29

Cancer associated syndromes (para neoplastic syndromes)

29

Cancer associated syndromes (para neoplastic syndromes)

29

Cancer associated syndromes (para neoplastic syndromes)

29

Cancer associated syndromes (para neoplastic syndromes)

  29 Cancer associated syndromes (para neoplastic syndromes)

Lothar Thomas

The majority of neoplasms are responsible for symptoms caused by mass effects to surrounding tissues and/or through the development of metastases.

Para neoplastic syndromes are a set of clinical features in patients with cancer that are attributed /12/:

  • By tumor secretion of functional peptides and hormones that lead to metabolic derangements
  • Immune cross-reactivity between tumor and normal host tissues that can lead to the development of characteristic clinical syndromes.

The syndromes are named para neoplastic when the specific components are unrelated to the anticipated tissue or organ of origin.

Para neoplastic syndromes /12/:

  • Affect up to 8% of patients with cancer /3/
  • Can complicate the patients’ clinical course, response to treatment, impact, prognosis and even be confused as metastatic spread
  • Are usually associated with poorer survival outcome in cases of highly malignant tumors
  • Can manifest before, at the time, or after the diagnosis of cancer
  • The detection can facilitate early diagnosis of the cancer, monitor response to treatment and/or detect early recurrences following successful initial management.

Clinically para neoplastic manifestations can affect many organs and tissues such as:

  • The endocrine system; this results in symptoms of endocrine hyper functional states such as ectopic ACTH release, syndrome of inappropriate ADH secretion, or tumor hypercalcemia
  • The hematopoietic system, leading to anemia, erythrocytosis, or thrombocytopenia
  • The hemostatic system including the development of thrombotic or hemorrhagic disorders
  • The central nervous system with para neoplastic effects on the brain, peripheral nerves, or muscles (refer also to Section 25.6 – Neurological syndromes associated with autoantibodies
  • The liver including the development of clinical signs such as hepatomegaly, jaundice, and other hepatic dysfunctions.

29.1 Para neoplastic disturbances of mineral and electrolyte metabolism

Hypercalcemia, hypophosphatemia, hypomagnesemia, hyponatremia, and hypokalemia are common disturbances that occur during the course of a malignant disease. Typically para neoplastic disturbances of mineral and electrolyte metabolism are detected in patients with secretion of functional peptides and hormones frequently with small cell lung carcinoma /4/. Refer to Tab. 29-1 – Para neoplastic disturbances of calcium and electrolyte metabolism.

29.2 Para neoplastic disturbances of glucose metabolism

Islet cell tumor associated hypoglycemia

Insulin producing islet cell tumors can cause tumor associated hypoglycemia.

Extra pancreatic tumors associated hypoglycemia

The extra pancreatic tumor hypoglycemia, termed non islet cell tumor hypoglycemia (NICTH) of mesenchymal, epithelial, and hematopoietic origin is associated with hepatocellular carcinoma, fibrosarcoma, mesothelioma, hemangiopericytoma, and adrenocortical carcinoma. The following metabolic characteristics are typical of NICTH /2/:

  • Decreased glucose synthesis due to inhibition of hepatic glycogenolysis and gluconeogenesis
  • Inhibition of lipolysis with reduction of free fatty acids in plasma
  • Increased glucose consumption by the muscles and to some extent by the tumor itself. In hepatocellular carcinoma with a big vascularized mass of 13 cm in diameter serum glucose of 28 mg/dL (1.54 mmol/L) with undetectable serum C-peptide and slightly increased serum insulin level of 35 mIU/L was measured /5/.
  • The increased production of “big” IGF-2 (insulin-like growth factor 2) by the tumor is the presumed cause of tumor induced hypoglycemia. IGF-2 leads directly or indirectly, via as yet undetermined biochemical pathways, to the stimulation of cellular insulin receptors, thus resulting in the metabolic characteristics of NICTH /6/.

Clinical symptoms: the symptoms are neuroglycopenic in nature and include a reduction in intellectual performance, headache, concentration weakness, fatigue, partial amnesia, seizures, focal neurological deficits, and syncopal episodes.

Laboratory findings /2/: recurrent or constant episodes of low glucose concentration, low insulin level (< 1.5 mIU/L; < 10 pmol/L), low C-peptide (< 0.3 ug/L; < 1 nmol/L) low levels of growth hormone, elevated concentration of IGF-2, IGF-2/IGF-1 ratio, often > 10.

Hyperglycemia

Para neoplastic ectopic ACTH production of small cell lung cancer can result in hyperglycemia because ACTH is an insulin antagonist. This can occur with by small cell lung cancer, pancreatic tumors, or carcinoid tumors that release growth hormone or growth hormone-releasing hormone.

29.3 Para neoplastic disturbances of complete blood count

Para neoplastic hematological syndromes can affect erythropoiesis, granulopoiesis and thrombopoiesis. The disturbances are usually detected after the diagnosis of cancer and are rarely symptomatic. Anemia is a common and erythrocytosis a rare symptom in solid malignant tumors and hematological neoplasms.

29.3.1 Anemia of malignancy

Anemia occurs in approximately 80% of patients with malignant tumors and in almost all patients who have incurable tumors. It is one of the main causes of death in tumor patients. The anemia may be due to the tumor itself or be caused by its treatment. The decrease in the hemoglobin (Hb) level is usually slow; Hb concentration only falls below 80–90 g/L in the terminal stages of the disease or during cytostatic therapy if banked blood is not administered in time to compensate for the reduction in Hb /7/. In the case of anemia, underlying direct mechanisms are differentiated from indirect ones (Tab. 29-2 – Direct and para neoplastic mechanisms in patients with anemia of malignancy). The indirect mechanisms are para neoplastic in nature.

The pathophysiological factors underlying anemia of malignancy are:

  • Ineffective erythropoiesis caused by inhibition of the anti apoptotic effect of erythropoietin by the pro apoptotic effect of inflammatory cytokines, especially hepcidin; the bigger the cytokine effect, the more extreme the anemia (refer to Section 7.6 – Hepcidin)
  • A reduction of the red blood cell life span to two-thirds of normal
  • Less frequently, bone marrow infiltration by tumor cells leading to the displacement of erythropoietic precursor cells and induction of marrow fibrosis. Immature red blood cells and white blood cells are released into the circulation as a result of alterations in the sinusoidal matrix
  • Para neoplastic pure red cell aplasia is most commonly associated with thymoma. Cytotoxic T cells appear to be functionally and phenotypically activated, skewed to produce type 1 cytokines (e.g., interferon-γ) induce apoptosis through Fas and the Fas ligand /8/.

Laboratory findings

Normocytic normochromic anemia in approximately 80% of cases, normal or elevated serum ferritin, reduced transferrin saturation, reduced serum iron, normal transferrin saturation, increased serum hepcidin. Leukoerythroblastosis may be demonstrated by the differential blood count while the red blood cells show poikilocytosis and an increase in the red blood cell distribution width.

29.3.1.1 Warm autoimmune hemolytic anemia (AIHA)

Approximately 20% of AIHA cases are associated with malignant disease; the most commonly seen are chronic lymphocytic anemia, non Hodgkin lymphoma, and more rarely, mucin producing adenocarcinomas such as ovarian carcinoma /9/.

Laboratory findings

Positive direct antiglobulin (Coombs) test with antisera directed against IgG or complement, reduced serum haptoglobin, and reticulocytosis.

29.3.1.2 Cold autoantibody hemolytic anemia

Cold antibody autoimmune hemolytic anemia mediated by cold autoantibodies occurs less frequently than autoimmune hemolytic anemia caused by warm autoantibodies. It occurs in patients with lymphoproliferative disease, especially Waldenstroem’s macroglobulinemia or non Hodgkin's lymphoma. The autoantibodies belong to the IgM class and are responsible for the agglutination of red blood cells. Cold autoantibody autoimmune hemolytic anemia develops slowly over the course of years.

Laboratory findings

The initial detection of cold autoantibodies often occurs when a high mean cellular volume (MCV) of the red blood cells is revealed by the complete blood count. The direct antiglobulin (Coombs) test is positive with antiserum to C3d and, to a lesser extent, C3b. IgM is no longer detectable since it is dissociated from the red blood cells. The complement fragment C3d is the result of proteolytic degradation of erythrocyte bound C3b.

29.3.1.3 Microangiopathic hemolytic anemia

Microangiopathic hemolytic anemia appears to be related to the activation of pro coagulants of the blood coagulation system by the malignant tumor. The pro coagulant proteins activate factor X, inducing the activation of fibrinogen with the formation of micro thrombi (Section 16.8.2 – Cancer-related venous thromboembolism). Overall, microangiopathic hemolytic anemia is rare, but it is more common in mucin producing tumors (ovary, adenocarcinoma of the gastrointestinal tract).

Laboratory findings

Thrombocytopenia, decreased MCV, presence of schistocytes, elevated levels of fibrin monomer and D-dimer due to a usually mild consumptive coagulopathy.

29.3.2 Para neoplastic erythrocytosis

Erythropoietin (EPO) induced erythrocytosis has been demonstrated in patients with renal cell carcinoma, hepatocellular carcinoma, and cerebellar hemangioblastoma. The cells of these tumors produce ectopic EPO. In children with Wilms’ tumor, ectopic EPO production (but no erythrocytosis) has been shown. The reason for this is the production of immunoreactive but biologically inactive EPO /10/.

Around 10–33% of patients with renal cell carcinoma have elevated concentrations of EPO but only ≤ 8% have erythrocytosis. Anemia is much more common than erythrocytosis /11/. The measured EPO concentration is usually within the range seen in patients with iron-deficiency anemia (40–120 U/L) and rarely exceeds this.

29.3.3 Para neoplastic disorders of thrombocyte count

Approximately one third of tumor patients have thrombocytosis defined as a thrombocyte count higher than 400 × 109/L /12/ e.g., in patients with epithelial ovarian cancer /13/.

Immune mediated thombocytopenia is most common in lymphomas and occasionally in solid tumors.

29.3.4 Para neoplastic granulocytosis

Para neoplastic granulocytosis occurs in approximately 15% of patients with solid tumors. The leukocyte count ranges between 12 and 30 × 109/L. In patients with leukocyte counts > 40 × 109/L the following etiologies were identified: hematopoietic growth factors (69%), Infection (15%), para neoplastic (10%) glucocorticoids or vasopressors (5%) /14/.

29.3.5 Para neoplastic eosinophilia

Para neoplastic eosinophilia is a clonal phenomenon or represents a secondary eosinophilia.

Clonal eosinophilia is associated with the rearrangement of genes (e.g., FIP1L1, PDGFR and FGFR1) caused directly by a hematologic neoplastic process /15/.

Secondary eosinophilia appears due to production of eosinophil growth factors (e.g., IL-2, IL-5 and GM-CSF). The most common associated malignancies are lymphomas and leukemias, but can also be seen with lung, gastrointestinal, and gynecologic tumors /2/.

29.4 Para neoplastic manifestations in hemostasis

Disorders of hemostasis are a common problem in patients with cancer, especially hyper coagulability and thrombosis. Thrombosis occurs more frequently in conjunction with solid tumors, while hemorrhage is more commonly associated with hematological neoplasia. Refer also to Section 16.8 – Hemostasis in tumor patients.

29.4.1 Hyper coagulability and thrombosis

The clotting factors most elevated are fibrinogen, F V, F VIII:C, F IX and F XI. Increased fibrinogen and platelet catabolism happen in many patients with disseminated malignancy. Intravascular coagulation may be mild and manifests only by laboratory findings such as elevated levels of D-dimer, increase in fibrinogen/fibrin degradation products (e.g., fibrinopeptide A or B), and a decrease in fibrin level. Clinically, intravascular coagulation may proceed as localized thrombosis or venous thromboembolism, or may be manifested as a systemic (disseminated) intravascular coagulation event associated with hemorrhage and thrombosis /12/.

29.4.2 Hemorrhage

In leukemia, hemorrhage may precede the clinical diagnosis by several months. Early manifestations are often petechiae, ecchymoses, and purpura. These findings are present in 40–70% of patients with acute leukemia at the time of diagnosis. Hemorrhage is a common cause of death in about 40% of these patients but has been surpassed by infection /12/.

Thrombocytopenia is the most common cause of life threatening hemorrhage in acute leukemias and end-stage chronic leukemias.

The hemostatic disturbances that occur in hematological neoplasms are listed in:

29.4.3 Disorders of hemostasis in solid tumors

In solid tumors, venous thromboses and venous thromboembolism predominate because of the release of tumor pro coagulants and/or the presence of thrombocytosis /16/. The general incidence of thrombosis is 15%. Postoperatively, patients with malignant tumors develop deep venous thrombosis more frequently than patients without cancer. In cases with a malignant gastrointestinal tumor, the incidence of a postoperative thrombotic or thromboembolic event can be as high as 40%. The occurrence of hemorrhage in patients with solid tumors is linked to the development of disseminated intra vascular coagulation and primary activation of fibrinolysis.

Venous thromboembolism (VTE) occurs in about 3% of lung cancer patients within 2 years of the cancer diagnosis /17/. The incidence is 40–100 cases per 1,000 person-years in lung cancer patients compared with 1–2 cases per 1,000 person-years in the general population. Non small cell lung cancer (NSCLC) is associated with a higher VTE risk than small cell lung cancer (SCLC) and of the NSCLCs, adenocarcinoma is associated with a higher risk of VTE than squamous cell carcinoma /18/.

The hemostatic disorders that are associated with solid tumors are presented in Tab. 29-6 – Hemostatic disturbances in patients with solid tumors.

29.5 Para neoplastic endocrine syndromes

Para neoplastic endocrine syndromes result from ectopic production of hormones or peptides by malignant tumors. Hormones and peptides released by these tumors cause symptoms of endocrine hyper functional states at sites that are remote from the tumor and are detected typically after cancer diagnosis /119/. Examples are SIADH, hypercalcemia, Cushing syndrome, and hypoglycemia. The development of these disorders does not correlate with cancer stage or prognosis /2/. Endocrine para neoplastic syndromes are usually associated with poorer survival outcomes. For clinical features, associated malignancies and diagnostic investigations refer to Tab. 29-7 – Para neoplastic hormone secretion.

29.6 Para neoplastic neurological syndromes (PNS)

Neurologic manifestations in patients with cancer can be caused by metastases, metabolic disorders, infections, vascular insults or by the neurotoxicity resulting from chemotherapy or radiotherapy /20/. PNS are triggered by an antitumor immune response producing antibodies that react with both the tumor and the nervous system that leading to functional or structural damages. A variety of antibodies are associated with different syndromes and cancer or its metastases /21/. Most para neoplastic neurological diseases have a prevalence of well below 1% and occur mainly in association with small cell lung cancer /21/. Refer also to Section 25.6 – Neurological syndromes associated with autoantibodies.

PNS are caused by neuronal autoantibodies which have diagnostic and possibly pathogenic roles. Para neoplastic neurological diseases include:

  • Limbic encephalitis
  • Myasthenia gravis, which occurs in 10–15% of patients with thymoma
  • Lambert-Eaton myasthenic syndrome (LEMS), which has a prevalence of 3% in small cell lung cancer.
  • Para neoplastic peripheral neuropathy, which have a prevalence of 10% in symptomatic monoclonal gammopathies.

Indication

A PNS may be present in cancer patients:

  • With combinations of clinical signs and symptoms (endocrine, neurologic, immunologic, dermatologic, metabolic, constitutional, and hematologic)
  • With subacute neurological symptoms that cannot be clarified by regular neurological or laboratory investigations
  • With carcinoma and neurological symptoms that cannot be explained by metastasis.

Autoantibodies associated with PNS are named according to nomenclatures:

  • Using the first two letters of the index patient’s name (e.g., Hu for Hull, Ma for Margaret, Yo for Young) as in the original nomenclature by Posner /21/.
  • According to the immunohistological appearance in the immunofluorescence test (e.g., ANNA-1 for neuronal antinuclear antibody 1).

Refer to Tab. 29-8 – Neuronal antibodies associated with paraneoplastic neurological syndrome.

Clinical and laboratory findings

The overall history, symptoms, and course of para neoplastic diseases are as follows:

  • Most para neoplastic diseases occur in patients before a cancer has been diagnosed
  • Para neoplastic diseases begin acutely or subacutely, progress over the course of weeks or months, and then stabilize. The neurological symptoms lead to considerable co morbidities.
  • Some neurological syndromes (e.g., LEMS) are so characteristic for a para neoplastic neurological disease that a malignant disease is immediately suspected
  • In the event of central nervous system involvement, pathological laboratory findings may be present: mild pleocytosis, increased IgG and oligoclonal bands in the cerebrospinal fluid (CSF), and autoantibodies against neuronal antigens in the CSF and serum. Antibody specificity is higher in the CSF than in the serum, which suggests that they are produced in the CSF.

Biochemistry and physiology

PNS are mediated by autoimmune processes. The tumor expresses an antigen that is normally only produced in the central nervous system. Although the tumor antigen is identical to the neuronal antigen, the immune system recognizes it as foreign and launches an immune response. However, this is only possible if the reactive T cells and anti-neuronal antibodies can cross the blood-brain barrier. Onconeural antigens can be demonstrated in the tumors of all patients with anti-onconeural antibody positive para neoplastic disease. Tumors such as small cell lung cancer always contain onconeural antigens, even in the absence of autoantibody formation or para neoplastic neurological disease.

29.7 Para neoplastic syndromes in lung cancer

Most patients with lung cancer and para neoplastic syndrome (PNS) will be symptomatic at presentation. The manifestations of PNS in lung cancer are shown in:

References

1. Dimitriadis GK, Angelousi A, Weickert MO, Randeva HS, Kaltsas G, Grossman A. Paraneoplastic endocrine syndromes. Endocr Relat Cancer 2017; 24: R173-R190.

2. Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010; 85: 838–54.

3. Baijens LW, Manni JJ. Paraneoplastic syndromes in patients with primary malignancies of the head and neck: four cases and a review of the litetature. Eur Arch Otorhinolaryngol 2006; 263: 32–6.

4. Barry MY, Knochel JP. Hypercalcemia and electrolyte disturbances in malignancy. Hematol Oncol Clin North Am 1996; 10: 775–90.

5. Sorlini M, Benni F, Cravarezza P, Romanelli G. Hypoglycemia, an atypical early sign of hepatocellular carcinoma. J Gastrointest Cancer 2010; 41: 209–11.

6. Daughady WH, Triverdi B, Baxter RC. Serum “big insulin-like growth factor II” from patients with tumor induced hypoglycemia lacks normal E-domain O-linked glycosylation, a possible determinant of normal propeptide processing. Proc Natl Acad Sci USA 1993; 90: 5823–7.

7. Frenkel EP, Bick RL, Rutherford C. Anemia of malignancy. Hematol Oncol Clin North Am 1996; 10: 861–73.

8. Young NS. Aplastic anemia. N Engl J Med 2017; 379: 1643–56

9. Brodsky RA. Warm autoimmune hemolytic anemia. N Engl J Med 2019; 381: 647–54.

10. Ljungberg B, Rasmuson T, Grankvist K. Erythropoietin in renal cell carcinoma: evaluation of its usefulness as a tumor marker. Eur Urol 1992; 21: 160–3.

11. Gross AJ, Wolff M, Fandrey J, Miersch WD, Dieckmann KP, Jelkmann W. Prevalence of paraneoplastic erythropoietin production by renal cell carcinomas. Clin Investig 1994; 72: 337–40.

12. Bick RL, Strauss JF, Frenkel EP. Thrombosis and hemorrhage in oncology patients. Hematol Oncol Clin North Am 1996; 10: 875–907.

13. Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford-Miller J, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2012; 366: 610–8.

14. Granger JM, Kontoyiannis DP. Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single-institution study. Cancer 2009; 115: 3919–23.

15. Tefferi A, Gotlib J, Pardanami A. Hypereosinophilic syndrome and clonal eosinophilia: point of care diagnostic algorithm and treatment update. Mayo Clin Proc 2010; 85: 158–64.

16. Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 1983; 62: 14–31.

17. Chew HK, Davies AM, Wun T, et al. The incidence of venous thromboembolism among patients with primary lung cancer. Fibrinolysis in cancer. J. Thromb Haemost 2008; 6: 601–8.

18. Yeung SCJ, Habra MA, Thosani SN. Lung cancer-induced paraneoplastic syndromes. Curr Opin Pulm Med 2011; 17: 260–8.

19. Keffer JH. Endocrinopathy and ectopic hormones in malignancy. Hematol Oncol Clin North Am 1996; 10: 811–23.

20. Viau M, Renaud MC, Gtegoire J, Sebastianelli A, Plante M. Paraneoplastic syndromes associated with gynecological cancers: a systematc review. Gynecologic Oncology 2017; 146: 661–71.

21. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N engl J Med 2003; 349: 1543–54.

22. Posner JB, Dalmau J. Clinical enigmas of paraneoplastic neurologic disorders. Clin Neurol Neurosurg 1995; 97: 61–70.

23. Beckles MA, Spiro SG, Colice GL, Rudd RM. Initial evaluation of the patient with lung cancer. Symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest 2003; 123: 97S–104S.

24. Stewart AF. Hypercalcemia associated with cancer N Engl J Med 2005; 352: 373–9.

25. Raue F, Ziegler R. Diagnostik paraneoplastischer endokriner Syndrome. Diagnose und Labor 1995; 45: 9–16.

26. Dispensieri A. POEMS syndrome: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 2011; 86: 592–601.

27. Krauth MT, Puthenbarambil J, Lechner K. Paraneoplastic autoimmune thrombocytopenia in solid tumors. Crit Rev Oncol/Hematol 2012; 81: 75–81.

Table 29-1 Para neoplastic disturbances of calcium and electrolyte metabolism /4/

Clinical and laboratory findings

Hypercalcemia

About 10–20% of patients with advanced carcinoma develop hypercalcemia during the course of the disease. The probability depends on the duration of the disease, the tumor location, and the presence of metastatic spread.

Solid tumors: hypercalcemia is often associated with breast cancer, lung cancer, cholangiocarcinoma, and squamous cell carcinoma of the head and neck region. Severe hypercalcemia occurs especially in renal cell carcinoma and in non small cell lung cancer. Refer to Section 6.2 – Calcium. Two thirds of patients with small cell carcinoma of the ovary are associated with hypercalcemia.

Hematological neoplasms: hypercalcemia is most commonly seen in lymphomas and in multiple myeloma. The hypercalcemia is usually of a moderate degree.

In children with malignant tumors, the prevalence of hypercalcemia is 0.4–0.7%. Most of the hypercalcemias have been described in patients with malignant rhabdoid tumor of the kidney and mesoblastic nephroma. In addition, para neoplastic hypercalcemia has been reported in renal sarcoma, leukemia, neuroblastoma and pheochromocytoma /2/.

In 80% of cases, tumor associated hypercalcemia is due to neoplastic calcium resorption as a result of bone metastases. Approximately 20% of patients with solid tumors and hypercalcemia have no bone metastases. In these cases, humoral factors are the underlying cause:

  • Parathyroid-related peptide (PTHrP). With the exception of multiple myeloma, PTHrP is found to occur much more commonly in solid tumors than in hematological neoplasms. Depending on the method of determination, elevated PTHrP concentrations are measured in 53–98% of non selected patients with tumor related hypercalcemia /5/.
  • Osteolytic prostaglandins, especially prostaglandin E. These occur in patients with, for example, lung, renal, and ovarian cancer.
  • Cytokines and growth factors such as interleukin-1, tumor necrosis factor α, colony stimulating factor, or lymphotoxin, which promote bone resorption by stimulating osteoclast activity.

Clinical findings of tumor hypercalcemia: nausea , vomiting, letargia, renal failure, and coma.

Laboratory findings: calcium levels > 14 mg/dL (3.5 mmol/l) are considered as severe, PTH normal, PTHrP elevated.

Therapy: intravenous bisphosphonates (pamidronate, zoledronate) inhibit osteoclast bone resorption. Serum calcium levels will decline within 2 to 4 days, reach a nadir between 4 and 7 days after infusion and remain suppressed for up to 3 weeks /24/.

Hypophosphatemia

In mesenchymal tumors, prostate cancer, and multiple myeloma, oncogenic osteomalacia may occur. Characteristic laboratory findings include hypophosphatemia, hyper phosphaturia, and a decreased serum concentration of 25-OH vitamin D.

Hypomagnesemia

The hypomagnesemia observed in tumor patients is presumed to be caused by the increased magnesium requirements of the rapidly proliferating neoplastic cells. However, non para neoplastically induced hypomagnesemia must also be taken into consideration such as the reduced tubular reabsorption of magnesium as a result of chemotherapy using cisplatin or of aminoglycoside therapy.

Hyponatremia /2/

Approximately 1–2% of patients with a malignant tumor develop the syndrome of inappropriate antidiuretic hormone secretion (SIADH). It is characterized by hypo-osmotic euvolemic hyponatremia. In contrast to hypovolemic hyponatremia caused by gastrointestinal losses, excessive diuresis, adrenal insufficiency, salt-wasting nephropathy, SIADH causes euvolemic hyponatremia.

The ectopic production of antidiuretic hormone (ADH) is induced mainly by small cell lung cancer (SCLC) and more rarely by pancreatic cancer, thymoma, hepatoma, or lymphoma. Often, ADH is secreted together with neurophysin and oxytocin, both of which are cleaved off from a mutual precursor molecule. Although the ADH concentration is elevated in up to 50% of patients with SCLC, only about 5% of them show SIADH symptoms /25/.

Clinical findings of tumor hyponatremia: the symptoms are dependent on the degree and rapidity of onset of hyponatremia. Mild symptoms include headache, weakness, and memory difficulties. Serious Na+ concentrations below 125 mmol/L developing within 2 days can be associated by seizures, altered mental status, coma, respiratory collapse, and death.

Laboratory findings: serum Na+ of less than 130 mmol/L, urine Na+ level > 40 mmol/L, urine osmolality > 100 mosmol/kg, normal central venous pressure, normal uric acid, normal blood urea nitrogen. Refer also to Section 8.5 – Osmolality.

Hypokalemia /4/

Hypokalemia occurs in up to 75% of tumor patients over the course of their disease. The causes are manifold, including an inadequate uptake of potassium as well as renal or extrarenal losses; underlying disturbances in K+ homeostasis between the intracellular and extracellular fluid compartment can also be responsible for hypokalemia. Hypokalemia can also be a symptom of para neoplastic ACTH secretion. Refer to Section 8.7 – Potassium.

Hyperkalemia in the form of a pseudo hyperkalemia, defined as a difference of more than 0.4 mmol/L between the measured K+ and the true value, can occur due to the release of K+ from blood cells in association with thrombosis as well as acute and chronic myeloproliferative syndromes and leukemias with high cell counts.

Table 29-2 Direct and para neoplastic mechanisms in patients with anemia of malignancy /7/

Direct causes

Acute or chronic exogenous blood loss

  • Gastrointestinal tumor
  • Genitourinary cancer
  • Cervical and vaginal tumor
  • Tumors of the head and neck region

Intra tumor bleeding

  • Sarcoma
  • Large melanoma, hepatoma, ovarian tumor, adrenocortical tumor

Displacement of hematopoietic bone marrow

  • Leukemia
  • Lymphoma
  • Multiple myeloma
  • Solid tumors (breast and prostate cancer)

Para neoplastic mechanisms

Antibody-mediated hemolytic anemia

  • Warm antibodies
  • Cold antibodies

Microangiopathic hemolytic anemia

Anemia of malignancy (increased hepcidin and cytokine secretion)

Table 29-3 Hemostatic disturbances in hematological neoplasias /12/

Clinical and laboratory findings

Acute leukemia

Hemorrhage can occur in any type of acute leukemia but is especially common in acute pro myelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), and acute myeloblastic leukemia (FAB M1 and M2).

Coagulation disorders: hepatic infiltration is associated with impaired synthesis of the vitamin K-dependent coagulation factors II, VII, IX, and X but also of F V, F VIII:C, F XI, F XII, F XIII, protein S, protein C, and antithrombin.

Thrombocytopenia: hemorrhage is usually not observed if the platelet count is above 10 × 109/L but occurs commonly if the count is below 5 × 109/L. During therapeutic remission, daily urine monitoring for the presence of erythrocytes and daily stool tests for occult blood should be performed if the platelet count is below 50 × 109/L. A platelet count of less than 5 × 109/L requires platelet replacement therapy.

Platelet function: platelet dysfunction is rare in acute leukemia.

Disseminated intravascular coagulation (DIC): in up to 50% of patients with acute leukemia, the clinical course can be complicated by the occurrence of DIC. This is especially the case, in descending order of frequency, in patients with acute pro myelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute myeloblastic leukemia (FAB M1, M2), and acute lymphoblastic leukemia.

Chronic leukemia

In chronic myeloid and chronic lymphocytic leukemia, hemorrhage is only a minor problem whereas local or diffuse thrombotic and thromboembolic events are common.

Coagulation disorders: as in acute leukemia, chronic leukemia with hepatic infiltration may be associated with a reduction in the vitamin K dependent coagulation factors but also of other coagulation factors. Many patients with chronic lymphocytic leukemia have a prolonged prothrombin time.

An acquired, usually type II von Willebrand syndrome is also frequently encountered. It occurs in combination with the hematological neoplasms listed in Tab. 29-4. The underlying cause is thought to be either a circulating inhibitor directed against the von Willebrand factor or proteolytic degradation of the factor.

Thrombocytopenia: with the occasional exception of the early stages of disease, chronic myeloid and chronic lymphocytic leukemia are associated with a platelet count > 50 × 109/L. In the terminal stage of chronic lymphocytic leukemia, thrombocytopenia does, however, become a serious problem.

Platelet function: platelet dysfunction occurs in 30% of patients with chronic myeloid leukemia, in 50% of those with osteomyelofibrosis, and in 70% of those with polycythemia vera.

DIC: granulocytes and lymphocytes may release pro coagulant factors into the circulation. Fulminant DIC is seen less often in chronic leukemia than in acute leukemia but is encountered more commonly in chronic myeloid leukemia than in chronic lymphocytic leukemia.

Multiple myeloma

Hemostatic disturbances in patients with monoclonal gammopathy can cause hemorrhage or thrombosis although hemorrhage occurs more frequently. Hemorrhage is found in 15% of patients with an underlying IgG myeloma, in 40% of those with an IgA myeloma, and in more than 60% of those with Waldenstroem’s macroglobulinemia or an IgM myeloma.

Coagulation disorders: monoclonal immunoglobulins bind to coagulation factors and are capable of inhibiting them (e.g., F VIII:C). The specific inhibition of coagulation factors by monoclonal immunoglobulins is shown in Tab. 29-5. The thrombin time or reptilase time are valuable indicators for detecting a disturbance in the polymerization of fibrin that occurs in more than 50% of patients with symptomatic monoclonal gammopathy.

Thrombocytopenia: mild thrombocytopenia is more commonly seen in symptomatic monoclonal gammopathy.

Thrombocytosis: this is a minor criterion; major criteria include clonal plasma cell disorder and polyradiculoneuropathy /26/.

Platelet function: platelet dysfunction occurs more frequently than thrombocytopenia. Platelet aggregation is impaired in approximately 80% of patients with multiple myeloma. However, the correlation between impaired platelet aggregation and the bleeding time is weak.

DIC: DIC does not usually occur in symptomatic monoclonal gammopathy.

Solid tumor and autoimmune thrombocytopenia

An autoimmune thrombocytopenia (AIT) can occur in association with solid tumors, in particular lung carcinoma and breast carcinoma. AIT is rare in prostate carcinoma but common in renal cell carcinoma and ovarian carcinoma. Thrombocytopenia occurs in about 50% of patients concurrently with cancer, in about 25% prior to cancer, and in another 25% during treatment.

Laboratory findings: a review /27/ of patients with AIT found the following: of the patients who were thrombocytopenic prior to cancer, 9 out of 17 had a platelet count of ≤ 20 × 109/L. Of those who had thrombocytopenia concurrently with cancer, 22 out of 35 had a platelet count of ≤ 20 × 109/L and the rest had a platelet count of ≤ 10 × 109/L. In patients in whom AIT occurred during treatment, the platelet count was always ≤ 20 × 109/L. Only a few patients had a complete response of AIT following cancer resection or chemotherapy. Some patients also had antibodies against red blood cells.

Myeloproliferative syndrome

Myeloproliferative disease is more commonly associated with thrombosis because of the presence of thrombocytosis. However, in an individual patient, the platelet count and increased platelet aggregation correlate only poorly with the actual risk of undergoing a thrombotic event.

Table 29-4 Hematologic neoplasias associated with an acquired von Willebrand syndrome /12/

  • Chronic myeloid leukemia
  • Chronic lymphocytic leukemia
  • Hairy cell leukemia
  • Myelodysplastic syndrome
  • Multiple myeloma
  • Polycythemia vera
  • Idiopathic thrombocythemia
  • Osteomyelofibrosis

Table 29-5 Specific inhibition of blood coagulation by monoclonal immunoglobulins /12/

Monoclonal Ig

Inhibition

IgG

Factor II, VII, X, thrombin

IgM, IgA

Factor V, VIII:C

In general

Inhibition of fibrin monomer polymerization into a stable fibrin clot

Table 29-6 Hemostatic disturbances in patients with solid tumors

Clinical and laboratory findings

Hypercoagulability and thromboembolism

Solid tumors that are commonly associated with thrombosis include /17/: lung cancer (27.9%), pancreas cancer (18.4%), stomach cancer (17%), colon cancer (15.7%), uterus and ovary cancer (7.2%), and prostate cancer (7.1%). Coagulation is activated by two tumor pro coagulants /17/:

  • Tissue factor; this is a F VII and lipid dependent cofactor for F X activation in pleural mesothelioma and ovarian cancer
  • F X activator (cancer pro coagulant). The factor is a cysteine protease that is produced in embryonic tissues such as amnion chorion cells and malignant tumor cells. Cancer pro coagulant is secreted by mucus producing adenocarcinomas, colon carcinoma, gastric carcinoma, breast carcinoma, squamous cell carcinoma of the vagina, renal cell carcinoma, hepatoma, melanoma, and sarcoma.

Hemorrhage

In patients with solid tumors, hemorrhage occurs as part of DIC, which may run a mild or fulminant course. Fulminant DIC with life threatening hemorrhage is found to occur more frequently in conjunction with cancer of the lung, stomach, gallbladder, colon, breast, and ovary as well as in malignant melanoma.

Activation of the fibrinolytic system by a tumor induced increase in urokinase type plasminogen activator (u-PA) is pronounced in cancer of the breast, prostate, and pancreas as well as in colorectal carcinoma /18/.

Table 29-7 Para neoplastic hormone secretion /19/

Hormone

ACTH

The ectopic ACTH syndrome is caused by small cell lung cancer (SCLC) in more than 50% of cases; other tumors that cause this syndrome include: bronchial carcinoid, thymoma, medullary thyroid cancer, pheochromocytoma, and nephroblastoma (up to 20% of childhood neoplasms, rare in adults). Ectopic ACTH production and, less commonly, ectopic corticotropin releasing factor (CRF) production, give rise to Cushing’s syndrome. Clinical apparent Cushing’s syndrome associated with ectopic ACTH production has been reported for 1.6–4.5% of SCLC cases, whereas biochemical abnormalities suggestive of Cushing’s syndrome have been found in as many as 30–50% of SCLC patients. However, Cushing’s syndrome can be easily overlooked in patients with cancer because they do not exhibit the typical cushingoid appearance due to cachexia.

Laboratory findings: serum ACTH over 15 ng/L, non suppressed cortisol concentration after high dose dexamethasone suppression (Tab. 34.3-1 – Conditions associated with pseudo Cushing's syndrome) , elevated 24 h urine free cortisol level, hypokalemia and hyperglycemia /18/.

ADH

The inappropriate secretion of ADH (SIADH) leads to hyponatremic hypovolemia as a result of renal sodium losses (refer to Section 8.6 – Arginine vasopressin (AVP), copeptin (CT-proAVP)). This syndrome is also known as Schwartz-Bartter syndrome and is caused by ectopic ADH production, mainly in 10–45% of SCLC cases, 1% of other lung cancer cases (squamous cell carcinoma) but also in duodenal cancer, pancreatic cancer, and thymoma.

Laboratory findings /18/: hyponatremia (below 130 mmol/L), hypo osmolality (below 275 mosm/kg), increased urine Na+ excretion (over 40 mmol/L), inappropriately high urine osmolality (over 500 mosm/kg) relative to the plasma osmolality. Exclusion of hypothyroidism, adrenal insufficiency or volume depletion.

PTHrP

PTHrP is produced by lung cancer as well as other solid tumors and causes tumor-associated hypercalcemia (refer also to Section 6.5 – Parathyroid hormone-related peptide (PTHrP)).

GH, GHRH

Growth hormone (GH) and its releasing hormone (GHRH) can be synthesized by pancreatic cancer and result in acromegaly and hyperglycemia.

hCG

Human chorionic gonadotropin (hGC) or hCG fragments are produced by many neoplasms. Increased production of hCG or hCG fragments is thought to occur in about 18% of patients with malignant tumors. In general, the concentrations are so low that they do not have any biological effect. However, giant cell carcinomas of the lung, gastric carcinomas, and renal cell carcinomas can produce serum concentrations that are high enough to cause gynecomastia in adult men.

In prepubescent males, hCG-producing hepatoblastomas lead to precocious puberty by stimulating the production of testosterone by testicular Leydig cells.

Vasoactive intestinal polypeptide (VIP)

The ectopic production of VIP leads to symptoms such as watery diarrhea, hypokalemia, and achlorhydria (WDHA). In adults WDHA syndrome has been described in a variety of tumors, but mostly in VIPomas originating from the pancreas. In children, VIP producing WDHA is associated with neural crest tumors (ganglioneuromas and ganglioneuroblastomas). For more about VIP, also refer to Section 14.5.1 – Neuroendocrine tumors.

Table 29-8 Neuronal antibodies associated with para neoplastic neurological syndrome /2122/

Antibody

Antigen
(kDa),
Gene

Immuno-
histochemistry

Tumor

Disease

Anti-Hu
(ANNA-1)

35–40

HuD, HuC,
Hel-N1

Nuclei of the CNS and peripheral nervous system neurons, retina, adrenal cortex

SCLC (70%), neuro­blastoma, prostate carcinoma

Paraneoplastic
Encephalomyelitis

Sens. neuropathy

Autonomic dysfunction

Anti-Yo
(PCA-1)

34, 62

CDR 34
CDR 62

Purkinje cell cytoplasm

Ovarian,
breast, lung carcinoma

Paraneoplastic cerebellar degeneration

Anti-Ri

55, 80

Nova

Nuclei of peripheral nervous system neurons

Breast, fallopian tube,
bladder carcinoma, SCLC

Ataxia with or without opsoclonus myoclonus

Anti-CRMP5
(Anti-CV2)

66

CRMP5
(POP66)

Cytoplasm of oligodendrocytes, neurons

SCLC,
thymoma

Encephalomyelitis, cerebellar degeneration, chorea, sensory neuropathy

Anti-
amphysin

128

Amphysin

Presynaptic nerve terminals

Breast carcinoma,
SCLC

Stiff person syndrome, encephalomyelitis

Anti-Ma2

41.5

Ma2

Neurons (nucleolus)

Testicular carcinoma

Limbic encephalitis

Anti-
recoverin

23, 65,
145, 205

Recoverin

Retinal photoreceptors, ganglion cells

SCLC, melanoma, gynecologic carcinoma

Retinopathy associated with carcinoma, melanoma

Anti-
titin

3.000

Titin

Titin

Thymoma

Myasthenia gravis

The immunohistochemical terms for the antibodies appear in parentheses ( ). Abbreviations: CNS, central nervous system; PNS, paraneoplastic neurological syndrome; SCLC, small cell lung cancer

Table 29-9 Lung cancer associated with endocrine paraneoplastic syndromes /23/

Endocrine

Neurologic

Skeletal

Renal

Metabolic

SIADH

Subacute sensory
neuropathy

Hypertrophic
osteopathy

Glomerulo-
nephritis

Lactic
acidosis

Non metastatic
hypercalcemia

Mononeuritis
multiplex

Clubbing

Nephrotic
syndrome

Hypo-
uricemia

Cushing’s
syndrome

Intestinal pseudo-
obstruction

 

Gynecomastia

Lambert-Eaton
syndrome

Hyper-
calcitoninemia

Encephalomyelitis

Elevated levels
of LH, FSH

Necrotizing
myelopathy

Hyper-
thypoidism

Cancer associated
retinopathy

Carcinoid
syndrome

 

Table 29-10 Lung cancer associated with endocrine para neoplastic syndromes /23/

Ectopic production

ACTH

Cushing’s syndrome can develop due either to ectopic production or to aberrant processing of ACTH by small cell lung cancer (SCLC) cells. Cushing’s syndrome is described in 1 to 5% of patients with SCLC. These patients present with extensive stage disease. Increased serum levels may be detected in up to 50% of patients with lung cancer.

ADH

Approximately 1–5% of lung cancer patients have symptoms attributable to SIADH (refer to Section 8.6 – Arginine vasopressin (AVP), copeptin (CT-proAVP)). Elevated ADH levels explain the impaired ability to excrete the water load. The syndrome resolves within 3 weeks with the initiation of cytotoxic chemotherapy in 80% of patients.

PTHrP

Increased PTHrP levels released from lung cancer cells cause increased bone resorption (refer to Section 6.5 – Parathyroid hormone-related peptide (PTHrP)). Approximately 2–6% of patients show hypercalcemia at presentation and 8–12% throughout the course of disease.

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