Cancer Biomarker Classification and Utility

It has been well established that a variety of biomarkers are used in risk assessment, early detection, diagnosis, treatment, and management of cancer.13,14 Molecular analyses at the protein, DNA, RNA, or miRNA levels can contribute to the identification of novel tumor subclasses, each with a unique prognostic outcome or response to treatment.15

Biomarkers enable the characterization of patient populations and quantitation of the extent to which drugs reach intended targets, alter proposed pathophysiological mechanisms, and achieve clinical outcomes.16 The most valuable biomarkers are highly sensitive, specific, reproducible, and predictable, and the majority of US Food and Drug Administration (FDA) approved that cancer biomarkers are serum-derived single proteins.17,18

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Biomarkers can be classified based on different parameters such as characteristics and function. Biomarkers that are classified according to their functions include type 0 biomarkers, which measure the natural history of a disease and they should correlate over time with known clinical indicators; type I biomarkers are associated with the effectiveness of pharmacologic agents; and type II biomarkers, also known as surrogate endpoint biomarkers, are intended to substitute for clinical endpoints.19

Current cancer biomarkers may be grouped into a variety of categories including proteins, glycoproteins, oncofetal antigens, hormones, receptors, genetic markers, and RNA molecules.11

Cancer biomarkers are also classified into prediction, detection, diagnostic, prognostic, and pharmacodynamics biomarkers.20 Prognostic biomarkers are based on the distinguishing features between benign and malignant tumors. Predictive biomarkers (also known as response markers) are used exclusively in assessing the effect of administering a specific drug, thus, allowing clinicians to select a set of chemotherapeutic agents, which will work best for an individual patient.

Pharmacodynamic biomarkers are cancer markers utilized in selecting doses of chemotherapeutic agents in a given set of tumor-patient conditions. Diagnostic markers may be present in any stage during cancer development

HIV-associated Kaposi Sarcoma and its Problems in Diagnosis

Kaposi sarcoma (KS) is an endothelial neoplasia that is found typically in cutaneous lesions, whose development stages entail macules, plaques, and nodules.21 KS is the most common malignancy in HIV patients. HIV-associated Kaposi sarcoma (HIV-KS) is a low-grade vascular tumor associated with human herpesvirus 8 (HHV8)/KS-associated herpes virus infection and is the most aggressive and frequent type of KS.22,23 KS primarily involves the skin but can also involve the viscera.24

Multiple mucocutaneous lesions typically evolve from flat macule (early or patch stage) into plaques (plaque stage) and then nodules (tumor or nodular stage) containing spindle-shaped tumor cells. KS has a variable clinical course, ranging from minimal disease presenting as an incidental finding to a rapidly progressing neoplasm that can result in significant morbidity and mortality, depending on the specific site of involvement.

It poses problems in histologic diagnosis due to its broad morphologic spectrum and mimicry of many benign vasoproliferative lesions and tumors with a prominent spindle component.25 Distinguishing KS from other benign or malignant vascular tumors, as well as other nonvascular spindle cell soft tissue neoplasms, can be challenging.26

Early-stage KS represents a reactive lesion that can either regress or progress. Progression is related to the long-lasting expression of HHV8 latency genes in KS lesions, including latent nuclear antigen-1 (LANA-1),21 cyclin-D1,27,28 and bcl-2.29 HHV8-related induction of the receptor tyrosine kinase c-kit was shown by gene expression profiling in cultured endothelial cells to play a key role in KS tumorigenesis.30,31

Biomarkers Used in HIV-KS Diagnosis/Prognosis

The differential diagnosis of KS may include cutaneous angiosarcoma, spindle cell hemangioma, dermatofibrosarcoma protuberans, vascular transformation of lymph nodes, pilar leiomyoma, stasis dermatitis, pyogenic granuloma, and spindled melanoma among others (Table 1).26Histologically, all epidemiologic forms of KS are characterized by the progressive proliferation of spindle-shaped cells and are associated with KSHV/HHV8.32

Thus, immunohistochemical detection of HHV8 in fixed tissues would be diagnostically useful, enabling one to differentiate KS from other entities. In latency, HHV8 genes produce numerous proteins that induce or maintain KS lesions, including K12, K13/viral FADD-like interferon converting enzyme inhibitory protein (vFLIP), vCyclin, and the LANA-1 that modulates cellular transcription.33–35

TABLE 1. Summary of current biomarkers in HIV-KS.

HHV8/LANA-1 Elevated 21,22,25,26,29,32
Cyclin D1 Elevated 22,27,28
bcl2 Elevated 29,33,35,51
c-kit Elevated 30,31
K12 Elevated 33,34
K13/vFLIP Elevated 33,46,47
vCyclin Elevated 35,43,45
P53 Suppressed  36,37
pRb Suppressed  27,33
D2-40 Elevated 24,38,40
CD31 Elevated 22,24,38,41
CD34 Elevated 24,38,41
FLI1 Elevated 38
vIL-6 Elevated 33,44,52
Tat Elevated 49
bFGF Elevated 42
TNF-α Elevated 42,52
IL-1 Elevated 42,51,52
Oncostatin M Elevated 42,53,54
Abbreviations: HHV8, human herpesvirus 8; LANA-1, latent nuclear antigen-1; bcl2, B-cell lymphoma 2; K13/vFLIP, K13/viral FADD-like interferon converting enzyme inhibitory protein; vCyclin, viral cyclin; pRb, retinoblastoma protein; FLI1, friend leukemia integration-1 transcription factor; vIL-6, viral interleukin-6; TNF-α, tumour necrosis factor-α.

HHV8 LANA-1 is a protein encoded by open reading frame-73 (ORF73) of the virus’ genome. The protein is expressed predominantly during viral latency and appears to play a role in viral integration into the host genome. It has also been shown to interfere in apoptosis via interactions with p53.36 LANA-1 protein may cause dysfunction of cell cycle regulatory checkpoints by degrading p53 and inactivating pRb.37

It has been previously shown that positive immunostaining for HHV8 LANA-1 exhibits high sensitivity and specificity, and it is a reliable and cost-effective method for the diagnosis of KS and is also useful for distinguishing it from the mimickers.21,25,29

Recently, it has been reported that immunohistochemical staining with D2-40, CD31 (a platelet/endothelial cell adhesion molecule, PECAM1), CD34 (a hematopoietic progenitor cell surface protein), and FLI1 (Friend leukemia virus integration 1) is useful for distinguishing cutaneous KS from other diseases.24,38 D2-40 is a novel monoclonal antibody, directed against Mr 40000 O-linked sialoglycoprotein, which reacts with a fixation resistant epitope on the lymphatic endothelium.39 It is considered to be a selective marker of lymphatic endothelium.40

Monoclonal antibodies directed against CD31 and CD34 are sensitive and specific markers of endothelial differentiation that are expressed by the majority of vascular tumors.

It has been previously demonstrated that immunostaining for CD31 and CD34 can be used as an aid in KS diagnosis in routinely processed tissues.41 In a study by Rosado and colleagues, it was reported that CD31, CD34, D2-40, and FLI1 markers demonstrated high sensitivity in both AIDS-related and non-AIDS-related KS as well as in stages of tumor progression.38