Cancers of Unknown Primary

DIAGNOSIS AND TREATMENT OF UNKNOWN PRIMARY CANCERS

21.03.2024

Cancer of unknown primary (CUP) is a condition in which the presence of cancer cells is detected in one or more parts of the body and it is not possible to determine where these cells initially originated. Usually, the cancer has metastasized and the primary tumor, that is, the main source where the cancer started, cannot be detected. This means less is known about the development and spread of cancer, which can make diagnosis and treatment difficult. CUP poses a significant challenge in cancer treatment because determining the source and type of cancer is critical in selecting the most effective treatment methods. In this case, doctors usually perform extensive testing to analyze the extent of disease spread, cell type, and molecular and genetic characteristics of the cancer to create the most appropriate treatment plan. Although CUP cases have become better understood and managed over time due to advances in cancer diagnosis and treatment, such cancers can still have high mortality rates and characteristics that are difficult to respond to treatment. Therefore, cancer cases of unknown primary continue to constitute an important focus in cancer research and treatment approaches.

WHAT ARE THE RISK FACTORS?

In cases of cancer of unknown primary (CUP), risk factors are generally non-specific and are similar to general cancer risk factors because the starting point of the cancer cannot be determined. However, some factors may increase the risk of developing CUP:

Age: Most cases of CUP occur in adults, especially those aged 60 and over. As age increases, the overall cancer risk also increases.

Smoking: Smoking is a major risk factor for many types of cancer and may also increase the risk of CUP.

Alcohol Consumption: Excessive alcohol consumption is a risk factor for some types of cancer and may also increase the risk of developing CUP.

Having Cancer Treatment in the Past: The risk of developing a new cancer of unknown primary may increase in people who have previously been treated for cancer.

Family History of Cancer: Having certain types of cancer in the family may increase the risk of PCK in terms of genetic predisposition.

Some Viral Infections: Some viral infections, such as human papillomavirus (HPV) and Hepatitis B and C, increase the risk of developing cancer, and this may also be true of CUP.

Environmental Factors: Environmental factors, such as exposure to radiation and exposure to certain chemicals and toxins, can increase the risk of cancer.

Lifestyle Factors: Lifestyle factors such as inadequate physical activity, unhealthy eating habits, and obesity increase the overall risk of cancer and may therefore also influence the risk of CUP.

Each of these risk factors may have varying degrees of influence on the development of CUP, and many cases of CUP can develop without any of these risk factors. In cases of CUP, extensive medical evaluations and testing are often necessary because the point of onset is unclear. Early diagnosis and appropriate treatment planning play an important role in the management of such cases.

Image 1: Treatment of cancer varies depending on the organ from which it originates.

HOW DOES IT OCCUR?

Cancer of unknown primary (CUP) is a complex condition in which the original starting point of the cancer cannot be determined, and the mechanisms of development of these cancers are not yet fully understood. In general, the development of CUP begins with the abnormal division and proliferation of cancer cells, characterized by genetic and epigenetic changes. These changes cause uncontrolled growth of cells, disruption of apoptosis (programmed cell death) mechanisms, and loss of normal functions of cells. In cases of CUP, there is a possibility that the primary tumor may not be detected due to its small size or being completely destroyed by the body. This results in metastatic cells spreading to other parts of the body and forming secondary tumors. Additionally, the molecular and biological properties of CUP cells may explain their tendency to spread rapidly and remain undetectable by current diagnostic methods. These cells often show a high degree of heterogeneity and adaptability, leading them to develop resistance to various treatments and prognosis difficult to predict. The complex nature of CUP constitutes one of the important research areas in cancer biology and treatment, and new studies are constantly being conducted to better understand this type of cancer.

WHAT ARE THE SYMPTOMS?

Cancer of unknown primary (CUP) is a type of cancer whose origin cannot be determined in the body, and this may cause its symptoms to be vague and general. The symptoms of CUP vary depending on the areas in the body where the cancer has spread and the organs it affects. General symptoms may include:

Weight Loss and Loss of Appetite: Unexplained weight loss and loss of appetite are common symptoms in CUP, as in many types of cancer.

General Weakness and Fatigue: Constant feelings of weakness and fatigue may be a result of the body fighting cancer.

Pain: As cancer cells spread to different parts of the body, pain and discomfort may occur in these areas.

Palpable Masses: Palpable masses under the skin or swollen lymph nodes may be a common symptom.

Digestive System Problems: Digestive system problems such as nausea, vomiting, diarrhea or constipation may occur.

Jaundice or Skin Changes: If the liver is affected, yellowing of the skin and eyes (jaundice) may occur.

Neurological Symptoms: Neurological symptoms such as headaches, visual disturbances, or seizures may occur if cancer has spread to the brain or spinal cord.

Respiratory Problems: Cough, shortness of breath or chest pain may occur in cases where the lungs are affected.

In CUP cases, these symptoms may vary depending on the extent of spread of the cancer and its location in the body. Because each of these symptoms may be caused by other health problems, in-depth medical evaluation is necessary for accurate diagnosis and treatment. Early diagnosis and appropriate treatment planning in CUP cases can increase the patient's survival time and quality of life.

HOW IS IT DIAGNOSED?

The diagnosis of cancer of unknown primary (CUP) is usually made after excluding other cancers and comprehensive medical evaluations. The process begins with a detailed evaluation of the patient's symptoms, medical history, and physical examination. After this stage, doctors usually try to determine the spread of cancer in the body by performing various imaging tests (for example, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound). In addition, biopsy is one of the most important diagnostic tools. Tissue samples obtained by biopsy are used to determine the histological type, genetic and molecular characteristics of the tumor. Advanced laboratory tests, such as immunohistochemistry, are performed to determine whether tumor cells express certain proteins, which can help identify the likely source of the primary tumor. However, despite the results of all these tests, sometimes the source of the primary tumor may not be found. The diagnosis of CUP is made based on the totality of available findings and exclusion of other possible sources of cancer. Diagnosis of CUP can make treatment difficult due to the uncertainty of the cause and source of the cancer and requires a multidisciplinary approach.

Image 2: There are many environmental and genetic risk factors in the development of cancer.

WHAT ARE THE PATHOLOGICAL TYPES

Cancer of unknown primary (CUP), as defined, are cancers whose starting point cannot be determined. Therefore, these cancers do not have a specific histological or pathological type. However, CUP cases are usually classified into specific categories through histological and immunohistochemical analysis of tumor cells. These analyzes are based on the appearance of tumor cells and certain molecular markers. Some pathological types into which CUP is often categorized are:

Adenocarcinomas: They are cancers arising from secretory cells and constitute the majority of CUP cases.

Squamous Cell Carcinomas: These are epidermoid cancers arising from skin or mucosal surfaces.

Neuroendocrine Tumors: It originates from hormone-producing cells and is usually found in areas such as the pancreas or gastrointestinal tract.

Poorly Differentiated Cancers: These cancers are cases in which cells are not differentiated enough to determine their origin, and they generally have a more aggressive course.

Melanomas: These are cancers arising from melanocytes on the skin, eyes and mucosal surfaces, but sometimes the primary tumor cannot be found.

In cases of CUP, immunohistochemical tests and molecular profile analyzes can help identify the potential source and origin of tumor cells. These tests include predictions based on specific proteins expressed by the tumor, gene mutations, and other molecular features. However, even these methods may not always identify a definitive primary source. In cases of CUP, diagnosis and treatment strategies are often personalized based on the histological type of the tumor, the patient's symptoms, and general health status.

Since the starting point in cancer of unknown primary (CUP) is unclear, various molecular and immunohistochemical tests are performed to characterize the tumor and identify potential treatment targets. These tests evaluate the presence and expression levels of specific receptors and molecular markers in tumor cells. Important receptors and markers may include:

Hormone Receptors: Estrogen and progesterone receptors are important in hormone-receptor positive cancers such as breast cancer and help determine treatment options.

HER2 Receptor: Overexpression of this receptor is seen in some breast and stomach cancers and may be an indication for targeted therapies.

Epidermal Growth Factor Receptor (EGFR): Expression of EGFR is used as a treatment target in some types of cancer, such as head and neck cancers, lung cancer, and colorectal cancer.

PD-L1 (Programmed Cell Death Ligand 1): It is an important marker for determining response to immunotherapy, especially used in lung cancer and melanoma.

Ki-67: This proliferation marker is used to evaluate the growth rate and aggressiveness of the tumor.

Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB): These molecular tests are used specifically to predict response to immunotherapy.

These receptors and markers help in determining treatment options and developing personalized treatment approaches in CUP cases. Immunohistochemistry and molecular profile analyzes are critical to determine the potential origin of the tumor and the most effective treatment options. However, due to the complexity of CUP, these tests may not always determine a definitive course of treatment and often require a multidisciplinary approach.

HOW IS TUMOR STAGING DONE?

Tumor staging in cases of cancer of unknown primary (CUP) requires a different approach than traditional cancer staging systems, since the starting point of the cancer is unknown. In CUP cases, the degree of spread of the tumor in the body and the size and location of the metastasis are the main criteria to determine staging. This staging process is carried out as follows:

Comprehensive Imaging Tests: The first step in staging CUP is to perform large-scale imaging studies to determine the extent of the disease. These studies often include computed tomography (CT) scans, magnetic resonance imaging (MRI), positron emission tomography (PET), and sometimes bone scans.

Evaluation of the Spread of the Disease: The spread of the tumor in the body, the organs to which it has metastasized, lymph nodes and other structures are evaluated. This information is used to determine the overall burden of the disease and the potential for response to treatment.

Histopathological and Molecular Analyzes: Tumor samples taken through biopsy are used for histopathological examination and molecular analysis. These analyzes help determine the type of tumor, its aggressiveness, and potential treatment targets.

Distinction between Limited and Widespread Disease: Cases of CUP are generally classified as "limited disease" or "extensive disease". Limited disease indicates that the tumor has spread less throughout the body and may potentially respond to local treatments (for example, surgery or radiotherapy). Disseminated disease usually requires systemic treatment approaches (e.g. chemotherapy).

Tumor staging in CUP cases plays an important role in determining cancer treatment and management strategies. However, since this process is complex and does not fully comply with standard staging criteria, it requires individual evaluation and a multidisciplinary approach in each case.

Image 3: Imaging tests and special pathological examinations are performed to determine the organ where the cancer originates.

HOW IS TREATMENT DONE ACCORDING TO STAGES?

In cases of cancer of unknown primary (CUP), treatment is determined according to the extent of spread of the disease and the general health condition of the patient. Due to the indeterminate nature of CUP, treatment options are often individualized and tailored to the characteristics of the disease.

Treatment in Case of Limited Disease

Surgery: If the tumor is localized in a limited area and can be removed surgically, surgery may be an important treatment option.

Radiotherapy: In addition to surgery or if surgery is not possible, radiotherapy may be applied to the affected area.

Targeted Therapies/Immunotherapy: Molecular profiling of the tumor may indicate the presence of suitable targets for specific targeted therapies or immunotherapy.

Treatment in Case of Extensive Disease

Chemotherapy: In case of widespread disease, systemic chemotherapy is often the main treatment option. Chemotherapy is determined according to the type of tumor and histological characteristics.

Targeted Therapies/Immunotherapy: Molecular testing can reveal specific genetic mutations or expression profiles, which may enable the use of targeted therapies or immunotherapy.

Palliative Care: In case of widespread disease, palliative care becomes important to manage symptoms and increase patient comfort.

General Approach

Supportive Care: Supportive care is important for dealing with the symptoms of cancer and the side effects of treatment.

Individualized Treatment Plan: For each CUP patient, treatment is adapted to the patient's individual condition, tumor characteristics and general health status.

Multidisciplinary Approach: Oncologists, surgeons, radiation oncologists, pathologists, and other physicians work together to develop the most appropriate treatment plan.

In cases of CUP, early and effective treatment is important, but determining and implementing treatment options may present difficulties due to the unknown origin of the tumor. The treatment plan should be tailored to each patient's unique situation, based on the latest research and current medical practice.

WHAT ARE THE SYSTEMIC DRUGS USED IN TREATMENT?

Treatment methods and drugs used in the treatment of cancer of unknown primary (CUP) vary depending on the histological characteristics of the cancer and patient characteristics. However, some treatment options frequently used in the treatment of CUP are as follows:

Chemotherapy pills

Platinum-Based Drugs: Cisplatin or carboplatin are generally used in the treatment of CUP.

Taxanes: Docetaxel or paclitaxel is often used in combination with platinum-based drugs.

Fluoropyrimidines: 5-Fluorouracil (5-FU) or capecitabine, sometimes used together with platinum-based drugs.

Gemcitabine: May be included in some CUP treatment regimens.

Etoposide: It can be used especially in cases of small cell cancer-like CUP.

Smart Drug Therapies (Targeted Therapies)

Bevacizumab: Vascular endothelial growth factor (VEGF) inhibitor.

Erlotinib or Gefitinib: Epidermal growth factor receptor (EGFR) inhibitors.

Trastuzumab: used in HER2 positive tumors (rarely found in cases of CUP).

Immunotherapies

Pembrolizumab and Nivolumab: Programmed cell death protein 1 (PD-1) inhibitors.

Ipilimumab: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor.

These drugs and treatment methods in the treatment of CUP are carefully selected depending on the biological characteristics of the disease and the general health condition of the patient. Therefore, the treatment plan for each patient is customized based on their personal health condition and molecular profiling of the tumor. A multidisciplinary approach is essential in choosing treatment, and the most appropriate treatment options for the patient are determined by oncologists, pathologists and other physicians.

HOW SHOULD FOLLOW-UP BE CARRIED OUT AFTER RECOVERY?

Follow-up during recovery following treatment for cancer of unknown primary (CUP) must be careful and comprehensive due to the nature of the cancer. This follow-up usually includes regular medical exams, monitoring of symptoms, and imaging tests (for example, CT, MRI, or PET scans) if necessary. Patients should promptly report any new symptoms or changes after treatment. Especially considering the potential for cancer to spread, symptoms such as new pain, weight loss, and persistent fatigue should be taken into consideration. Patients should also be monitored for long-term side effects of chemotherapy and radiotherapy. These side effects; Fatigue, neuropathy, cognitive changes, and potential changes in other organ functions may occur. The follow-up plan is personalized depending on the patient's overall health, type of treatment, and characteristics of the cancer. Additionally, psychological and emotional support is an important part of the recovery process, as diagnosis and treatment of CUP can be significant sources of stress and uncertainty. Access to psychological counseling, support groups, and other medical resources for patients and their families should be encouraged.