Prominent Stromal Component Research Articles

Tubular Adenoma of the Breast: Radiologic-Pathologic Correlation.

Breast tubular adenomas (TAs) are rare, benign glandular epithelial tumors that arise from a proliferation of acini in the terminal duct lobular units. In the literature, 40 TA cases have previously been reported, and we describe 5 additional cases in this article. In the small number of reported cases, TAs present most often in women of reproductive age but may also occur in postmenopausal women. Mammographically and sonographically, TAs are almost indistinguishable from fibroadenomas (FAs), and they typically present on US as hypoechoic, oval, circumscribed, parallel masses with variable internal vascularity. TAs can also be seen on mammography as oval masses with microlobulated margins, or as grouped coarse, heterogeneous microcalcifications with or without associated mass or asymmetry. On MRI, TAs present as heterogeneously enhancing, T2-hyperintense oval masses with persistent kinetics. Histopathologically, TAs consist of closely packed round tubules with minimal stroma, in distinction to FAs, which have a prominent stromal component that surrounds and can distort the associated tubules. Because of their benign classification and excellent prognosis, patients with biopsy-confirmed TAs may resume routine screening. Complete surgical excision may be considered for cosmetic purposes or for TAs exhibiting associated suspicious calcifications or rapid growth.

Pancreatic Adenocarcinoma Invasiveness and the Tumor Microenvironment: From Biology to Clinical Trials.

Pancreatic adenocarcinoma (PDAC) originates in the glandular compartment of the exocrine pancreas. Histologically, PDAC tumors are characterized by a parenchyma that is embedded in a particularly prominent stromal component or desmoplastic stroma. The unique characteristics of the desmoplastic stroma shape the microenvironment of PDAC and modulate the reciprocal interactions between cancer and stromal cells in ways that have profound effects in the pathophysiology and treatment of this disease. Here, we review some of the most recent findings regarding the regulation of PDAC cell invasion by the unique microenvironment of this tumor, and how new knowledge is being translated into novel therapeutic approaches.

Stromal hyaluronan accumulation is associated with low tumor grade and nodal metastases in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma is an aggressive malignancy characterized by abundant desmoplastic stroma. Hyaluronan is a prominent stromal component of pancreatic ductal adenocarcinoma and is associated with unique clinical-pathological profiles in other tumor types. The current study aimed to delineate clinical and pathological features associated with hyaluronan accumulation in pancreatic ductal adenocarcinoma using a novel hyaluronan-binding assay currently being used in a clinical trial targeting hyaluronan. Sixty-four formalin-fixed, paraffin-embedded samples of pancreatic ductal adenocarcinomas from 49 patients treated at a single tertiary care hospital were stained. Fifty-two percent of tumors had high levels of hyaluronan. High levels were associated with low tumor grade and lymph node metastases, novel associations not previously seen in pancreatic ductal adenocarcinoma. This study has elucidated a novel clinical-pathological profile in pancreatic ductal adenocarcinomas using a new assay, suggesting hyaluronan may act as a biomarker for a subset of pancreatic tumors that could be targeted by hyaluronan-degrading agents.

Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions

A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component.

Differential expression of miRNAs in pancreatobiliary type of periampullary adenocarcinoma and its associated stroma

Periampullary adenocarcinomas can be of two histological subtypes, intestinal or pancreatobiliary. The latter is more frequent and aggressive, and characterized by a prominent desmoplastic stroma, which is tightly related to the biology of the cancer, including its poor response to chemotherapy. Whereas miRNAs are known to regulate various cellular processes and interactions between cells, their exact role in periampullary carcinoma remains to be characterized, especially with respect to the prominent stromal component of pancreatobiliary type cancers. The present study aimed at elucidating this role by miRNA expression profiling of the carcinomatous and stromal component in twenty periampullary adenocarcinomas of pancreatobiliary type. miRNA expression profiles were compared between carcinoma cells, stromal cells and normal tissue samples. A total of 43 miRNAs were found to be differentially expressed between carcinoma and stroma of which 11 belong to three miRNA families (miR-17, miR-15 and miR-515). The levels of expression of miRNAs miR-17, miR-20a, miR-20b, miR-223, miR-10b, miR-2964a and miR-342 were observed to be higher and miR-519e to be lower in the stromal component compared to the carcinomatous and normal components. They follow a trend where expression in stroma is highest followed by carcinoma and then normal tissue. Pathway analysis revealed that pathways regulating tumor–stroma interactions such as ECM interaction remodeling, epithelial–mesenchymal transition, focal adhesion pathway, TGF-beta, MAPK signaling, axon guidance and endocytosis were differently regulated. The miRNA-mRNA mediated interactions between carcinoma and stromal cells add new knowledge regarding tumor-stroma interactions.

Concurrent fibroadenoma and intraductal papilloma – A recurring complex lesion in a premenarcheal girl

Breast diseases are rare in childhood and adolescence, most lesions being fibroadenomas and papillomas. We report the case of an 11-year old girl with a complex breast lesion with hybrid features of fibroadenoma and intraductal papilloma with an early recurrence. Microscopically, the lesion was composed of dilated ducts showing intraluminal papillary projections with small to broad fibrovascular stalks. The typical leaf-like appearance of fibroadenoma was determined by the presence at the periphery of ducts compressed and distorted by the prominent stromal component. Despite its florid epithelial hyperplasia and mild cytological atypia (more evident in the relapse), immunohistochemical staining for p63 and smooth muscle actin highlighted a continuum outer myoepithelial layer, confirming the non-invasive appearance of the lesion. Two pathogenetic links have been hypothesized: one is based on the morphological continuum between these two entities, which may represent different evolutive stages in the same lesion; the other is based on epithelial/mesenchymal interactions. The possible malignant transformation of such complex lesion is also discussed, along with its differential diagnoses.The relevance of this case lies in its rarity, as well as in the therapeutic strategies related to its biological potential and to the necessity of a conservative treatment, due to the young age of the patient.

LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis

Germline mutations in STK11 (also known as LKB1) are found in individuals with Peutz-Jeghers syndrome (PJS) manifesting with gastrointestinal polyps that contain a prominent stromal component. Epithelia in polyps of Stk11(+/-) mice can retain a functional copy of Stk11 (refs. 2,3), and loss of heterozygosity is not an obligate feature of human polyps, raising the possibility of non-epithelial origins in tumorigenesis. Here we show that either monoallelic or biallelic loss of murine Stk11 limited to Tagln-expressing mesenchymal cells results in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in PJS. Stk11-deficient mesenchymal cells produced less TGFbeta, and defective TGFbeta signaling to epithelial cells coincided with epithelial proliferation. We also noted TGFbeta signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in PJS.

Smad4 signalling in T cells is required for suppression of gastrointestinal cancer

SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-beta signalling. Germline mutations in SMAD4 are found in over 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Here we show that selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4(-/-) T cells produce abundant T(H)2-type cytokines including interleukin (IL)-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.

Phyllodes Tumor of the Prostate: A Rare Condition Requiring Careful Surveillance

An 80-year-old man presented with a single episode of frank painless hematuria without other significant lower urinary tract symptoms. Digital rectal examination revealed a benign feeling prostate. Prostate specific antigen was 1 ng/ml, and x-ray of the kidneys, ureters and bladder was normal, as was renal ultrasound. Flexible cystoscopy demonstrated a polypoid lesion at the bladder neck, which was subsequently resected. Pathological examination showed a polyp with a complex glandular architecture and a prominent stromal component. The stromal cells had a prominent eosinophilic cytoplasm and uniform round nuclei without mitosis. Review elsewhere suggested a phyllodes tumor, which had been one of the differential diagnoses (fig. 1). At subsequent resection 2 months later it was apparent that the polypoid lesion had recurred locally (fig. 2). The original tumor and the secondary tumor were sent to the Armed Forces Institute of Pathology in Washington, D. C., where they were confirmed as phyllodes tumors of the prostate, staining positively for desmin (a smooth muscle marker) and CD34 (a mesenchymal marker). Additional staging investigations included transrectal ultrasound, which revealed further regrowth of the polyp but no other suspicious lesions in the prostate gland. The polyp was resected, and sextant biopsies of the peripheral zone demonstrated normal prostatic tissue. Magnetic resonance imaging showed no evidence of local extension.

Histiocyte-rich, T-cell-rich B-cell lymphoma: a distinct diffuse large B-cell lymphoma subtype showing characteristic morphologic and immunophenotypic features.

The clinicopathological features of histiocyte-rich, T-cell-rich B-cell lymphoma (HRTR-BCL) were first recognized in 1992. In this study, 60 cases of HRTR-BCL were analysed in order to provide a detailed morphological and immunophenotypical profile of the disorder. HRTR-BCL is easily distinguished from other B-cell lymphomas rich in stromal T-cells by (i) a diffuse or vaguely nodular growth pattern, (ii) the presence of a minority population of CD15-, CD20+ large neoplastic B-cells, (iii) a prominent stromal component composed of both T-cells and non-epithelioid histiocytes, and (iv) the scarcity of small reactive B-cells. These criteria also enable a reliable distinction from lymphocyte-rich classical Hodgkin's lymphoma (CHL), from lymphocyte-predominant Hodgkin's lymphoma (LPHL), paragranuloma type and from peripheral T-cell lymphoma. Based on the morphology of the neoplastic cells and on their frequent bcl-6 immunoreactivity, we speculate that HRTR-BCL may be derived from a progenitor cell of germinal centre origin. HRTR-BCL presents characteristic clinical features, affecting predominantly middle-aged men who present with advanced stage disease and are at high risk of treatment failure. Considering these distinctive clinicopathological features, recognizing HRTR-BCL as a lymphoma entity may be justified.

Multinucleated stromal giant cells in mammary phyllodes tumours

Mammary phyllodes tumour (PT) is an uncommon fibroepithelial neoplasm with a prominent stromal component. We report five cases of PT (one benign, three borderline, one malignant) with giant cells in the stroma. All occurred in adults and ranged from 1.8 to 4.0 cm in size. The overall cellularity, stromal cell pleomorphism and mitotic count was higher for the malignant and borderline than the benign PT. The giant cell number ranged from 18 to 35 cells per 10 high power fields, but there was no relationship between this number and the grade of the PT. Most giant cells were subepithelial, with multiple nuclei arranged in a linear or irregular pattern, and moderate amount of cytoplasm. The immunohistochemical profile of the giant cells was similar to the stromal cells. In all cases, both giant cells and stromal cells expressed vimentin strongly but not desmin; in two cases, both cell populations expressed actin weakly. The respective percentage of giant cells and stromal cells expressing MIB1 was also similar. This suggests that these giant cells do not represent a different, more active stromal population, despite the more bizarre appearance. In view of the small number of cases, the significance of such giant cells on the prognosis of PT remains uncertain.

Cytokine, cell adhesion receptor, and tumor suppressor gene expression in vulvar squamous carcinoma: correlation with prominent fibromyxoid stromal response.

In a previous report, we observed by light microscopy the extracellular matrix in 51 vulvar squamous carcinomas and found that some tumors has a prominent stromal response in the form of a regional or diffuse zone of extracellular myxoid matrix containing immature collagen and fibroblasts at the tumor-stromal junction. These tumors were associated with clitoral involvement, ulcerative nonexophytic growth pattern, older age groups, poorer survival rate, and more extensive lymph node metastases than when prominent fibromyxoid stromal response (PFSR) was absent. This behavior was demonstrated despite the fact that these tumors were not larger, more deeply invasive, or of higher grade than when PFSR was absent. In the current immunohistochemical study, we examined cytokine, cell adhesion receptor, and tumor suppressor gene expression in 50 vulvar squamous carcinomas using a panel of antibodies to identify any potential role of these proteins in the development of a PFSR. Semiquantification of expression into none, focal (< 25% of cells showing expression), regional (25-50%), and diffuse (> 50%) patterns revealed PFSR to be statistically associated with high CD44, transforming growth factor (TGF) beta 3, and p53 protein expression, but not with fibroblast growth factor, epidermal growth factor, epidermal growth factor receptor, or E-cadherin expression. When expression of CD44 and either stromal or tumor TGF-beta 3 expression was high, i.e., regional or diffuse in distribution, 15 (50%) of 30 cases were associated with PFSR. In contrast, only 1 (7%) of 14 cases was associated with PFSR when expression was high for only one of these two proteins and none of 3 cases was associated with response when expression was low for both proteins (p = 0.005). Furthermore, in cases showing high expression for both TGF-beta 3 and CD44, PFSR was found in 13 (72%) of 18 cases when p53 expression was diffuse compared with 2 (17%) of 12 cases when expression was less (p = 0.01). Since TGF-beta acts mitogenically for fibroblasts and has been shown to be an inhibitor of epithelial cell growth, its high expression in a carcinoma with PFSR would suggest loss of effect on the epithelial component but an intact effect on the stroma. Since CD44 is known to act as a receptor for hyaluronic acid, which is a prominent stromal component and known to play an important role in cell mobility and tumor aggressiveness, its high expression in association with PFSR would suggest a role of CD44 overexpression in altered hyaluronate metabolism with accelerated tumor cell migration and subsequent distal spread. The current study demonstrates that alterations in cytokine and cell adhesion receptor status variably occur in vulvar squamous carcinoma and that such alterations may affect tumor morphology and behavior.

Papillary Carcinoma of Thyroid with Exuberant Nodular Fasciitis-like Stroma: Report of Three Cases

Three examples of an unusual morphologic variant of papillary thyroid carcinoma (PTC) are reported. The presence of a prominent stromal component resulted in low-power microscopic appearances resembling fibroadenoma, phyllodes tumor, or fibrocystic disease of the breast in two cases. The carcinomatous component grew in the form of anastomosing narrow tubules, clustered glands, solid sheets with or without squamous differentiation, and/or papillae, and exhibited the typical nuclear features of PTC. The abundant stroma had a nodular fasciitis-like quality and was composed of short fascicles of spindle cells separated by varying amounts of mucoid matrix, collagen, and extravasated red blood cells; this was interpreted as an exuberant mesenchymal reaction to the carcinoma. The importance of recognizing this variant of PTC is that, when one encounters a fibroproliferative lesion of the thyroid, a diligent search should be made for papillary carcinoma. This variant also must be distinguished from the vastly more aggressive papillary carcinomas with anaplastic transformation and the so-called carcinosarcomas.

Glycogen-rich adenoma of the parotid gland. An uncommon benign clear-cell tumor resembling certain clear-cell carcinomas of salivary origin.

An instance of glycogen-rich adenoma of the parotid gland is presented. This lesion contains conspicuous numbers of clear cells, causing confusion with certain clear-cell salivary carcinomas. In the glycogen-rich adenoma, the clear cells form a peripheral mantle within tubular complexes and contain abundant glycogen, whereas similar appearing clear cells within acinic cell and mucoepidermoid carcinomas occur in nests and trabeculae, and lack glycogen. Although the precise nosologic position of this lesion is speculative, the admixture of epithelial and clear-celled myoepithelial elements may justify placing this lesion in the broad category of mixed tumors, particularly those variants lacking a prominent stromal component elaborated by such myoepithelium. The presence of areas of cytologically atypical, locally invasive growth in the recurrent tumor are interpreted as evidence of malignant degeneration, and may have been related to prior radiotherapy.