Faculty Bibliography

BackgroundCollision tumors, composed of 2 histologically distinct neoplasms at the same site, are rare. They encompass a variety of subtypes, where either lesion may be benign or malignant and where they may "collide" by direct invasion or metastasis. Carcinoma-sarcoma collisions are especially uncommon, and so-called tumor-to-tumor metastasis is even rarer. Tumor-to-tumor metastasis involving lung adenocarcinoma has only been reported within benign mesenchymal tumors; no such report to date has described metastasis into a malignant soft tissue sarcoma.Patient PresentationA 90-year-old man presented with a rapidly growing soft tissue mass on the anterolateral aspect of the right knee. Biopsy revealed high-grade leiomyosarcoma. Imaging also identified a dominant pulmonary nodule. The soft tissue mass was resected, revealing not only leiomyosarcoma but also a distinct glandular proliferation. Subsequent lung biopsy confirmed adenocarcinoma. Immunohistochemistry demonstrated that the glandular component within the sarcoma shared an identical profile with the lung tumor, consistent with metastatic lung adenocarcinoma into the primary sarcoma.DiscussionThis is the first reported example of lung adenocarcinoma metastasizing into a malignant soft-tissue tumor, representing a rare tumor-to-tumor metastasis resulting in a carcinoma-sarcoma collision tumor. A review of the literature identified 12 comparable reports, none involving both a malignant donor and a malignant mesenchymal recipient. This report underscores the importance of distinguishing such lesions from carcinosarcoma using histology and immunophenotyping.ConclusionThis unique example of carcinoma-to-sarcoma metastasis expands the differential diagnosis of biphasic soft-tissue tumors. Accurate classification is critical for guiding treatment, which may require tailored oncologic strategies addressing both tumor types.

Schwannomas are benign encapsulated nerve sheath tumors that are rarely found in the lower extremity. We report a unique case of a 65-year-old woman presenting with chronic lateral ankle instability and a palpable mass posterior to the lateral malleolus. Magnetic resonance imaging revealed an 11 by 6 by 10 mm lesion contiguous with the sural nerve. The mass was excised via meticulous enucleation with nerve preservation. Histopathology confirmed a cellular schwannoma. The patient underwent concurrent ankle arthroscopy and lateral ligament repair, thereby achieving complete resolution of symptoms and return to function at 6 months. This is the first reported case of a sural nerve schwannoma associated with chronic lateral ankle instability.

Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy. Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors. See related commentary by Trembath and Spanheimer, p. 407.

Liposarcoma is a malignant soft tissue tumor with several subtypes, the most common of which is well-differentiated liposarcoma (WDL) or atypical lipomatous tumor (ALT). WDL/ALTs are further divided into three histological subtypes, including lipoma-like, sclerosing, and inflammatory. While the majority of these tumors are predominantly fatty, the sclerosing variant demonstrates diverse histologic and radiographic characteristics, including variable amounts of fibrosis and fat. Because of this histological variability and relative rarity, the sclerosing WDL/ALT can present diagnostic dilemmas. We present two cases of sclerosing WDL/ALT, both of which demonstrated high degrees of fibrosis and a paucity of fat, mimicking desmoid fibromatosis and other fibrotic soft tissue tumors. Thus, it is important for radiologists to be aware of the subtypes of liposarcoma and their unique characteristics, and to consider sclerosing WDL/ALT in cases of fibrotic soft tissue tumors.

Gene fusions involving JAZF1 are a recurrent event in low grade endometrial stromal sarcoma, and have been more recently described in few instances of endometrial stromal sarcoma-like tumors in the genitourinary tract of men. In this article, we describe a previously unreported spindle cell sarcoma harboring an in-frame JAZF1::NUDT5 gene fusion, arising in the chest wall of a 51-year-old man. The tumor had unique morphologic features resembling both endometrial stromal sarcoma and endometrial stromal sarcoma-like tumors, consisting of a mixture of cytologically bland and pleomorphic spindle cells with brisk mitotic activity, within an alternating myxoid and fibrous stroma. It had diffuse immunohistochemical expression of CD10, CD34 and CD56, and variable expression of androgen receptor. To our knowledge, neoplasms with these clinico-pathologic characteristics and novel gene fusion have not been previously reported in the English language literature.

OBJECTIVE:To describe the morphologic sonographic appearances and frequency of the "halo sign" in the setting of fat necrosis on shear wave elastography (SWE). METHODS:Patients with clinically suspected fat necrosis were prospectively scanned using SWE in addition to standard gray-scale and Doppler images. Cases were qualitatively grouped into one of three sonographic appearances: focal hypoechoic lesion with increased internal tissue stiffness ("focal stiffness"), focal hypoechoic lesion with isoechoic or hyperechoic periphery demonstrating increased tissue stiffness relative to the central hypoechoic lesion ("halo stiffness"), heterogeneously echogenic lesion with diffusely increased stiffness ("heterogeneous stiffness"). RESULTS:Exactly 19 patients met inclusion criteria (female n = 14; male n = 5). Shear wave velocities were recorded and retrospectively evaluated. The mean clinical follow-up was 11.4 months (range 3.0-25.5). Lesions demonstrated higher average tissue stiffness than background tissue (overall mass shear wave velocity 3.26 m/s, background 1.42 m/s, P < .001; lesion Young's modulus 40.85 kPa vs background 7.22 kPa, P < .001). The halo sign was identified in 10/19 (55%) patients. CONCLUSION/CONCLUSIONS:The halo sign is a potentially useful sign in the setting of fat necrosis seen in the majority of clinically suspected cases.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased γ-H2AX protein expression. Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment.

In medical education, pathology has traditionally been concentrated in only the preclinical years, often without sufficient emphasis on its practical application in clinical practice. Correspondingly, medical students' interest in pathology as a career has been low. To address this issue and foster a deeper understanding of pathology's clinical relevance and encourage appropriate utilization, we introduced a required exposure to pathology in the surgery clerkship featuring clinicopathological case review in a small group setting. Unlike other approaches, we wanted to create a program that concentrates on pathology cases directly linked to patients whom students cared for during their clerkship rotation, emphasizing the relevance of pathology diagnosis. Feedback has been overwhelmingly positive from participating students, who report an increased awareness of pathology's importance in patient management and of the significance of interdisciplinary collaboration between pathologists and clinicians. A notable feature of this program is its relatively low time and personnel requirements, which facilitate inclusion in the busy clerkship and acceptance in the Department of Pathology. Challenges, such as timely case selection and administrative co-ordination, are being addressed to optimize the program's implementation. In the future, we are considering expanding this model to other clerkships. By rekindling interest in pathology through practical engagement and highlighting its real-world relevance, this approach offers a promising strategy to counteract recruitment challenges in this crucial medical field.

PURPOSE OF REVIEW/OBJECTIVE:The pathogenesis of dedifferentiated chondrosarcoma is controversial, and no genetic abnormality has consistently been identified in the disease. Focusing on the diagnostic challenges encountered in dedifferentiated chondrosarcoma, the following review aims at summarizing the tumor's active neoplastic pathways while highlighting therapeutic modalities that could potentially be explored to enhance patient survivorship. RECENT FINDINGS/RESULTS:Owing to the challenging examination of small needle biopsy sampling as well as the disease's overlapping morphological and immunohistochemical features with other bone and soft-tissue sarcomas, the diagnosis of dedifferentiated chondrosarcoma can be problematic. While combined doxorubicin- and cisplatin-based regimens remain the first-line systemic chemotherapy in the disease, ~50% of tumors carry EXT1/2 or IDH1/2 mutations, advancing EXT or IDH inhibitors as potential alternative therapies, respectively. Despite systemic chemotherapy, dedifferentiated chondrosarcoma remains an aggressive tumor with dismal prognosis and limited survival. A multidisciplinary collaboration across multiple cancer centers is warranted to yield an accurate diagnosis, understand the disease's underlying pathogenesis, develop adequate treatment, and improve patient survivorship.

Ca2+ signals regulate the function of many immune cells and promote immune responses to infection, cancer, and autoantigens. Ca2+ influx in immune cells is mediated by store-operated Ca2+ entry (SOCE) that results from the opening of Ca2+ release-activated Ca2+ (CRAC) channels. The CRAC channel is formed by three plasma membrane proteins, ORAI1, ORAI2, and ORAI3. Of these, ORAI1 is the best studied and plays important roles in immune function. By contrast, the physiological role of ORAI3 in immune cells remains elusive. We show here that ORAI3 is expressed in many immune cells including macrophages, B cells, and T cells. To investigate ORAI3 function in immune cells, we generated Orai3-/- mice. The development of lymphoid and myeloid cells in the thymus and bone marrow was normal in Orai3-/- mice, as was the composition of immune cells in secondary lymphoid organs. Deletion of Orai3 did not affect SOCE in B cells and T cells but moderately enhanced SOCE in macrophages. Orai3-deficient macrophages, B cells, and T cells had normal effector functions in vitro. Immune responses in vivo, including humoral immunity (T cell dependent or independent) and antitumor immunity, were normal in Orai3-/- mice. Moreover, Orai3-/- mice showed no differences in susceptibility to septic shock, experimental autoimmune encephalomyelitis, or collagen-induced arthritis. We conclude that despite its expression in myeloid and lymphoid cells, ORAI3 appears to be dispensable or redundant for physiological and pathological immune responses mediated by these cells.