Immunohistochemical detection of PAX-FOXO1 fusion proteins in alveolar rhabdomyosarcoma using breakpoint specific monoclonal antibodies.

Alveolar Rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer with about 80% of cases characterized by either a t(1;13)(p36;q14) or t(2;13)(q35;q14), which results in the formation of the fusion oncogenes PAX7-FOXO1 and PAX3-FOXO1, respectively. Since patients with fusion-positive ARMS (FP-RMS) have a poor prognosis and are treated with an aggressive therapeutic regimen, correct classification is of clinical importance. Detection of the translocation by different molecular methods is used for diagnostics, including fluorescence in situ hybridization and RT-PCR or NGS based approaches. Since these methods are complex and time consuming, we developed specific monoclonal antibodies (mAbs) directed to the junction region on the PAX3-FOXO1 fusion protein. Two mAbs, PFM.1 and PFM.2, were developed and able to immunoprecipitate in vitro-translated PAX3-FOXO1 and cellular PAX3-FOXO1 from FP-RMS cells. Furthermore, the mAbs recognized a 105 kDa band in PAX3-FOXO1-transfected cells and in FP-RMS cell lines. The mAbs did not recognize proteins in fusion-negative embryonal rhabdomyosarcoma cell lines, nor did they recognize PAX3 or FOXO1 alone when compared to anti-PAX3 and anti-FOXO1 antibodies. We next evaluated the ability of mAb PFM.2 to detect the fusion protein by immunohistochemistry. Both PAX3-FOXO1 and PAX7-FOXO1 were detected in HEK293 cells transfected with the corresponding cDNAs. Subsequently, we stained 26 primary tumor sections and a rhabdomyosarcoma tissue array and detected both fusion proteins with a positive predictive value of 100%, negative predictive value of 98%, specificity of 100% and a sensitivity of 91%. While tumors are stained homogenously in PAX3-FOXO1 cases, the staining pattern is heterogenous with scattered positive cells only in tumors expressing PAX7-FOXO1. No staining was observed in stromal cells, embryonal rhabdomyosarcoma, and fusion-negative rhabdomyosarcoma. These results demonstrate that mAbs specific for the chimeric oncoproteins PAX3-FOXO1 and PAX7-FOXO1 can be used efficiently for simple and fast subclassification of rhabdomyosarcoma in routine diagnostics via immunohistochemical detection.

YAP1-TFE3-fused hemangioendothelioma: a multi-institutional clinicopathologic study of 24 genetically-confirmed cases.

YAP1-TFE3-fused hemangioendothelioma is an extremely rare malignant vascular tumor. We present the largest multi-institutional clinicopathologic study of YAP1-TFE3-fused hemangioendothelioma to date. The 24 cases of YAP1-TFE3-fused hemangioendothelioma showed a female predominance (17 female, 7 male) across a wide age range (20-78 years old, median 44). Tumors were most commonly located in soft tissue (50%), followed by bone (29%), lung (13%), and liver (8%), ranging from 3 to 115 mm in size (median 40 mm). About two-thirds presented with multifocal disease, including 7 cases with distant organ metastasis. Histopathologically, we describe three dominant architectural patterns: solid sheets of coalescing nests, pseudoalveolar and (pseudo)vasoformative pattern, and discohesive strands and clusters of cells set in a myxoid to myxohyaline stroma. These patterns were present in variable proportions across different tumors and often coexisted within the same tumor. The dominant cytomorphology (88%) was large epithelioid cells with abundant, glassy eosinophilic to vacuolated cytoplasm, prominent nucleoli and well-demarcated cell borders. Multinucleated or binucleated cells, prominent admixed erythrocytic and lymphocytic infiltrates, and intratumoral fat were frequently present. Immunohistochemically, ERG, CD31, and TFE3 were consistently expressed, while expression of CD34 (83%) and cytokeratin AE1/AE3 (20%) was variable. CAMTA1 was negative in all but one case. All cases were confirmed by molecular testing to harbor YAP1-TFE3 gene fusions: majority with YAP1 exon 1 fused to TFE3 exon 4 (88%), or less commonly, TFE3 exon 6 (12%). Most patients (88%) were treated with primary surgical resection. Over a follow-up period of 4-360 months (median 36 months) in 17 cases, 35% of patients remained alive without disease, and 47% survived many years with stable, albeit multifocal and/or metastatic disease. Five-year progression-free survival probability was 88%. We propose categorizing YAP1-TFE3-fused hemangioendothelioma as a distinct disease entity given its unique clinical and histopathologic characteristics in comparison to conventional epithelioid hemangioendothelioma.

RANK ligand blockade with denosumab in combination with sorafenib in chemorefractory osteosarcoma: a possible step forward?

BACKGROUND: There is no established systemic treatment option for unresectable osteosarcoma progressing after standard chemotherapy. A recently published clinical trial has demonstrated some activity of sorafenib in this situation. Preclinical research suggests a role for the inhibition of the receptor activator of nuclear factor-ĸB ligand (RANKL), but no clinical data have been reported so far. CASE REPORT: A 37-year-old man was diagnosed with unresectable osteoblastic, osteoblastoma-like osteosarcoma in the C7/Th1 vertebra. The tumour progressed locally despite two lines of chemotherapy and stereotactic radiotherapy. On treatment with sorafenib and denosumab, a complete metabolic remission was achieved and is ongoing for over 18 months. Immunohistochemistry revealed an overexpression of RANK and RANKL in the patient's primary tumour. DISCUSSION: This is the first report of activity achieved by the combination of the tyrosine kinase inhibitor sorafenib and the RANKL inhibitor denosumab in a patient with osteosarcoma. It confirms preclinical data on RANK/RANKL inhibition in osteosarcoma and could serve as a hypothesis-generating approach for clinical trials in this patient population.

Response of an aggressive periosteal aneurysmal bone cyst (ABC) of the radius to denosumab therapy.

Aneurysmal bone cyst (ABC), once considered a reactive lesion, has been proven to be a neoplasia characterized by rearrangements of the USP6-gene. Aggressive local growth and recurrences are common and therapeutic options may be limited due to the vicinity of crucial structures. We describe a case of a locally aggressive, multinucleated giant cell-containing lesion of the forearm of a 21-year old woman, treated with denosumab for recurrent, surgically uncontrollable disease. Under the influence of this RANKL inhibitor, the tumor showed a marked reduction of the content of the osteoclastic giant cells and an extensive metaplastic osteoid production leading to the bony containment, mostly located intracortically in the proximal radius. The diagnosis of a periosteal ABC was confirmed by FISH demonstrating USP6 gene rearrangement on the initial biopsy. Function conserving surgery could be performed, enabling reconstruction of the affected bone. Inhibition of RANKL with denosumab may offer therapeutic option for patients not only with giant cell tumors but also with ABCs.

Xanthogranulomatous epithelial tumor: a novel entity of uncertain biologic potential.

Xanthogranulomatous epithelial tumor (XGET) is an extremely rare and recently described mesenchymal neoplasm characterized by a distinctive histological appearance and clinical presentation. This case report describes a unique case of XGET in a 66-year-old female patient who presented with a 5 cm mass in the dorsal distal left thigh. The clinical, radiological, and pathological findings, as well as the management and follow-up, are discussed.

The Sarcoma-Specific Instrument to Longitudinally Assess Health-Related Outcomes of the Routine Care Cycle.

Patient-based health related quality of life (HRQoL) measurements are associated with an improvement in quality of care and outcomes. For a complex disease such as sarcoma, there is no disease-specific questionnaire available which covers all clinically relevant dimensions. Herein, we report on the development of an electronically implemented, sarcoma-specific instrument to assess health-related outcomes, which encompasses a combination of generic questionnaires tailored to the respective disease and treatment status covering the entire longitudinal care cycle. An interoperable digital platform was designed to provide a node between patients and physicians and to integrate the sarcoma-specific HRQoL instrument with patient and physician-based quality indicators to allow longitudinal structured real-world-time data evidence analytics. This approach enables the prediction modeling of disease, and by attributing cost tags to quality indicators, treatment effectiveness for a given disease will be directly correlated with financial expenses, which may ultimately lead to a more sustainable healthcare system.

Determining HER2 Status by Artificial Intelligence: An Investigation of Primary, Metastatic, and HER2 Low Breast Tumors.

The expression of human epidermal growth factor receptor 2 (HER2) protein or gene transcripts is critical for therapeutic decision making in breast cancer. We examined the performance of a digitalized and artificial intelligence (AI)-assisted workflow for HER2 status determination in accordance with the American Society of Clinical Oncology (ASCO)/College of Pathologists (CAP) guidelines. Our preliminary cohort consisted of 495 primary breast carcinomas, and our study cohort included 67 primary breast carcinomas and 30 metastatic deposits, which were evaluated for HER2 status by immunohistochemistry (IHC) and in situ hybridization (ISH). Three practicing breast pathologists independently assessed and scored slides, building the ground truth. Following a washout period, pathologists were provided with the results of the AI digital image analysis (DIA) and asked to reassess the slides. Both rounds of assessment from the pathologists were compared to the AI results and ground truth for each slide. We observed an overall HER2 positivity rate of 15% in our study cohort. Moderate agreement (Cohen's κ 0.59) was observed between the ground truth and AI on IHC, with most discrepancies occurring between 0 and 1+ scores. Inter-observer agreement amongst pathologists was substantial (Fleiss´ κ 0.77) and pathologists' agreement with AI scores was 80.6%. Substantial agreement of the AI with the ground truth (Cohen´s κ 0.80) was detected on ISH-stained slides, and the accuracy of AI was similar for the primary and metastatic tumors. We demonstrated the feasibility of a combined HER2 IHC and ISH AI workflow, with a Cohen's κ of 0.94 when assessed in accordance with the ASCO/CAP recommendations.

Biopsy Ratio of Suspected to Confirmed Sarcoma Diagnosis.

The ratio of malignancy in suspicious soft tissue and bone neoplasms (RMST) has not been often addressed in the literature. However, this value is important to understand whether biopsies are performed too often, or not often enough, and may therefore serve as a quality indicator of work-up for a multidisciplinary team (MDT). A prerequisite for the RMST of an MDT is the assessment of absolute real-world data to avoid bias and to allow comparison among other MDTs. Analyzing 950 consecutive biopsies for sarcoma-suspected lesions over a 3.2-year period, 55% sarcomas were confirmed; 28% turned out to be benign mesenchymal tumors, and 17% non-mesenchymal tumors, respectively. Of these, 3.5% were metastases from other solid malignancies, 1.5% hematologic tumors and 13% sarcoma simulators, which most often were degenerative or inflammatory processes. The RMST for biopsied lipomatous lesions was 39%. The ratio of unplanned resections was 10% in this series. Reorganizing sarcoma work-up into integrating practice units (IPU) allows the assessment of real-world data with absolute values over the geography, thereby enabling the definition of quality indicators and addressing cost efficiency aspects of sarcoma care.

Metastatic mesenchymal chondrosarcoma showing a sustained response to cabozantinib: A case report.

Mesenchymal chondrosarcoma is a rare and aggressive sarcoma subtype with high risk for distant metastases and poor prognosis. Currently NCCN- and ESMO-Guidelines recommend using Ewing sarcoma protocols as standard treatment. Nevertheless, in localized disease overall 5-year survival rates are below 50% whereas in metastatic spread median progression-free survival rates of only 5 months can be expected. Here we present a patient with metastatic osseous spread of mesenchymal chondrosarcoma that showed a sustained clinical improvement and a good partial response on imaging over a period of one year when treated with the multi-tyrosine kinase inhibitor cabozantinib. Although we cannot explain the exact mechanism underlying this treatment effect, tumors with similar genetic patterns might respond to the same therapy as well.

Quality of Sarcoma Care: Longitudinal Real-Time Assessment and Evidence Analytics of Quality Indicators.

Sarcomas represent a large group of rare to very rare diseases, requiring complex management with a transdisciplinary approach. Overall progress has been hampered because of discipline, institution and network fragmentation, and there is no global data harmonization or quality standards. To report on and improve quality, a common definition of quality indicators (QIs) of sarcoma care as well as the capacity to assess longitudinal real-time data is required. An international advisory board of world-renowned sarcoma experts defined six categories of QIs, totaling more than 80 quality indicators. An interoperable (web-based) digital platform was then created combining the management of the weekly sarcoma board meeting with the sarcoma registry and incorporating patient-reported outcome measures (PROMs) into the routine follow-up care to assess the entire care cycle of the patient. The QIs were then programmed into the digital platform for real-time analysis and visualization. The definition of standardized QIs covering all physician- (diagnostics and therapeutics), patient- (PROMS/PREMS), and cost-based aspects in combination with their real-time assessment over the entire sarcoma care cycle can be realized. Standardized QIs as well as their real-time assessment and data visualization are critical to improving the quality of sarcoma care. By enabling predictive modelling and introducing VBHC, precision health care for a complex disease is on the horizon.

Is dynamic gadolinium enhancement needed in MR imaging for the preoperative assessment of scaphoidal viability in patients with scaphoid nonunion?

PURPOSE: To compare the accuracy of dynamic gadolinium-enhanced magnetic resonance (MR) imaging with that of standard MR imaging for assessing the viability of the proximal pole of the scaphoid in patients with nonunion. MATERIALS AND METHODS: The study protocol was submitted to the institutional review board, and the need to obtain additional approval was waived for this retrospective study. Twenty-eight patients (mean age ± standard deviation, 24.3 years ± 6.4) with nonunion of a scaphoid fracture underwent dynamic gadolinium-enhanced MR imaging of the wrist 28 days ± 19 before surgery. Dynamic gadolinium-enhanced MR imaging consisted of acquisition of 40 consecutive coronal T1-weighted images over 1 minute. Two readers retrospectively evaluated MR images obtained with a standard protocol and rated the viability of the proximal scaphoid pole. The steepest upslope of gadolinium uptake was calculated in a region of interest placed in the proximal scaphoid pole by a third reader. Receiver operating characteristic curves were calculated, and the areas under the receiver operating characteristic curve (A(z) values) were compared. Diagnostic performance in determining scaphoid viability was calculated for readers 1 and 2. Histologic findings in 11 patients and surgical findings in all patients served as the standard of reference. RESULTS: The sensitivity, specificity, and accuracy of standard MR imaging in the detection of scaphoid necrosis were 54%, 93%, and 75%, respectively, for reader 1 and 62%, 93%, and 78% for reader 2. Interreader reliability was excellent (κ = 0.92). The A(z) was 0.82 for reader 1 and 0.87 for reader 2. The diagnostic performance of dynamic gadolinium-enhanced MR imaging, determined with the steepest upslope value, was inferior to that of standard MR imaging, with an A(z) of 0.57. Findings at histologic examination (viable bone, necrotic bone, callus formation) did not correlate with those at dynamic gadolinium-enhanced MR imaging. CONCLUSION: Because the diagnostic performance of dynamic gadolinium-enhanced MR imaging in the evaluation of scaphoid viability was inferior to that of a standard MR imaging protocol, dynamic acquisition may not be needed in patients with nonunion of scaphoid fractures.

Optimized workflow for digitalized FISH analysis in pathology.

BACKGROUND: Effective workflow management in a diagnostic pathology laboratory is critical to achieve rapid turnover while maintaining high quality. Fluorescence in situ hybridization analysis (FISH) is the preferred technique for detecting single chromosomal aberrations in diagnostic surgical pathology. MATERIAL AND METHODS: FISH analysis applying a rapid hybridization protocol and using an automated whole-slide fluorescence scanning device (3DHISTECH, Sysmex, Switzerland) were implemented in our workflow. By analyzing 42 diagnostic cases, effects of two different scanning profiles on scanning time, and device memory usage were investigated. Manual signal counting (CaseViewer) and software based signal counting (FISHQuant) were compared. RESULTS: The two scanning profiles, both including a Z-stack function, differed in their exposure time and digital gain. The "low profile" setting (LP) resulted in a significantly shorter scanning time and lower storage volume compared to the "high profile" (HP) setting, making the LP ideal for routine applications. Both signal counting methods (manual versus software based) provided similar cut-offs on a test-cohort of 13 samples. CONCLUSION: Scanning FISH slides provides good picture quality, reduces the analysis time and allows easy picture archiving and facilitates remote diagnostics, allowing an effective workflow.

Development of a value-based healthcare delivery model for sarcoma patients.

The urgent need to restructure healthcare delivery to address rising costs has been recognised. Value-based health care aims to deliver high and rising value for the patient by addressing unmet needs and controlling costs. Sarcoma is a rare disease and its care is therefore usually not organised as an institutional discipline. It comprises a set of various diagnostic entities and is highly transdisciplinary. A bottom-up approach to establishing sarcoma integrated practice units (IPUs) faces many challenges, but ultimately allows the scaling up of quality and outcomes of patient care, specific knowledge, experience and education. The key for value-based health care - besides defining the shared value of quality - is an integrated information technology platform that allows transparency by sharing values, brings all stakeholders together in real-time, and offers the opportunity to assess quality of care and outcomes, thereby ultimately saving costs. Sarcoma as a rare disease may serve as a model of how to establish IPUs through a supraregional network by increased connectivity, to advance patient care, to improve science and education, and to control costs in the future, thereby restructuring healthcare delivery. This article describes how the value-based health care delivery principles are being adopted and fine-tuned to the care of sarcoma patients, and already partially integrated in seven major referral hospitals in Switzerland.

Radiological and histological findings in ancient salt mummies from the salt mine of Douzlakh, Iran.

Computed tomography studies and histological analyses were performed on the mummified remains found in the Chehrabad salt mine in northwestern Iran. The ancient salt mummies are dated to the Achaemenid (550-330 BC) and Sassanid (3rd-7th century AD) time period and died in mining incidents. The aim of the study was to describe the radiological and histological findings of several ancient Iranian salt mummies with special interest in pathological and postmortem changes. The mummified remains show multiple traumatic alterations, such as fractures and signs of massive compression. Histological analyses can clearly differentiate soft tissue, however the preservation status is variable. These Iranian salt mummies are a rare example of the ancient Iranian population. The soft tissue and organs are well preserved, however in different degrees due to the varying conditions.

Morton neuroma: MR imaging after resection--postoperative MR and histologic findings in asymptomatic and symptomatic intermetatarsal spaces.

PURPOSE: To evaluate the prevalence of postoperative magnetic resonance (MR) imaging findings in asymptomatic and symptomatic patients after resection of Morton neuroma. MATERIALS AND METHODS: This study was approved by the institutional review board. Informed consent was obtained from each participant. Fifty-eight consecutive patients (46 women, 12 men) who had undergone resection of a painful Morton neuroma (90 Morton neuromas were removed in 66 feet), pre- and postoperative MR imaging, and clinical follow-up for a minimum of 2 years after surgery were identified. Two experienced musculoskeletal radiologists evaluated MR images with regard to the presence of presumed recurrent Morton neuroma, scar, or intermetatarsal bursitis. The prevalence of abnormalities in asymptomatic and symptomatic intermetatarsal spaces was determined. The results of the second radiologist were used only to determine interobserver reliability. The kappa statistics were obtained to assess interobserver agreement. Seven patients with presumed recurrent Morton neuroma underwent repeat surgery. RESULTS: Clinically speaking, 68 intermetatarsal spaces (44 of 58 patients [76%], 47 feet) were asymptomatic at follow-up and 22 (14 of 58 patients [24%], 19 feet) were symptomatic. A presumed Morton neuroma was found in 18 (26%) of the asymptomatic spaces and 11 (50%) of the symptomatic spaces. A presumed scar was found in six (9%) of the asymptomatic spaces and two (9%) of the symptomatic spaces. A presumed intermetatarsal bursitis was found in six (9%) of the asymptomatic spaces and six (27%) of the symptomatic spaces. Interobserver agreement for presumed recurrent Morton neuroma was substantial (kappa = 0.64). Histologic examination of presumed recurrent Morton neuroma revealed fibrous tissue but no sign of peripheral neural tissue. CONCLUSION: MR imaging after Morton neuroma resection commonly reveals Morton neuroma-like abnormalities in asymptomatic and symptomatic intermetatarsal spaces.

New Insights into Tumor Heterogeneity: A Case of Solid-Oncocytic Epithelial-Myoepithelial Carcinoma of the Parotid Gland Harboring a HRAS and Heterogeneous Terminating ARID1A Mutation.

Epithelial-myoepithelial carcinoma (EMC) can be a challenging diagnosis due to a lack of obvious invasion and bland cytology. We report an unusual case of a low-grade EMC with prominent fibrous stroma, an extensive solid-oncocytic differentiation and limited areas of morphological clearly identifiable characteristic biphasic (tubular) differentiation, clear cells and PAS-positive secretions/calcifications. Both areas were investigated by next generation sequencing (Oncomine comprehensive assay) and revealed a typical concordant HRAS p.Q61R mutation. An additional heterogeneous ARID1A (p.E672*) terminating mutation with loss of heterozygosity, which could be visualized predominantly in the solid-oncocytic differentiation by immunohistochemical loss of ARID1A protein expression, was found. This is the first case of an EMC of the salivary gland to be described with two separate tumor clones involving concordant HRAS and heterogeneous ARID1A mutations. The latter seem to be a "second hit" and was predominantly found in the solid-oncocytic differentiation, suggesting a potential morpho-molecular association.

Incidence, mortality, and survival trends of soft tissue and bone sarcoma in Switzerland between 1996 and 2015.

BACKGROUND: Research on soft-tissue sarcoma (STS) and bone sarcoma (BS) is increasingly in the focus of physicians and pharmaceutical companies. Expanding knowledge has improved the management of sarcoma and possibly survival. Here we provide the first population-based data on time trends of incidence, mortality, and survival of STS and BS diagnosed in Switzerland between 1996 and 2015. METHODS: We performed a retrospective registry study with data from the National Institute for Cancer Epidemiology and Registration (NICER) database in Switzerland between 1996 and 2015. RESULTS: We identified 5384 STS patients and 940 BS patients. The three most common STS subtypes were undifferentiated/unclassified sarcoma (22.3%), liposarcoma (20.6%) and leiomyosarcoma (20.6%). Chondrosarcoma, osteosarcoma and Ewing sarcoma represented 40.4%, 27.0% and 15.2% of the BS group, respectively. The age-standardized incidence and mortality rates in 2011-2015 were 4.43 and 1.42 per 100,000 person-years for STS, and 0.91 and 0.42 for BS. Age-standardized incidence of STS in males was significantly higher during 1996-2000 than during 2001-2015; however, mortality rates did not change significantly over time. Five-year relative survival (RS) for STS improved significantly from 56.4% (95%CI 52.9-59.7 for 1996-2001) to 61.6% (95%CI 58.6-64.4 for 2011-2015) (p = 0.025). No improvement in 5-year RS for BS could be observed (RS 1996-2000: 69.6%, 95%CI 61.2-76.6; RS 2011-2015: 73.1%, 95%CI 66.6-78.6; p = 0.479). CONCLUSION: Incidence rates of STS and BS have been stable since 2001. The longer RS in STS can be attributed to advances in sarcoma patient management.

Targeted therapeutic approach for an anaplastic thyroid cancer in vitro and in vivo.

Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies, being responsible for the majority of thyroid cancer-related deaths. Despite multimodal therapy including surgery, chemotherapy, and radiotherapy, the outcome of ATC is poor. The human ATC cell line MB1, derived from tumor tissue of a 57-year-old man with thyroid cancer and pronounced neutrophilia, was established from surgically excised tumor tissue. The karyotype of the cell line shows many chromosomal abnormalities. Preclinical investigations have shown antitumor activity and effectiveness of the BRAF kinase inhibitor Sorafenib and the proteasome inhibitor Bortezomib. After establishment of the MB1 cell line these agents were applied in vitro and, showing activity in a cell culture model, were also used for in vivo treatment. Sorafenib had some clinical effect, namely normalization of leucocytosis, but had no sustained impact on subsequent tumor growth and development of distant metastasis. Molecular diagnostics of the tumor demonstrated no BRAF mutations in exons 11 and 15 concordant with a rather modest effect of Sorafenib on MB1 cell growth. Clinical benefit was seen with subsequent bortezomib therapy inducing a temporary halt to lymph node growth and a progression-free interval of 7 weeks. Our observations together with previous data from preclinical models could serve as a rationale for selecting those patients suffering from ATC most likely to benefit from targeted therapy. A prospective controlled randomized trial integrating kinase and proteasome inhibitors into a therapeutic regime for ATC is warranted.

Fibrosis and adventitious bursae in plantar fat pad of forefoot: MR imaging findings in asymptomatic volunteers and MR imaging-histologic comparison.

PURPOSE: To retrospectively evaluate plantar fat pad (PFP) signal intensity alterations in magnetic resonance (MR) imaging studies of asymptomatic volunteers and to compare PFP alterations with histopathologic findings in cadavers and patients. MATERIALS AND METHODS: After appropriate institutional review board approval and any required informed consent were obtained, MR imaging studies of 70 asymptomatic volunteers (35 women, 35 men; mean age, 45 years; range, 21-69 years) obtained for another investigation were retrospectively analyzed by two musculoskeletal radiologists in consensus. The location, signal intensity, margin, extent, and size of PFP alterations were determined. MR imaging-histopathologic comparison was performed in six cadaveric feet and six feet of symptomatic patients (one woman, five men; mean age, 43 years; range, 31-60 years). For volunteers, the relationship between PFP alterations and Morton neuroma, age, and sex was analyzed by using the Fisher exact test, Spearman rank correlation, and the Wilcoxon rank sum test, respectively. Bonferroni correction was applied, and P < .01 was considered to indicate a significant difference. RESULTS: Fifty-nine (84%) volunteers had PFP signal intensity alterations. Forty-nine (70%), six (9%), one (1%), four (6%), and 43 (61%) volunteers had alterations beneath the first, second, third, fourth, and fifth metatarsal heads, respectively. Ninety-four (91%) of 103 signal intensity alterations were in the form of hypointensity on T2-weighted images. Blurred margins were present in 90 (87%) alterations. Ninety percent of all PFP alterations in asymptomatic volunteers were 14 mm or smaller. The relationship between PFP alterations and Morton neuroma, age, and sex was not statistically significant. In cadaveric forefeet, PFP alterations corresponded histopathologically to a variable amount of fibrosis. In nine PFP alterations, development of fluid-containing spaces resembling bursae was present. Among the six patients with PFP alterations, histopathologic examination revealed fibrosis and adventitious bursae in two, fibrosis with inflammation in three, and a soft-tissue chondroma in one. CONCLUSION: PFP signal intensity alterations are commonly seen in asymptomatic volunteers under the first and fifth metatarsal heads. At histologic examination, PFP signal intensity alterations correspond most commonly to fibrosis and adventitious bursae.