The inter-relationships of 32 pathologic and 7 clinical parameters encountered in the study of 1000 examples of invasive breast carcinoma have been presented. In some instances the biological significance of these associations is at present unclear. In others it is to be noted that there is no information provided as to the rank of their significance. Nevertheless, the associations that were encountered not only help further characterize the various forms of breast cancer but also provide information regarding the possible biological significance of some of their features. Although it is not our intention to minimize the possible significance of the inter-relationships of pathologic parameters, most emphasis in the summarizing statements which follow has been placed upon those correlations which may relate to prognosis. In this regard reference has been made to short-term treatment failure, vis a vis local recurrence and/or metastases, which may not necessarily accurately reflect patient survival, although generally such a relationship exists. Information in this regard as well as to the rank of the significance of these pathologic features shall be forthcoming when sufficient time has elapsed since the inception of this study to allow for such conclusions, i.e. survival or long-term treatment failure rates. Lastly, it becomes evident that the guidelines followed in the examination of these specimens appear to represent at least the minimum requirements necessary for a meaningful pathologic evaluation of breast carcinoma.

The pathology of invasive breast cancer. A syllabus derived from findings of the National Surgical Adjuvant Breast Project (protocol no. 4).

Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness

Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single-cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism.

Inflammatory cytokines produced in response to various infectious and non-infectious stimuli are potent inducers of intrahepatic cholestasis (inflammation-induced cholestasis). The cholestatic effect of cytokines results mainly from inhibition of expression and function of hepatocellular transport systems which normally mediate hepatic uptake and biliary excretion of bile salts and various non-bile salt organic anions (e.g. bilirubin). These cytokine effects are reversible and bile secretory function is restored upon disappearance of the inflammatory injury. This review summarizes the clinical, pathophysiological and molecular aspects of inflammation-induced cholestasis.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1440-1746.1999.01982.x

Inflammation-induced cholestasis

Cancer cells possess remarkable abilities to adapt to adverse environmental conditions. Their survival during severe nutrient and oxidative stress depends on their capacity to acquire extracellular lipids and the plasticity of their mechanisms for intracellular lipid synthesis, mobilisation, and recycling. Lipid droplets, cytosolic fat storage organelles present in most cells from yeast to men, are emerging as major regulators of lipid metabolism, trafficking, and signalling in various cells and tissues exposed to stress. Their biogenesis is induced by nutrient and oxidative stress and they accumulate in various cancers. Lipid droplets act as switches that coordinate lipid trafficking and consumption for different purposes in the cell, such as energy production, protection against oxidative stress or membrane biogenesis during rapid cell growth. They sequester toxic lipids, such as fatty acids, cholesterol and ceramides, thereby preventing lipotoxic cell damage and engage in a complex relationship with autophagy. Here, we focus on the emerging mechanisms of stress-induced lipid droplet biogenesis; their roles during nutrient, lipotoxic, and oxidative stress; and the relationship between lipid droplets and autophagy. The recently discovered principles of lipid droplet biology can improve our understanding of the mechanisms that govern cancer cell adaptability and resilience to stress.

https://www.mdpi.com/1420-3049/23/8/1941/pdf

Lipid Droplets in Cancer: Guardians of Fat in a Stressful World

A critical review of over 900 mammary carcinomas treated at St. Louis University Hospitals disclosed 13 that fulfilled the histologic picture of lipid‐rich carcinoma. All clinical and pathologic data were tabulated; 1 case was studied by electron microscopy. Five of the patients were dead within 2 years, and 2 others had evidence of metastatic tumor within 2 years. One patient died 6 years after treatment. On the basis of the following characteristics we believe lipid‐rich carcinomas should be regarded as a specific type of mammary carcinoma: 1. The presence of non‐degenerative lipid material within the cytoplasm of tumor cells; 2. The presence of intramitochondrial crystals; 3. The pattern of metastatic involvement of lymph nodes and the orbit; 4. The presence of intraductal and lobular carcinoma in situ associated with this type of tumor; and 5. The more aggressive clinical behavior.

Lipid-rich carcinoma of the breast. A clinicopathologic analysis of 13 examples.

Although first described in 1961, the association of renal carcinoma with hepatosplenomegaly, hepatic dysfunction, and thrombocytosis remains unexplained and is still not widely recognized. Among the most recent 50 patients with renal carcinoma treated at the St. Louis University Hospitals, five had this constellation of findings. The median age, 59 years, was the same for patients with or without the syndrome; the lesions were histologically identical to renal carcinomas without hepatic dysfunction. None of the five patients had evidence of metastasis to the liver at the time of operation, and the liver was histologically normal in one patient from whom a biopsy was taken. The hepatic dysfunction, hepatomegaly, and thrombocytosis disappeared postoperatively in the four patients who underwent nephrectomy. It seems clear that a humoral mechanism is responsible for the hepatic and hematopoietic alterations, but the nature of the mechanism remains to be demonstrated.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197205%2929%3A5%3C1287%3A%3AAID-CNCR2820290524%3E3.0.CO%3B2-G

Hepatic dysfunction associated with renal carcinoma.

An example of Kaposi’s sarcoma with primary involvement of lymph nodes is reported. The patient, a woman, was admitted because of generalized lymphadenopathy and anemia. She was also known to have congestive heart failure of rheumatic origin. SMA-12 screening disclosed hypercalcemia on several occasions during her hospitalization. Levels of circulating parathormone and prostaglandins E2 and F were markedly increased. Total bone scan was negative for involvement by tumor. Electronmicroscopic examination of an involved lymph node disclosed secretory bodies in the cytoplasm of malignant cells and other cells, with clear indication of endothelial origin. The rarity of Kaposi’s sarcoma with primary lymph nodal involvement in the United States is discussed. So far as is known by the authors, no example of Kaposi’s sarcoma has been associated with hypercalcemia due to ectopic endocrine production.

Primary Kaposi’s Sarcoma of Lymph Nodes

An ultrastructural study of pleomorphic liposarcoma with an unusual clinical presentation is described. A 69-year-old Caucasian female presented with recurrent superficial phlebitis of left leg, which responded only partially to conventional therapy. Following investigations, a mass was excised. Diagnosis of pleomorphic liposarcoma was made on microscopic examination. Numerous lipid droplets in the cytoplasm and often within intranuclear extensions of cytoplasm were seen on oil red O stain of frozen sections. Ultrastructural features are quite distinctive. The cells varied from small to often large pleomorphic cells with numerous lipid spaces without limiting membrane, large pleomorphic nuclei, and an abundance of cytoplasmic organelles. Centrioles were very prominent, in close proximity to nuclei, and collections of autophagocytic inclusions. Intercellular collagen was immature and scant. These features are compared to ultrastructural features of malignant fibrous histiocytoma, pleomorphic rhabdomyosarcoma, and cardiac myxoma, indicating that ultrastructural features are distinctive and help differentiate similar soft tissue tumors.

Carlos V. Ramos

Papers

Lipid-rich carcinoma of the breast. A clinicopathologic analysis of 13 examples.

Hepatic dysfunction associated with renal carcinoma.

Primary Kaposi’s Sarcoma of Lymph Nodes

Ultrastructural observations in pleomorphic liposarcoma.