Tumor-associated fibroblasts predominantly come from local and not circulating precursors.

Fibroblasts are common cell types in cancer stroma and lay down collagen required for survival and growth of cancer cells. Although some cancer therapy strategies target tumor fibroblasts, their origin remains controversial. Multiple publications suggest circulating mesenchymal precursors as a source of tumor-associated fibroblasts. However, we show by three independent approaches that tumor fibroblasts derive primarily from local, sessile precursors. First, transplantable tumors developing in a mouse expressing green fluorescent reporter protein (EGFP) under control of the type I collagen (Col-I) promoter (COL-EGFP) had green stroma, whereas we could not find COL-EGFP(+) cells in tumors developing in the parabiotic partner lacking the fluorescent reporter. Lack of incorporation of COL-EGFP(+) cells from the circulation into tumors was confirmed in parabiotic pairs of COL-EGFP mice and transgenic mice developing autochthonous intestinal adenomas. Second, transplantable tumors developing in chimeric mice reconstituted with bone marrow cells from COL-EGFP mice very rarely showed stromal fibroblasts expressing EGFP. Finally, cancer cells injected under full-thickness COL-EGFP skin grafts transplanted in nonreporter mice developed into tumors containing green stromal cells. Using multicolor in vivo confocal microscopy, we found that Col-I-expressing fibroblasts constituted approximately one-third of the stromal mass and formed a continuous sheet wrapping the tumor vessels. In summary, tumors form their fibroblastic stroma predominantly from precursors present in the local tumor microenvironment, whereas the contribution of bone marrow-derived circulating precursors is rare.

Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy.

Malignant cells may evade death from cytotoxic agents if they are in a dormant state. The host microenvironment plays important roles in cancer progression, but how niches might control cancer cell dormancy is little understood. Here we show that osteopontin (OPN), an extracellular matrix molecule secreted by osteoblasts, can function to anchor leukemic blasts in anatomic locations supporting tumor dormancy. We demonstrate that acute lymphoblastic leukemia (ALL) cells specifically adhere to OPN in vitro and secrete OPN when localized to the endosteal niche in vivo. Using intravital microscopy to perform imaging studies of the calvarial bone marrow (BM) of xenografted mice, we show that OPN is highly expressed adjacent to dormant tumor cells within the marrow. Inhibition of the OPN-signaling axis significantly increases the leukemic cell Ki-67 proliferative index and leads to a twofold increase in tumor burden in treated mice. Moreover, using cell-cycle-dependent Ara-C chemotherapy to produce minimal residual disease (MRD) in leukemic mice, we show that OPN neutralization synergizes with Ara-C to reduce detectable BM MRD. Taken together, these data suggest that ALL interacts with extracellular OPN within the malignant BM, and that this interaction induces cell cycle exit in leukemic blasts, protecting them from cytotoxic chemotherapy.

PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas.

Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (∼40%) and/or mutations disrupting autoregulation (∼16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen-induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 transgene, we hypothesized that mutated genes are likely to play an important cooperative role in BCL6-associated lymphoma development. We used retroviral insertional mutagenesis in an effort to identify which genes cooperate with BCL6 in lymphomagenesis in our BCL6 transgenic mice. We identified PIM1 as the most frequently recurring cooperating gene in our murine BCL6-associated lymphomas (T- and B-cell types), and we observed elevated levels of PIM1 mRNA and protein expression in these neoplasms. Further, immunohistochemical staining, which was performed in 20 randomly selected BCL6-positive human B- and T-cell lymphomas, revealed concurrent expression of BCL6 and PIM1 in these neoplasms. As PIM1 encodes a serine/threonine kinase, PIM1 kinase inhibition may be a promising therapy for BCL6/PIM1-positive human lymphomas.

Diffuse blastoid B-cell lymphoma: a histologically aggressive variant of t(14;18)-negative follicular lymphoma.

Among the diffuse lymphomas of B-cell origin, we have encountered one variant displaying blastoid features that morphologically mimic lymphoblastic lymphoma, the blastoid variant of mantle cell lymphoma, and the so-called blastoid transformation of follicular lymphoma. To better characterize this entity, we studied eight cases morphologically, immunohistochemically, and by fluorescence in situ hybridization (FISH) for cytogenetic abnormalities commonly associated with follicular lymphoma and B-cell lymphomas exhibiting high-grade histological features. All eight cases were presented as de novo neoplasms, and displayed an entirely diffuse (five cases) or only minimal follicular (three cases) growth pattern. The neoplastic lymphoid cells were of medium size with round nuclei, fine chromatin, inconspicuous nucleoli, and high mitotic rate; they expressed CD10, BCL6, and BCL2-a phenotype consistent with follicle center cell origin. A proportion of cases expressed MUM1. Their lack of TdT and CYCLIN D1 distinguished them from lymphoblastic lymphoma and the blastoid mantle cell lymphoma, respectively. The neoplastic lymphoid cells consistently expressed CD43 (seven of eight cases) and occasionally other T-cell-associated antigens, including CD5, CD7, CD8, and CD57. Although all cases overexpressed BCL2, t(14;18) was not detected in any of the five cases examined by FISH; instead, extra copies of chromosome 18 were found in four of five cases. Finally, other cytogenetic abnormalities, including structural abnormalities of BCL6 (allelic loss/gain, rearrangement), monosomy 7, del(13)(q14), and MYC allelic loss, were frequently detected. The combination of a B-cell CD10+ BCL6+ BCL2+ phenotype in the presence of structural abnormalities of BCL6 is consistent with a follicular center cell derivation for our cases. The lack of t(14;18) seen in our cases, although rare in most cases of follicular lymphoma, has been nevertheless reported in cases of follicular lymphoma with a predominantly diffuse growth pattern. The molecular pathogenesis, clinical manifestations, and prognostic significance of these lesions remain to be elucidated.

Intrathoracic Rosai Dorfman Disease with Focal Aggregates of IgG4-bearing Plasma Cells. Case Report and Literature Review.

Rosai Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy, is a rare histiocytic disorder that typically presents as painless cervical adenopathy. Occasionally, Rosai Dorfman disease may involve extranodal sites and it can be associated with constitutional symptoms. In this report, we present a patient with progressive dyspnea on exertion, obstruction on spirometry, and paratracheal soft tissue thickening extending to the proximal bronchi and hila. After extensive radiologic and interventional measures, including multiple biopsies, the diagnosis was established on pathology showing characteristic features of Rosai Dorfman disease in a paratracheal lymph node and features of extranodal Rosai Dorfman disease with extensive fibrosis in the paratracheal mass. In addition, the involved paratracheal lymph node demonstrated focally increased IgG4-positive plasma cells, a finding that was not present in the tracheal mass. A review of intrathoracic manifestations of Rosai Dorfman disease including the proposed causes and causative triggers is presented. The histological features and the current understanding of the management and prognosis are also discussed. This unusual presentation highlights the need to consider histiocytic disorders in the differential diagnosis of paratracheal disease.

Enteropathy-associated intestinal T-cell lymphoma in cavitating mesenteric lymph node syndrome: fine-needle aspiration contributes to the diagnosis.

Cavitating mesenteric lymph node syndrome (CMLNS) is an infrequently reported manifestation of unrecognized/longstanding celiac disease and may be associated with enteropathy-associated intestinal T-cell lymphoma and hyposplenism. Unrecognized malignancy and life-threatening infections can pose a significant risk to patients in cases of delayed diagnosis. Fine-needle aspiration of the mesenteric lesions may contribute significantly to the correct diagnosis and can expedite patient management. We report on the cytologic characteristics of enteropathy-associated intestinal T-cell lymphoma first detected in a cyst fluid specimen obtained from a patient with cavitating mesenteric lesions. Image-guided fine-needle aspiration resulted in chylous fluid that contained a lymphoid cell population with neoplastic morphology and abnormal immunophenotype. Further work-up led to the diagnosis of enteropathy-associated intestinal T-cell lymphoma with bone marrow involvement. Cytologic assessment of the cyst fluid is an important part of the diagnostic cascade in patients with CMLNS to exclude clinically occult lymphoma.

The vanishing testis: a histomorphologic and clinical assessment.

Of patients with cryptorchidism, 5% have no palpable gonad. Physical examination or scrotal exploration demonstrates tissue nubbins or small nodules that constitute the vanishing testis syndrome. At the University of Chicago Hospitals (Chicago, IL; 2004-2008), 30 surgical pathology specimens from 29 patients with this clinical diagnosis underwent scrotal exploration. Histologic and immunohistochemical comparison was done with 7 fetal testes, 8 surgically removed nonneoplastic testes, and 2 cryptorchid testes. Routine histologic studies showed no seminiferous tubules in 18 cases (60%), fibrosis in all (100%), calcifications in 16 (53%), and hemosiderin deposits in 9 (30%). In 12 cases with seminiferous tubules (40%), there were Sertoli cells only. Scrotal exploration in such cases is clinically driven and results in the removal of any tissue present. Although published studies suggest the risk for future tumor development is low, possibly absent, the definitive removal of a testicle is established by an awareness of the histologic spectrum exhibited by testicular remnants.