Cellular Pathology of Paraneoplastic Syndromes
Cellular pathology is a branch of pathology that entails the study of cellular injury, cell adaptation, cell aging, and cell death.
It is also a branch of clinical care that deals with the examination of tissues and organs from patients for their histological diagnosis. The tissues are mainly examined for abnormal features that mainly represent carcinogenesis, but additional non-carcinogenic findings of various cellular characteristics are also documented.
The procedure begins with obtaining the specimen from the patient via a consented procedure such as surgery in an operating theatre, simple procedure in an outpatient clinic and endoscopy samples or tissues. The obtained specimens are then stored in preserving solutions, such as paraffin and formalin, to avoid degeneration, destruction, or loss of specimen quality.
Thin slices of up to 0.004 mm in thickness are made from the tissues which are later fixed on microscope slides, stained, and observed under a microscope for features of carcinogenesis. Additional characteristics of stain uptake depending in the present molecular markers are also assessed to characterize the pathology further.
The common findings of histopathological reports are features that show the inability of the cell to adapt to cellular injury (DNA damage) and other cancer-causing changes. The findings may also represent various stages of cell adaptation:
Also known as tumorigenesis which stands for the process of transforming a normal cell into a cancerous cell. Strictly defined carcinogenesis represents the initiation of a tumor-forming process while oncogenesis represents maintenance of the tumorous state in cells that have already changed into a cancerous state. The process is largely dependent on the imbalance between proliferation and programmed cell death (apoptosis) in the cell division pattern.
The process is influenced by a variety of risk factors that are considered etiological factors of cancer. They are known as carcinogens and they exert their effects by one of the two methods:
- Epigenetic i.e. they promote uncontrollable growth that leads to cancer.
- Genotoxic i.e. they induce direct DNA damage and hence genetic mutation that leads to
- Primary determining factors that work to initiate DNA mutation/damage that kicks off the tumor-forming process. These are the molecular etiologies of cancer which are radiation, carcinogenic viruses, chemicals such as asbestos and tar, hormonal influence, lifestyle changes such as smoking, alcohol intake and sun exposure, and immunologic factors.
- Secondary determining factors which represent genetic transformation that increases the risk of developing cancer. This has been observed in hereditary tumors such as retinoblastoma and nephroblastoma.
- Favoring factors which are risk factors that have been associated with increased incidence of malignant tumors such as geographical distribution, nutrition, age, and sex. These factors affect the function of various genes and lead to formation of abnormal genes that are central to the formation of a tumor.
Proto-oncogenes are genes that control the normal cell division. They are targeted by carcinogenic toxins for induction of mutations that may arise from viruses, chemicals, and spontaneous mutations.
Upon sustaining various mutations, proto-oncogenes become oncogenes which are the tumor causing genes due to their uncontrollable cell division properties. Examples of oncogenes include the K-ras gene found in colon cancer.
Tumor suppressor genes
Tumor suppressor genes are genes that control the rate of cell division and protein synthesis. In simple terms, they put the oncogenes in check. In carcinogenesis, there is increased expression of carcinogens and reduced tumor suppressor genes expression. Examples of tumor suppressor genes include the p53 gene found in cancer of the breast colon and stomach.
DNA mismatch repair genes
DNA mismatch repair genes are thought to be found in tumor cells thus giving them some level of risk to spontaneous mutations. They are easily triggered into mutation by carcinogenic materials.
Multistage carcinogenesis theory
It puts forward that carcinogenesis is a protracted process involving various stages that begin with damage to cellular DNA and comptonization of the cells ability to repair this damage. These interventions require a lot of time to take effect and hence the long latency period for cancer formation before the tumor is clinically evident.
This is the stage where there is the interaction of a normal cell with a carcinogen to induce genetic mutation/DNA damage. This damage can be repaired or reproduced by the cell division mechanisms. The most common outcome at this stage is repaired by the body and thus this step rarely leads to malignancy more so if the injury is the first attempt. However, if the body fails to repair the damage, the body continues reproducing the error/damage and this leads to more errors/damage and eventually cancerous states. Genotoxic factors such as viruses, radiation, and chemicals (asbestos) initiate this process.
Here, the cells with chronic genetic mutations lead to the autonomic production of the cells leading to a faster division of already mutated cells. This leads to further spread of the already damaged DNA. The substances that accelerate this process are known as promoters. They may be non-carcinogenic or weakly carcinogenic, but rely on the damage caused by initiating carcinogens. Unlike initiating carcinogens that work by binding to DNA, promoters work by binding to cell membranes. Examples of promoters include tar in cigarette smoke, alcohol, and carcinogenic hormones. The rapid division of the affected cells leads to accumulation and formation of a benign mass. The process is still reversible by removal of the carcinogenic triggers and removal of the tumorous cells.
This refers to a stage where the abnormal cells exceed the normal cells in the pathogenic region. The cells are prone to more damage that increases the damage and rate of cell division paving a way to the next stage of carcinogenesis.
The last stage where the tumor acquires invasive and metastatic properties causing damage and symptoms consistent with cancer.
The genetic mutation theory
It holds that mutations arise from structural abnormalities of genes regulating cell division. The mutations are then carried down to daughter cells leading to initiation of the cancer formation process. The theory is supported by the fact that most genetic diseases pose an increased risk of developing cancer. For example, patients with Down’s syndrome and Klinefelter’s syndrome have an increased risk of developing leukemia. Moreover, most tumors have an incriminated genetic mutation that is pathognomonic of the disease such as retinoblastoma and nephroblastoma.
The aberrant differentiation theory
It puts forward that cancer emanates from functional disorders of genetic mutation with no structural changes seen. This theory is supported by laboratory demonstration that incubation of cancer cells in an environment with cells free of cancer leads to reversal of the tumorigenesis; thus, this theory views cancer as an epigenetic and reversible process influenced by nearby situations.
Viral oncogenes are thought to be solely responsible for triggering the oncogenesis. They induce carcinogenesis by interaction and damage of the cellular DNA.
Cell selection theory
It views carcinogenesis as a mere increase in the rate of cell division and downplays the presence or the impact of genetic mutations in oncogenesis.
These are disorders that occur because of an immunologic response to the presence of a neoplasm in the body. They are also described as clinical syndromes that arise from substances produced by the tumor and not by a direct effect of the tumor such as metastasis, mass effects or invasiveness of the tumor.
In most situations, the link between the tumor and the paraneoplastic syndrome is not well understood, but it is thought to arise from hormones, peptides or cytokines produced by the tumor such as ACTH and ADH.
Paraneoplastic syndromes are seen in all patients with tumors, but they are more common in the middle-aged patients. They have no racial or sexual predisposition. The common cancers that present with paraneoplastic syndromes include cancer of the lung breast, ovaries, kidney, liver, stomach, and lymphomas.
The neoplastic syndromes are found in 10-15% in all malignancies. Neurological paraneoplastic syndromes are seen in 1% of cancer patients.
With the occurrence of tumor cells, body tries to fight against it to destroy it by production of antibodies as an immune response. These antibodies cross-react with normal body tissues that possess similar proteins as the tumor cells leading to the development of a paraneoplastic syndrome. Another theory for the pathogenesis of the syndromes is from the hormones produced by the tumor, such as a posterior pituitary tumor secreting antidiuretic hormone that are meant to produce interference with the normal body mechanisms. These hormones are known as tumor markers that are diagnostic of the disease.
Presentation and classification
Paraneoplastic syndromes are classified into various systemic syndromes that have varying symptoms as follows:
Endocrine paraneoplastic syndromes
- They include syndrome of inappropriate ADH secretion that is evident in small cell lung cancer and central nervous system malignancies. Their symptoms are hyponatremia, hypokalemia, headaches, weakness and altered mental status.
- Cushing syndrome is seen in pancreatic carcinoma and thymoma. It may be present with hypokalemia. Its symptoms are moon facies, truncal obesity, and gynecomastia.
- Hypercalcemia is seen in lung, breast, and renal carcinoma.
- Carcinoid syndrome is evident with a secretion of serotonin and bradykinin in cancer of the bronchus.
Hematological paraneoplastic syndromes
- Granulocytosis that may lead to itching.
- Trousseau sign is seen in pancreatic carcinoma and bronchial carcinoma.
- Disseminated intravascular coagulation
- Cryoglobulinemia in lung cancer
Neurological paraneoplastic syndromes
- Lambert Eaton myasthenic syndrome manifests xerostomia, sexual impotence, myopathy, and peripheral neuropathy.
- Paraneoplastic cerebellar degeneration seen in lung cancer, ovarian cancer, and breast cancer that presents with features of depression, seizures, and memory loss.
- Polymyositis and limbic myelitis
- Paraneoplastic limbic encephalitischaracterized by depression , seizures ,irritability and memory loss.
- Myasthenia gravis
Mucocutaneous paraneoplastic syndromes
- Acanthosis nigricans and a sweet syndrome that leads to the development of flushes, alopecia, and migratory thrombophlebitis.
- herpes zoster
- a blackish pigmentation of skin known as dermic melanosis
Rheumatological paraneoplastic syndromes
- rheumatoid polyarthritis
- Polymyositis and dermatomyositis that presents with muscle enlargement and weakness,
- as well as osteoarthropathy that presents with painful joints, effusions, and swollen joints are forms of rheumatological paraneoplastic syndromes.
- Systemic lupus erythematosus
- Secondary amyloidosis
- Nephrotic syndrome
Laboratory work-ups is prefered to determine the functionality of the paraneoplastic syndrome and best way for management. Paraneoplastic syndrome can be evaluated by following tests :
- A CT scan is opted for the diagnosis and staging of tumors.
- A MRI offers better screening of soft tissue and anatomical assessment compared to CT scans.
- A PET scanis preferred for the evaluation of micrometastasis and response to treatment.
- ESR, Complete blood count, CEA, AFP and other hormones and tumor markersis done to identify antibodies, hormones, infection and possible nutrient disorder in the blood. It is advocated to detect the possible etiology and progress of the disease
- Lumber puncture to obtain a samople of CSF to detect possible presence of antibodies .
Treatment of the tumor causing the paraneoplastic syndrome
- Surgery for excision of the tumor, such as adrenalectomy, is an ACTH producing adrenal mass and thyroidectomy for a functional thyroid tumor.
- Combination therapy with any two/three of the above treatment modalities.
Treatment of the paraneoplastic syndrome
Immunosuppression with corticosteroids, such as prednisone, inhibit inflammation.
- Corticosteroids, such as prednisone, inhibit inflammation.
- Immunosuppressants slow the production of disease-fighting white blood cells. They include azathioprine and cyclophosphamide.
- Plasma exchange to separate blood cells from the fluid part of blood and reduce the immune components.
- Intravenous immunoglobulin (IVIg). Immunoglobulin contains healthy antibodies from blood donors. High doses of immunoglobulin speed up the destruction of the damaging antibodies in your blood.
Supportive treatment of other complications or slowing the progress of the paraneoplastic syndrome:
- Anti-seizure medications, which may help control seizures associated with syndromes that cause electrical instability in the brain.
- Physical therapy. Exercises help in the quick recovery and setting in of complications associated with immobility.
- Speech therapy. It helps in gaining the necessary muscle control in patients with trouble speaking or swallowing.
Course and prognosis
As every individual exhibit different paraneoplastic syndromes from others, so prognosis also vary in great extent.Course and prognosis also vary with each paraneoplastic syndrome; desseminated intravascular coagulation donot resolve easily whereas hypertophicosteoarthropathy show good results with medications. Some of the paraneoplastic disorders may get settled spontaneously. Mortality is mainlymarked due to comorbidities such as chronic heart failure and tumor burden itself or kidney failure.