A report of two cases

Tissue integrity is maintained by the stroma in physiology. In cancer, however, tissue invasion is driven by the stroma. Myofibroblasts and cancer-associated fibroblasts are important components of the tumor stroma. The origin of myofibroblasts remains controversial, although fibroblasts and bone marrow-derived precursors are considered to be the main progenitor cells. Myofibroblast reactions also occur in fibrosis. Therefore, we wonder whether nontumorous myofibroblasts have different characteristics and different origins as compared to tumor-associated myofibroblasts. The mutual interaction between cancer cells and myofibroblasts is dependent on multiple invasive growth-promoting factors, through direct cell-cell contacts and paracrine signals. Since fibrosis is a major side effect of radiotherapy, we address the question how the main methods of cancer management, including chemotherapy, hormonotherapy and surgery affect myofibroblasts and by inference the surrogate endpoints invasion and metastasis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.23925

Stromal myofibroblasts are drivers of invasive cancer growth.

Beside having roles in energy homeostasis and endocrine modulation, adipose tissue (AT) is now considered a promising source of mesenchymal stromal cells (adipose-derived stromal cells or ASCs) for regenerative medicine. Despite numerous studies on cultured ASCs, native human ASCs are rarely investigated. Indeed, the phenotype of ASCs in their native state, their localization within AT and comparison with bone marrow-derived mesenchymal stromal cells (BM-MSCs) has been poorly investigated. To address these issues, the stroma vascular fraction (SVF) of human AT was extracted and native cell subtypes were isolated by immunoselection to study their clonogenic potential in culture. Immunohistology on samples of human AT in combination with reconstruction of confocal sections were performed in order to localize ASCs. Compared with BM-MNCs, all native ASCs were found in the CD34+ cell fraction of the AT-SVF. Native ASCs expressed classical mesenchymal markers described for BM-MSCs. Interestingly, CD34 expression decreased during ASC cell culture and was negatively correlated with cell proliferation rate. Immunohistological analysis revealed that native ASCs exhibited specific morphological features with protrusions. They were found scattered in AT stroma and did not express in vivo pericytic markers such as NG2, CD140b or alpha-smooth muscle actin, which appeared during the culture process. Finally, ASCs spontaneous commitment to adipocytic lineage was enhanced in AT from obese humans. The use of complementary methodological approaches to study native human ASCs revealed their immunophenotype, their specific morphology, their location within AT and their stemness. Furthermore, our data strongly suggest that human ASCs participate in adipogenesis during AT development.

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Native human adipose stromal cells: localization, morphology and phenotype

Current models suggest that at a certain but yet undefined time point of tumour development malignant cells with an aggressive phenotype start to disseminate via the blood stream into distant organs. This invasive phenotype appears to be associated with an epithelial–mesenchymal transition (EMT), which enables detachment of tumour cells from a primary site and migration. The reverse process of mesenchymal–epithelial transition (MET) might play a crucial role in the further steps of metastasis when circulating tumour cells (CTCs) settle down in distant organs and establish (micro-)metastasis. Nevertheless, the exact mechanisms and interplay of EMT and MET are only partially understood and their relevance in cancer patients is unclear. Research groups have just started to apply EMT-related markers in their studies on CTCs in cancer patients. In the present review, we summarize and discuss the current state of investigations on CTCs in the context of research on EMT/MET.

Plasticity of disseminating cancer cells in patients with epithelial malignancies.

Chronic inflammation often precedes or accompanies a substantial number of cancers. Indeed, anti-inflammatory therapies have shown efficacy in cancer prevention and treatment. The exact mechanisms that turn a wound healing process into a cancer precursor are topics of intense research. A pathogenic link has been identified between inflammatory mediators, inflammation related gene polymorphisms and carcinogenesis. Animal models of cancer have been instrumental in demonstrating the diversity of mechanisms through which every tumor compartment and tumor stage may be affected by the underlying inflammatory process. In this review, we focus on the interaction between chronic inflammation, tumor stem cells and the tumor microenvironment. We summarize the proposed mechanisms that lead to the recruitment of bone marrow derived cells and explore the genetic and epigenetic alterations that may occur in inflammation associated cancers.

Chronic inflammation, the tumor microenvironment and carcinogenesis

The connective tissue of virtually all human organs harbors huge amounts of resident CD34(+) fibrocytes. Recent studies have shown that CD34(+) fibrocytes derive from circulating CD14(+) monocytes. CD34(+) fibrocytes are involved in wound healing, act as antigen presenting cells and secrete a multitude of cytokines. Due to their diverse functions CD34(+) fibrocytes play a role in connective tissue diseases, pulmonary fibrosis and tumor associated stromal remodeling. Stromal remodeling precipitated by invasive carcinomas is characterized by a loss of CD34(+) expression paralleled by a gain of alpha-SMA expression in stromal cells resulting in a phenotype change from CD34(+) fibrocytes towards alpha-SMA positive myofibroblasts. This process is very stereotypic and may play an essential role in local tumor invasion and systemic dissemination, since a reduction of antigen presenting CD34(+) fibrocytes might constitute a step in escaping the hosts' immune control directed against invasive carcinoma cells.

CD34+ fibrocytes: morphology, histogenesis and function.

CD34+ fibrocytes are constitutive elements of the human connective tissue. The stroma associated with invasive carcinomas is characterized by a stereotypic loss of CD34+ fibrocytes and a phenotype change towards CD34− α-Smooth muscle actin (SMA)+ myofibroblasts. Secreted protein acidic and rich in cysteine (SPARC) is an important mediator of tumor-associated stromal remodeling. Melanocytic lesions of the skin have not been investigated as to this aspect up to now. Thus, we investigated a total of 20 malignant melanomas and 29 melanocytic nevi. The normal dermis and benign melanocytic nevi showed numerous CD34+ fibrocytes, whereas malignant melanomas were devoid of this cell type. α-SMA-positive myofibroblasts were absent from the normal dermis, melanocytic nevi, and malignant melanomas. SPARC was positive in malignant melanoma cells and negative in their associated stroma, while all melanocytic nevi were completely negative. The stromal phenotype of malignant melanomas (CD34− α-SMA−) differs from that of invasive carcinomas (CD34− α-SMA+) suggesting different pathogenic mechanisms involved in tumor-associated stromal remodeling. SPARC expression appears to be closely related to malignancy in melanocytic lesions.

CD34(+) fibrocytes in melanocytic nevi and malignant melanomas of the skin.

It is generally agreed that invasive carcinomas of the breast consistently lack stromal CD34+ fibrocytes. The pertinent literature shows that this assumption is well based for invasive ductal carcinomas, but evidence of loss of stromal CD34+ cells in lobular carcinomas is weak. We present a series of 22 invasive lobular carcinomas (ILCs) which, in contrast to invasive ductal carcinomas, display a gradual reduction of stromal CD34+ fibrocytes. One third of the study population showed a completely preserved population of CD34+ fibrocytes, in another third, this cell population was reduced in comparison to normal breast tissue, and in the remaining third, loss of CD34+ fibrocytes comparable to that occurring in virtually all invasive ductal carcinomas was found. The present study shows that loss of CD34+ fibrocytes is not a consistent feature of invasive carcinomas of the breast. Therefore, a preserved CD34+ stromal cell population does not exclude malignancy, and analysis of the stromal CD34 expression should be handled with care when used as a diagnostic tool.

CD34+ fibrocytes are preserved in most invasive lobular carcinomas of the breast.

Multinodular goiter represents the most common thyroid disease in Europe and the United States. Regressive changes like hemorrhage, infarction or fibrosis are frequently observed. Calcifications have also been detected by microscopic investigation of thyroid tissue. Extramedullary hematopoiesis has been described in almost every organ, especially in patients with hematologic diseases. However, true bone formation is uncommon and to date only two cases of metaplastic bone formation with extramedullary hematopoiesis in the thyroid have been reported in the literature. We present a case of total thyroidectomy due to multinodular goiter harboring an area of mature bone and hematopoiesis in an otherwise healthy female patient. Furthermore, we reviewed and summarized for the first time all available cases from the literature. We report the third case of metaplastic bone formation with foci of hematopoietic tissue in the thyroid gland. All three patients were young females without any obvious stimulus for extramedullary hematopoiesis. Isolated extramedullary hematopoiesis seems to be more frequent in the thyroid gland than metaplastic bone formation with hematopoiesis, particularly in older people with underlying hematologic disorders. It also represents an important differential diagnosis of anaplastic carcinoma of the thyroid, particularly in intra-operative frozen sections and fine-needle aspiration biopsy.

Intrathyroidal hematopoiesis: a rare histological finding in an otherwise healthy patient and review of the literature

Liposarcomas are the most common soft tissue sarcomas of adults. The identification of lipoblastic cells in soft tissue sarcomas is mandatory for the diagnosis of most subtypes of liposarcomas but may be difficult in conventional histology. The present study focuses on the expression and possible diagnostic impact of two PAT family proteins, perilipin 1/perilipin and perilipin 2/adipophilin in human liposarcomas. Eighty-seven cases of liposarcomas and 30 cases of non-lipomatous sarcomas were investigated immunohistochemically for perilipin 1 and 2 using entire tissue sections. Statistical analyses were performed using appropriate tests. Most liposarcomas and non-lipomatous sarcomas displayed positivity for perilipin 2. In contrast, while more than two-thirds of liposarcomas presented perilipin 1 positivity, all non-lipomatous sarcomas studied were negative for this marker, with statistical significance (p < 0.001). Perilipin 1 expression increased with adipocytic differentiation of liposarcoma subtypes showing statistical significance (p < 0.001). Non-lipomatous sarcomas demonstrated variable expression levels of perilipin 2. The expression level of perilipin 2 appeared to be correlated with tumor cell degeneration, e.g., through hypoxia. Perilipin 2 is not well suitable for distinction between liposarcomas and non-lipomatous sarcomas. However, perilipin 1 appeared to be a highly specific marker for liposarcoma and adipocytic differentiation in sarcomas with intermediate sensitivity.

Christina C. Westhoff

Papers

CD34+ fibrocytes: morphology, histogenesis and function.

CD34(+) fibrocytes in melanocytic nevi and malignant melanomas of the skin.

CD34+ fibrocytes are preserved in most invasive lobular carcinomas of the breast.

Intrathyroidal hematopoiesis: a rare histological finding in an otherwise healthy patient and review of the literature

Perilipin 1 is a highly specific marker for adipocytic differentiation in sarcomas with intermediate sensitivity.