Patient selection

A retrospective review was performed to identify mass-forming hepatic lesions with a pathologic diagnosis or descriptive diagnosis favouring hepatic IPT. A natural language search was performed for the diagnosis of IPT made during 2000–2023 at the University of California, San Francisco. Cases were excluded if the slides were not available or if the pathology was diagnostic of or highly suspicious for neoplasia. The study was approved by the Committee on Human Research, the Department of Pathology, University of California, San Francisco (San Francisco, CA).

Histological examination

All cases with a diagnosis of hepatic IPT or IPT-like features were evaluated by D.J.B. and E.D.N. Cases were subcategorized based on predominant morphology as paucicellular/sclerotic (characterized by dense fibrotic and variably hyalinized stroma with minimal associated inflammation), lymphoplasmacytic (characterized by sheets of lymphocytes or plasma cells with or without lymphoid aggregates), neutrophilic (characterized by predominantly neutrophilic inflammation), or histiocytic (characterized by variable xanthogranulomatous inflammation with or without multinucleated giant cells or admixed neutrophils, lymphocytes, and eosinophils). Cases with mixed features were categorized based on the predominant morphology. The presence or absence of the following histologic features were recorded for each case: duct damage or ductular reaction, well-formed epithelioid granulomas, prominent haemorrhage and/or hemosiderin, sinusoidal dilatation and/or hepatic plate atrophy. Special stains and immunohistochemistry were reviewed, when available.

Clinical evaluation

The patients' medical records were reviewed for features including age, gender, imaging data (including size of the lesion, location, and the presence of multifocal hepatic lesions), relevant medical history, and infectious history. Any history of malignancy, biliary disease, abdominal surgery, or cirrhosis was noted.

Follow-up data

Radiologic data after liver biopsy was evaluated when available, including progression or resolution of the biopsied mass. Patients were designated as having a “likely neoplastic” or “reactive/infectious” aetiology based on radiologic features and/or subsequent pathologic biopsies.

Statistical analysis

Comparisons of categorical variables were performed using the Pearson method or Fisher's exact test when appropriate. Statistical calculation was applied using Student's t test for continuous variables. The log-rank (Mantel–Cox) test was used to compare the survival distribution. All statistical results were considered significant if the P value was <0.05.

Clinical features

A total of 161 patients with liver biopsies or resections with a diagnosis of “IPT” were identified.

A total of 81 cases were excluded. Five cases (n = 5) were excluded in which the pathology was diagnostic of or highly suspicious for neoplasia including one case of Epstein–Barr virus-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) (n = 1) and four cases (n = 4) suspicious for spindle cell neoplasm (including morphologically low-grade spindle cell neoplasm and atypical spindle cell proliferation). One case of benign biliary cyst (n = 1) was excluded. Additional cases were excluded due to lack of radiologic mass lesion correlate (n = 6) or sampling of a gallbladder mass (n = 1). The remaining cases were excluded due to unavailability of slides (including n = 1 hepatic resection suspicious for IgG4-related disease in which materials were unavailable).

The clinical features of the study cohort (n = 81) are summarized in Table 1. The diagnosis was rendered on core-needle biopsy in the majority of cases (n = 80), with one (n = 1) resection included in the study. The average age was 58.3 years (range 3–86 years), with a male predominance (66%). The masses were often identified incidentally on computed tomography (CT-) or positron emission tomography (PET)-CT (25%, n = 20), with other patients presenting with abdominal pain (24%, n = 19), fever (14%, n = 11), elevated liver enzymes (11%, n = 9), or weight loss (6%, n = 5). Patients with hepatic IPT frequently had an underlying history of malignancy (34%, n = 27), prior abdominal surgery (24%, n = 19), or biliary disease/obstruction (15%, n = 12). Cirrhosis was present in 10% (n = 8).

Of the cases with cirrhosis (n = 8), two patients had a clinical history of hepatitis C virus (HCV), two patients had a history of alcohol-related cirrhosis, and one patient had a history of chronic hepatitis B virus (HBV). In one patient, the underlying aetiology of cirrhosis was unclear, with a clinical history of diabetes type 1 as well as portal vein thrombosis (PVT) and chronic SMV thrombosis. Clinical data were insufficient in the remaining two patients.

The most common oncologic history included pancreaticobiliary neoplasm (8.8% of total cohort, n = 7) followed by lymphoproliferative disorder (7.5% of total cohort, n = 6) and genitourinary malignancy (6.3% of total cohort, n = 5 including three cases with a history of prostatic carcinoma, one case with a history of renal cell carcinoma, and one case with a history of “testicular neoplasm”). Three patients had a history of lung carcinoma (3.8% of total cohort, n = 3) and two patients had a history of colorectal carcinoma (2.5% of total cohort, n = 2) Other past medical history included metastatic adenocarcinoma of unknown primary (n = 1), papillary thyroid carcinoma (n = 1), gastric “low grade myxoid tumour” (n = 1), and epithelioid sarcoma (n = 1).

The underlying cause of biliary obstruction included cholelithiasis (n = 5) and pancreaticobiliary malignancy (n = 6). One patient (n = 1) presented with recurrent pancreatitis and cholangitis after resection for congenital choledochal cyst.

Radiologic findings

The average size was 5.1 cm (range 0.8–12 cm), with multifocal lesions in 36% (n = 29) of cases (Table 2). Of the solitary lesions (n = 51), detailed radiologic reports including lesion location within the liver was available in 31 patients, with most cases seen in the right lobe (77%, n = 24 of 31) and a minority in the left lobe (23%, n = 7 of 31). A subset of cases (14%, n = 11) showed areas of peripheral enhancement/rim enhancement which raised a differential diagnosis of hepatic abscesses versus hepatic metastases. One (n = 1) peripheral lesion and no perihilar masses were identified.

Microbiology studies

Of the total patients, 21 of 80 had documented microbiologic studies performed (including bacterial, mycobacterial, or fungal cultures from tissue biopsy, peripheral blood cultures, and/or tissue polymerase chain reaction, PCR) (Table 3).

A specific organism was identified in 15% of all patients (n = 12) via concurrent or subsequent microbiologic assay. Of the patients with positive microbiologic assay, multifocal lesions were seen in five patients (41.7%). Six (50%) were immunocompromised (postchemotherapy or posttransplant) and two patients (16.7%) had a history of colorectal perforation.

Four of the patients (patients 1, 2, 6, and 9) had radiologic characteristics that were suspicious for infectious aetiologies (areas of rim enhancement and surrounding parenchymal hyperenhancement on postcontrast imaging and/or hypoenhancing lesions).

Blood culture or serum PCR was the most frequently positive assay (n = 6 of 12, 50%) followed by direct culture of the hepatic lesion (n = 5 of 12, 41.7%) and tissue culture/PCR of another site (n = 2 of 12, 16.7%). Patient 4 initially presented with a nonspecific mass at the right lobe and subsequently developed progressive abdominal pain, radiologic findings of fluid collection, and aspiration with culture of the organism. Patient 12 also underwent repeat biopsy due to persistent radiographic targetoid hypodensity, with moderate methicillin-resistant Staphylococcus epidermidis (MRSA) growing both from culture of the liver biopsy as well as blood culture. Patient 3 presented with multiple hepatic lesions and lymphadenopathy, with PCR of a concurrent lymph node biopsy positive for Mycobacterium tuberculosis. Patient 7 presented with multiple hepatic and skin lesions and was diagnosed with disseminated Trichosporon asahii via PCR and culture of a skin lesion. Klebsiella sp. (n = 4 of 12, 33.3%) and Staphylococcus sp. (n = 3 of 12, 25%) were commonly isolated in cases with positive microbiology.

Histologic features

Histology from the liver biopsies were reviewed on all patients, including H&E-stained slides and additional histochemical and immunohistochemical stains performed for clinical diagnosis (see Figure 1; Table 4). Histiocytic (n = 29, 36%) and lymphoplasmacytic inflammatory background (n = 27, 34%) were the most common, followed by neutrophilic in 24% (n = 19) of cases and paucicellular/sclerotic in 6% (n = 5). Many of the cases with histiocytic inflammation showed either sheets of foamy macrophages or numerous histiocytes with admixed lymphocytes, eosinophils, and neutrophils, whereas well-formed granulomas were less commonly seen (n = 14, 18%). Other commonly seen features included hepatic plate atrophy (n = 20, 25%) associated haemorrhage and/or hemosiderin (n = 25, 31%), necrosis (n = 22, 28%), and ductular reaction (n = 10, 13%).

Five (n = 5) cases showed paucicellular/sclerotic histologic features. Histologically, the biopsies demonstrated hypocellular proliferation of bland-spindled cells with sclerotic, hyalinized, and variably edematous stroma without obliterative phlebitis or storiform fibrosis. No overt cytologic atypia or mitotic activity was present in any of these cases. Preserved portal tracts were noted within lesional biopsies, some with entrapped bile ducts within the lesion. Immunohistochemistry for ALK1 was performed in three of five cases with paucicellular/sclerotic stroma to evaluate for IMT and was negative.

One case (n = 1) showed features suggestive of IgG4-related disease including storiform fibrosis and obliterative phlebitis. A histiocytic-predominant background was noted including well-formed granulomas in addition to plasma cells and lymphocytes.

Half of the cases with positive clinical microbiologic studies (6 of 12, 50%) showed histiocytic predominant inflammation, including three cases with bacterial organisms (including one case each with methicillin-susceptible Staphylococcus aureus, Streptococcus anginosus, and Klebsiella pneumonia).

No parasitic organisms were identified in any of the cases. Polarizable foreign-material suggestive of prior stones was seen in one case with a clinical history of prior cholecystectomy and stent placement, and foreign-body giant cell reaction with associated vegetable matter was present in one case with a history of prior colorectal perforation.

Histochemistry, immunohistochemistry, and in situ hybridization

Immunohistochemistry was often performed to exclude other entities with similar morphology (Table 5). Stains performed that were negative include ALK (to exclude IMT, n = 43), pankeratin (to exclude carcinoma, n = 25), HMB-45 (to exclude inflammatory angiomyolipoma, n = 13), CD1a (to exclude interdigitating dendritic cell sarcoma, n = 14), CD34 (to exclude solitary fibrous tumour and peripheral nerve tumours, n = 25), and CD117/DOG1 (to exclude gastrointestinal stromal tumour (n = 18). Stains performed to evaluate for lymphoproliferative disorders (CD3, n = 29; CD20/PAX5, n = 23; CD21/CD23, n = 23; kappa/lambda, n = 23; and CD30, n = 7) showed no evidence of abnormal lymphoid proliferation.

IgG and IgG4 were performed in n = 11 of 26 cases, with an average of 15.6 IgG4-positive cells per high-power field. Material was unavailable to perform immunohistochemistry for IgG or IgG4 on the case (n = 1) with storiform fibrosis and obliterative phlebitis. All cases stained demonstrated an IgG4-to-IgG ratio of less than 40%.

Infectious special stains were commonly performed to exclude infectious aetiologies, including acid-fast bacteria (AFB) stain (n = 48), immunohistochemistry for Treponema pallidium (n = 14) and in situ hybridization for Epstein–Barr virus (n = 20), all of which were negative. Grocott–Gömöri's methenamine silver stain (GMS) was performed in 36 cases; 35 of these cases were negative, and one case displayed rare budding yeast.

Follow-up clinical data and outcome

Detailed clinical information with follow-up data was available in 36 patients (45%) (Figure 2, Table 6). Repeat biopsies were performed on 12 patients (15%), with follow-up radiologic imaging in 29 patients (36%). The details of follow-up data are summarized in Figure 2.

Of the patients with clinical follow-up (n = 36), most patients were clinically determined to be either infectious or reactive in aetiology (83%, n = 30), based on radiologic resolution (69%, n = 25 of 36) and/or repeat negative biopsies (19%, 7 of 36). Antimicrobial therapy was documented prior to resolution of the lesion in 17% (5 of 29) of patients with presumed reactive lesions, and was given either empirically or in response to positive microbiologic testing (Table 3).

A minority of patients (n = 6 of 80 total cohort, 8%) were subsequently clinically or pathologically diagnosed with neoplastic hepatic lesions. Of the six cases initially diagnosed with IPT or IPT-like lesion in the lesion, this represented hepatic involvement by the patient's known underlying malignancy in 66.7% (four of six patients).

Three cases had follow-up biopsies with malignancy. Two patients (n = 2) had repeat biopsies demonstrating lymphoproliferative disorder, including one repeat liver biopsy demonstrating prominent lymphoid aggregates with positive B-cell clonality for a new diagnosis of malignancy. A second case with repeat liver biopsy demonstrated involvement of the patient's known peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). A third patient (n = 1) showed radiologic progression with a repeat fine-needle aspiration of the liver demonstrating metastatic adenocarcinoma of the patient's known pancreatic primary.

The remaining three patients (n = 3) were categorized as likely neoplastic based on radiologic progression and clinical management. Two patients with a history of abdominal sarcoma (n = 1 with epithelioid sarcoma and n = 1 with type not specified) showed radiologic progression of the hepatic lesion(s), and were clinically managed with additional systemic chemotherapy without repeat biopsy. One patient with a history of HCV and cirrhosis was diagnosed as multifocal hepatocellular carcinoma based on radiologic findings.

The clinical, radiologic and histologic features of likely reactive/infectious cases (n = 29) and likely neoplastic cases (n = 6) are summarized in Table 6. Tumour size and focality were similar, as well as histologic features. The positive microbiologic cultures were exclusively seen in reactive/infectious lesions.