asymptomatic. Twelve months following surgery he developed enlargement of the left testis. This was excised and showed a seminoma. A follow-up CT performed 35 months later revealed a mass in the porta hepatis measuring 4.0 cm in diameter. Discussion Inflammatory myofibroblastic tumor (IMT) is uncommon but not excessively rare. It was originally described in the lung, but has subsequently been identified in a variety of intra-abdominal locations including the liver, retroperitoneum and urinary bladder. Examples arising primarily in soft tissues have also been recorded. Whether tumors arising at different sites (particularly lymph nodes and spleen) represent the same clinical and biologic entity is as yet undetermined. IMT is the preferred name for this condition but here are a variety of synonyms including plasma cell granuloma, post-inflammatory tumor, xanthomatous pseudotumor, inflammatory pseudotumor and inflammatory fibrosarcoma. It is however important not to confuse IMT with non-specific inflammatory masses such as resolving abscesses and infected infarcts. As the variety of synonyms suggests, there is some confusion as to whether IMT is truly neoplastic or whether it represents a reactive proliferation of myofibroblastic cells. At the present time, most authors regard it as a neoplasm. Although it is usually cured if completely excised, in 25% of cases it may recur locally and in a small number of examples metastases have been recorded. Extrapulmonary IMT may occur at any age, but is characteristically a disease of children and young adults. No clear sex difference is recorded. Intra abdominal tumors typically present as large mass lesion. Sometimes there is intestinal obstruction, but in many instances the tumor is discovered incidentally. In 15-30% of patients there may be constitutional symptoms consisting of fever, malaise and weight loss. As with the present case, these constitutional symptoms disappear after surgical excision. Laboratory investigations are not usually helpful in arriving at a diagnosis. Low-grade anemia, leukocytosis and polyclonal hypergammaglobulinemia may be present. The gross appearance of intra abdominal IMT is that of a single or multifocal (contiguous or separate) mass often measuring greater than 10 cm in diameter. Large areas of necrosis and hemorrhage are common. The tumor nodules are either rubbery or myxoid in texture and are grey or tan-yellow in color. A whorled appearance may be present. Microscopically, three tissue patterns may be encountered: cellular, myxoid (resembling nodular fasciitis) or fibrous (resembling a scar or desmoid fibromatosis). In all areas there are plump spindle cells interspersed with inflammatory cells particularly lymphocytes, plasma cells and eosinophils. The spindle cells (myofibroblasts) are plump with inconspicuous pale cytoplasm. Generally, there is little pleomorphism or mitotic activity. Cells resembling ganglion cells may occasionally be encountered. In a small percentage of tumors the spindle cells areas may be highly cellular and there may be some mitotic activity. This type of tumor is more common in children and has been labelled inflammatory fibrosarcoma. However, the name is probably unjustified as the long-term prognosis is generally good and does not materially differ from the more usual type of IMT. Immunohistochemistry is a valuable adjunct to light microscopic diagnosis. Vimentin is almost invariable positive in the spindle cells. Smooth muscle actin and muscle specific actin are present in 80% of cases, desmin and CD68 are positive in 40% of cases and pankeratin and p53 positive in 30% of cases. S100, CD21 and myoglobin are uniformly negative. It has recently been established that many IMTs have abnormalities of chromosome 2p23 and express ALK 1 (anaplastic lymphoma kinase). Studies of a large number of extrapulmonary IMTs suggest that 25% of cases will recur and 8% will undergo malignant transformation. Cellularity, mitotic activity and an inflammatory component do not predict prognosis. Tumors that are aneuploid, express p52 or demonstrate ganglion-like cells are more likely to have an adverse course although these markers are imperfect predictors. The etiology of IMT has been the subject of considerable speculation. Tumors that occur in the lung have in some instances been linked to infections. A wide variety of organisms have been implicated, but no clear-cut pattern has emerged. For extrapulmonary tumors a history of infection is usually not present. Differential Diagnosis Postoperative (or post inflammatory) reactive spindle cell nodule (i.e. a true pseudotumor), spindle cell carcinoma, spindle cell sarcoma, and follicular dendritic cell tumor. True pseudotumors certainly occur and on biopsy these may be difficult or even impossible to distinguish from IMT. They represent a myofibroblastic response to injury or infection. These lesions do not show chromosomal abnormalities or aneuploidy. Chronic liver abscess secondary to recurrent pyogenic cholangitis is a reasonable differential diagnosis in the current case given that the patient originated in Hong Kong, had recurrent fevers and that most of the excised mass consisted of necrotic liver tissue. Spindle cell carcinoma is an uncommon primary neoplasm in the liver. Absolute reliability cannot be placed on immunohistochemical positivity for keratin subsets or p53, as these may also be positive in a minority of IMTs. Spindle cell carcinomas are usually mitotically active and do not have the myxoid or fibrotic foci that are characteristic of IMT. Spindle cell sarcoma (rhabdomyosarcoma, leiomyosarcoma, GIST and nerve sheath tumors) pose a significant differential diagnostic challenge. Before IMT was described many cases may have been mis-diagnosed as sarcomas. Rhabdomyosarcoma, nerve sheath tumor and GIST can usually be excluded by immunostaining. Leiomyosarcomas typically have eosinophilic fibrillary cytoplasm. IMT in the liver is virtually histologically identical with follicular dendritic cell tumors (FDCT). However, most IMTs are positive for smooth muscle markers but negative for follicular centre cell markers (CD21). FDCTs have the reverse pattern of positivity. Some liver FDCTs are positive for EBV and are heavily infiltrated by plasma cells. 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