Haematology & Oncology Flashcards
(164 cards)
1
Q
What is the most likely diagnosis?
What biochemical defect is responsible for this condition?
A
Acute intermittent porphyria (AIP).
AIP is caused by a deficiency in
porphobilinogen deaminase (also known as hydroxymethylbilane synthase), an enzyme required for hemoglobin production. Typically, patients have accumulation of porphobilinogen and present with neuropathy and attacks of abdominal pain caused by precipitants that increase α-aminolevulinic acid (ALA) synthase activity. ALA production from glycine and succinyl CoA by ALA synthase is the rate-limiting step of heme production. As a result, any increase in ALA production leads to more AIP symptoms (Figure 8-1).
2
Q
What are the most likely precipitants of this patient’s attacks?
A
Precipitants that increase ALA synthase activity include the following:
1. Endogenous/exogenous gonadal steroids.
2. Low-calorie diets.
3. Drugs (sulfonamides, antiepileptic agents).
4. Stress.
5. Alcohol.
3
Q
What other condition should be considered if the patient has neurologic manifestations but no abdominal pain?
A
Ascending muscle weakness with hyporeflexia or areflexia is the classic presentation of Guillain-Barré syndrome. However, the high level of porphobilinogen in the urine of this patient is essentially pathognomonic for AIP. If the diagnosis is unclear, a lumbar puncture can be performed. Albuminocytologic dissociation is seen in the cerebrospinal fluid of patients with Guillain-Barré syndrome. Other possible causes of peripheral muscle weakness include muscle atrophy, leprosy, myeloma, lead poisoning, and diabetes.
4
Q
What is the appropriate treatment for Acute intermittent porphyria (AIP)?
A
Heme, as the end product of the biosynthetic pathway, is a repressor of ALA synthase. Therefore, an intravenous injection of hemin (IV heme) decreases synthesis of ALA synthase via negative feedback and often reduces the severity of symptoms. Intravenous infusion of dextrose solution can also help abate acute attacks. Hemin is used for refractory cases after failure of carbohydrate loading. Treatment of pain and monitoring for neurologic and respiratory compromise are essential.
5
Q
What is the most likely diagnosis? What conditions should be considered in the differential diagnosis?
A
Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. The classic presentation and laboratory findings include fever (the most common sign), fatigue, lethargy, bone pain, arthralgia, and elevated serum lactate dehydrogenase (LDH). Less common symptoms include headache, vomiting, altered mental function, oliguria, and anuria.
6
Q
What is the etiology of the physical examination findings in this patient with acute lymphoblastic leukemia?
A
Most findings derive from leukemic expansion and crowding out of the normal marrow. This causes anemia and thrombocytopenia as well as bone or joint pain from invasion into the periosteum. Fever results from pyrogenic cytokines released from leukemic cells. Elevated LDH is a consequence of increased cellular turnover. Painless enlargement of the scrotum and central nervous system symptoms may also be signs of more extensive extramedullary invasion.
7
Q
What is the appropriate treatment for Acute lymphoblastic leukemia (ALL)?
A
Complex chemotherapy regimens are standard and divided into induction, consolidation, and maintenance phases. Most regimens involve combinations of cyclophosphamide, doxorubicin, vincristine, dexamethasone/prednisone, methotrexate, asparaginase, and cytarabine. Recent advances in treatment have resulted in complete remission rates as high as 80% in children with ALL.
8
Q
What is the most likely diagnosis?
What cells are affected in this condition?
What other symptoms are common at presentation in this condition?
A
Acute myelogenous leukemia (AML) is the most common acute leukemia in adults. The median age of diagnosis in the United States is 65 years.
AML is a neoplasm of myelogenous progenitor cells. The progenitor cells may appear as granulocyte precursors, monoblasts, megakaryoblasts, or erythroblasts.
9
Q
What are the likely bone marrow biopsy findings in Acute myelogenous leukemia (AML)?
A
The proliferation of myeloblasts with characteristic eosinophilic, needle-like cytoplasmic inclusions, or Auer rods, is pathognomonic for AML (Figure 8-3).
10
Q
How can genetic testing influence treatment of Acute myelogenous leukemia (AML)?
A
Genetic abnormalities are critical in the diagnosis and treatment of AML. For example, t(15;17) chromosomal translocation indicates acute promyelocytic leukemia (M3 variant) as the specific diagnosis. This can be treated with targeted drugs such as all-trans retinoic acid, which differentiates promyelocytes into mature neutrophils, thereby inducing apoptosis of the leukemic promyelocytes. This results in a high likelihood of remission and cure.
11
Q
Why is cellulitis commonly associated with Acute myelogenous leukemia (AML)?
A
Neutropenia caused by replacement of mature WBCs with leukemic cells increases susceptibility to infection.
12
Q
What is the most likely diagnosis? What is the most likely cause of this patient’s condition?
A
Aplastic anemia results from bone marrow failure or autoimmune destruction of myeloid stem cells, which leads to pancytopenia. Pancytopenia affects all cell lines, resulting in neutropenia, anemia, and thrombocytopenia, all of which are seen on a complete blood count.
13
Q
What other test can help confirm the diagnosis of aplastic anaemia?
A
Bone marrow biopsy reveals hypocellular bone marrow (< 30% cellularity) with a fatty infiltrate. Figure 8-4A shows a normal bone marrow biopsy; Figure 8-4B shows a biopsy sample from a patient with aplastic anemia.
14
Q
What is the appropriate treatment for Aplastic anemia?
A
Initial treatment is to withdraw any possible toxic agent causing the condition. Supportive care, including antibiotics for infection and blood transfusion if symptoms develop, is also important. If testing reveals severe depression of one or several cell lines, definitive therapy, including stem cell transplantation or immunosuppression, is appropriate. If possible, transfusion should be avoided before bone marrow transplantation because of the risks of alloimmunization and graft rejection.
15
Q
What is the most likely diagnosis?
A
β-Thalassemia major is the homozygous form of the genetically transmitted disease β-thalassemia, where the β-globin gene of hemoglobin is mutated, resulting in microcytic anemia. It is prevalent in Mediterranean populations.
By contrast, in α-thalassemia, α-globin genes in hemoglobin are deleted; this condition is most commonly present in Southeast Asians and blacks.
16
Q
What mutations are present in α-thalassemia and in β-Thalassemia major?
A
Humans have two α-globin genes on chromosome 16, resulting in four alpha alleles. α-Thalassemia results
in four types of thalassemia, depending on the number of alpha allele deletions that occur. Increasing severity results from increasing numbers of deletions. These deletions result from unequal meiotic crossover between adjacent alpha genes.
Humans have one β-globin gene on chromosome 11, resulting in two beta alleles. In β-thalassemia, beta allele mutations, rather than deletions, occur. These mutations can occur in the promoter, exon, intron, or polyadenylation sites. Some mutations may produce no β-globin, whereas others may produce a small amount.
17
Q
What are the symptoms and signs of β-thalassemia major?
A
Symptoms of β-thalassemia major emerge after approximately 6 months of life and are due to the decline in γ-hemoglobin production without a rise in β-hemoglobin production. The early signs and symptoms include pallor, growth retardation, hepatosplenomegaly, and jaundice.
18
Q
How is β-thalassemia diagnosed?
A
Definitive laboratory testing using gel electrophoresis is used for diagnosis, as it can distinguish mutated and normal forms of hemoglobin. An increased concentration of fetal haemoglobin (HbF) may also be seen on electrophoresis. Notably, an increase in HBA2 is seen in β-thalassemia minor.
19
Q
What is the appropriate treatment for β-thalassemia major?
A
β-Thalassemia major causes severe anemia. HbF induction may be used. Treatment with repeated blood transfusions may also be required. Subsequently, iron chelation for overload is important. Splenectomy may be necessary to treat the resulting hypersplenism. Stem cell transplantation may also be used in selected cases. β-Thalassemia minor is usually asymptomatic and its treatment requires only avoidance of oxidative stressors of RBCs.
20
Q
What is the most likely diagnosis?
What does the positive Coombs test indicate?
A
Warm autoimmune hemolytic anemia (WAIHA) secondary to SLE. Most cases of this condition are idiopathic or associated with autoimmune processes, lymphoproliferative disorders, or drugs.
The positive Coombs test indicates the presence of antibodies against RBCs, which can cause hemolysis.
21
Q
What is the difference between a direct and indirect Coombs test?
A
The difference between the direct and indirect Coombs test is where the antibodies against RBCs are detected. In a positive direct Coombs test, antibodies are detected directly on RBCs. This occurs in WAIHA, called such because a positive agglutination test will be present at 37°C (98.6°F). In a positive indirect Coombs test, antibodies are detected in the serum. This occurs at 4°C (39.2°F), which is why this is referred to as cold hemolytic anemia.
22
Q
What are other causes of Warm autoimmune hemolytic anemia (WAIHA) other than SLE?
A
The two most common causes are primary (idiopathic) and secondary due to such underlying conditions as autoimmune disorders, such as SLE. Medications (methyldopa), lymphomas, and leukemias are also common triggers.
23
Q
What is the pathogenesis of Warm autoimmune hemolytic anemia (WAIHA)?
A
This is typically an IgG-mediated process. IgG coats RBCs and acts as an opsonin, such that the RBCs are phagocytized by monocytes and splenic macrophages.
When medications are the underlying cause, the hapten model has been suggested. RBC-bound drugs are recognized by antibodies and targeted for destruction.
24
Q
What is the other form of autoimmune hemolytic anemia (AIHA)?
A
Cold agglutinin hemolytic anemia is the other form, and it occurs when IgM antibodies bind, fix complement, and agglutinate RBCs at low temperatures. These antibodies typically appear acutely following certain infections such as mononucleosis and Mycoplasma. This disease is usually self-limited but treatment-resistant forms exist. Clinical manifestations include pallor and cyanosis of distal extremities exposed to cold temperatures; this is secondary to vascular obstruction from complement deposition.
25
What is the likely diagnosis?
Breast cancer is the leading cause of cancer death in women. Most tumors develop in the upper/outer quadrants (Table 8-1).
26
What is the pathophysiology of breast cancer?
Breast cancer results from a transforming, or oncogenic, event that leads to clonal proliferation and survival of breast cancer cells. There are two general types of breast cancer: sporadic and hereditary. The events that trigger sporadic breast cancer are often unknown, but abnormalities in cell-cycle pathways, including HER-2, estrogen, and progesterone signaling, have been implicated. BRCA1 and BRCA2 genes have been linked to hereditary breast and ovarian cancer and are linked to defects in DNA mismatch repair. Notably, hereditary breast cancer only accounts for 5%–10% of all breast cancers diagnosed in the United States. This patient appears to have the sporadic type, supported by the late onset of diagnosis, increased hormone exposure from early menarche, late menopause, and obesity.
27
What 11 risk factors are associated with an increased incidence of breast cancer?
1. Female gender.
2. Alcohol intake.
3. Breast density.
4. Early menarche or late menopause.
5. Age.
6. Family history (50%–70% of women carrying the BRCA1 or BRCA2 mutations develop breast cancer).
7. Hormone replacement therapy (estrogen and progesterone).
8. Nulliparity or late first pregnancy.
9. Obesity (in postmenopausal women).
10. Prior breast biopsy, particularly for lesions with atypia.
11. Radiation exposure to the chest.
28
What is the most likely diagnosis?
Carcinoid syndrome (secretory) is the most likely diagnosis. Approximately 75%–80% of carcinoid syndrome cases arise from a small bowel carcinoid tumor. However, only approximately 10% of carcinoid tumors result in carcinoid syndrome (see Table 8-2 for signs and symptoms).
29
What laboratory test can help confirm the diagnosis of Carcinoid syndrome (secretory)?
Many conditions, such as menopause, as well as reactions to alcohol, glutamate, and calcium channel blockers, may cause flushing. However, flushing in conjunction with an increase in 5-hydroxyindoleacetic acid on urinalysis occurs only in carcinoid syndrome.
30
What is the pathophysiology of Carcinoid syndrome (secretory)?
Carcinoid syndrome occurs only when sufficient concentrations of substances secreted by carcinoid tumors (derived from neuroendocrine cells) reach the circulation. Carcinoid tumors secrete a variety of gastrointestinal peptides, including gastrin, somatostatin, substance P, vasoactive intestinal polypeptide, pancreatic polypeptide, histamine, chromogranin A, and serotonin. Carcinoid syndrome is unlikely to occur in intestinal carcinoid tumors unless liver metastases are present.
31
What type of cardiac involvement is typically seen in patients with Carcinoid syndrome?
Right-sided valvular involvement occurs in 11% of patients initially and up to 41% during the course of the disease. Cardiac disease results from serotonin-mediated fibrosis in the endocardium, most commonly in the tricuspid valve. Up to 80% of patients with cardiac involvement develop heart failure.
32
What type of cardiac involvement is typically seen in patients with Carcinoid syndrome (secretory)?
Right-sided valvular involvement occurs in 11% of patients initially and up to 41% during the course of the disease. Cardiac disease results from serotonin-mediated fibrosis in the endocardium, most commonly in the tricuspid valve. Up to 80% of patients with cardiac involvement develop heart failure.
33
What is the appropriate treatment for Carcinoid syndrome (secretory)?
If localization of a discrete carcinoid tumor is possible, surgical resection is the optimal therapy. For other cases, symptomatic management with octreotide is most beneficial.
34
What is the most likely diagnosis?
What are the three forms of this condition?
Burkitt lymphoma, a highly aggressive B-cell non-Hodgkin lymphoma. The “starry-sky” pattern on histology (Figure 8-5) is classic for this condition. Burkitt lymphoma of the gastrointestinal tract typically involves the ileocecum and peritoneum.
35
What is the typical cytogenetic change in Burkitt lymphoma and what gene does it involve?
All forms of Burkitt lymphoma involve the c-MYC gene found on chromosome 8. The characteristic translocation is t(8;14), which places the c-MYC proto-oncogene adjacent to the immunoglobulin heavy- chain locus on chromosome 14. This results in overexpression of c-MYC, a transcription factor that controls cellular metabolism, leading to increased cell growth. The tumor cells are typically CD20, CD10, and BCL-6 positive.
36
What is the appropriate treatment for Burkitt lymphoma?
Endemic Burkitt lymphoma is treated with chemotherapy, but HIV-associated and sporadic Burkitt are not necessarily as readily treatable. Both HIV-associated and sporadic cases also commonly metastasize to the central nervous system, requiring CNS radiation and intrathecal chemotherapy for control.
37
What is tumor lysis syndrome?
Tumor lysis syndrome is due to the large amount of neoplastic cell death during treatment with chemotherapy, typically seen in the most rapidly growing cancers, such as Burkitt lymphoma. Laboratory analysis shows multiple metabolic complications including hyperphosphatemia, hypocalcemia, hyperuricemia, and hyperkalemia leading to acute renal failure. Allopurinol or rasburicase, aggressive hydration, and diuresis can be used to prevent these consequences.
38
What is the most likely diagnosis?
Chronic myelogenous leukemia (CML) is likely given the t(9;22) translocation coupled with the uncontrolled production of maturing granulocytes (neutrophils, eosinophils, and basophils), platelets, and mild anemia (Figure 8-6). This marked leukocytosis leads to splenic enlargement. There are approximately 5000 new cases of CML in the United States annually.
39
What the chromosomal abnormality associated with Chronic myelogenous leukemia (CML) called and what is its product?
The translocation of the BCR gene on chromosome 22 with the ABL gene on chromosome 9 leads to the Bcr-Abl fusion product. This abnormality is called the Philadelphia chromosome, and it is considered pathognomonic for CML.
40
What is the pathophysiology of Chronic myelogenous leukemia (CML)?
This Bcr-Abl fusion protein results in a constitutively active Abl tyrosine kinase in the Ras/Raf/MEK/MAPK pathway. This leads to inhibition of apoptosis and unregulated cell division (Figure 8-7).
41
What is the targeted drug treatment for Chronic myelogenous leukemia (CML)?
Imatinib, a highly specific Bcr-Abl tyrosine kinase competitive inhibitor, has been the agent of choice and has radically changed the prognosis for CML patients. Dasatinib is a second-line treatment. Either treatment has shown a 90% cytologic remission rate. Historically, allogeneic bone marrow transplantation has been used for potential cure (with cure rates in the 40%–50% range). However, it is now used in only selected patients who fail to achieve cytogenetic remission with tyrosine kinase inhibitors.
42
What is a blast crisis?
Untreated CML inevitably progresses, usually in 3–5 years, to an accelerated phase and then a blast crisis in which additional genetic abnormalities accumulate and lead to acute myeloid (or 20% of the time lymphoid) leukemia. Peripheral smears will show a large percentage (> 20%) of blast cells.
43
What is the most likely diagnosis?
Colorectal cancer (CRC) is suggested by the symptoms of abdominal pain, anorexia, weight loss, palpable rectal mass, and anemia. Likewise, he has a family history of CRC at a relatively young age. CRC is the third-leading cause of cancer death in men (after lung and prostate cancer).
44
What 6 risk factors are associated with Colorectal cancer (CRC)?
1. Age > 50 years.
2. Lifestyle (alcohol, obesity, low-fiber and high-fat diet).
3. Family history/ syndromes (hereditary nonpolyposis CRC ([HNPCC]), familial adenomatous polyposis ([FAP]).
4. Diabetes.
5. Inflammatory bowel disease.
6. Tumor suppressor gene and proto-oncogene changes.
45
What are the guidelines for primary screening of Colorectal cancer (CRC)?
Screening for CRC includes the following modalities:
- Fecal occult blood testing for individuals older than 40 years of age (controversial).
- Colonoscopy every 10 years in patients aged 50–75 years.
- More frequent screening for patients with genetic risk factors (eg, familial adenomatous polyposis,
hereditary nonpolyposis colorectal cancer), family history, and/or history of colorectal neoplasia.
46
What signs and symptoms are commonly associated with Colorectal cancer (CRC)?
Signs and symptoms of colorectal cancer include abdominal pain, anemia with low mean corpuscular volume (MCV), bleeding/mucus per rectum, changes in bowel habits, weight loss, and tenesmus (the feeling of needing to pass stool with an empty rectal vault).
47
What are the appropriate treatments for Colorectal cancer (CRC)?
Surgical treatment is usually the initial treatment of choice. Adjuvant therapy will depend on TNM staging, with adjuvant chemotherapy providing a survival advantage for stage 3 (node-positive) colon cancer. Stage 2 and 3 rectal cancers should be treated with combination chemotherapy and radiation, either before surgery or afterward. In the metastatic setting, radiation can be used for palliation, and current chemotherapy agents can provide disease control for 20–24 months on average. If there are only a few metastatic foci in the liver, resection can be considered, with a 25% chance for long-term control. Carcinoembryonic antigen (CEA) can be a useful tumor marker to monitor for the recurrence of disease.
48
What is the most likely diagnosis? What signs and symptoms are commonly associated with this condition?
What are the typical laboratory findings in this condition?
Gastric cancer. Diagnosis is determined by esophagogastroduodenoscopy and biopsy.
Anemia is present in 50% of patients. CEA levels are elevated in two-thirds of patients.
49
What risk factors are associated with gastric cancer? (10)
50
What is the appropriate treatment for gastric cancer?
Surgical resection for early local disease. A combination of radiation and chemotherapy is often used along with resection in situations where the lesion is initially unresectable, or as adjuvant therapy postsurgery for node-positive disease.
51
What is the most likely diagnosis?
Disseminated intravascular coagulation (DIC).
52
What is the pathophysiology of Disseminated intravascular coagulation (DIC)?
What are 3 common possible causes of this condition?
DIC is a systemic process in which widespread activation of hemostasis causes thrombosis and hemorrhage. Systemic, rather than localized, clotting depletes coagulation factors (Figure 8-8).
**Causes**:
1. Infectious causes include sepsis.
2. Malignant causes include acute leukemia (especially acute myeloid leukemia) and other cancers (eg, prostate, causing a chronic DIC).
3. Other causes include trauma, obstetric complications (eg, abruptio placentae, amniotic fluid embolism),
and snake venom.
53
Which clotting factors are involved in the intrinsic, extrinsic, and common pathways?
The intrinsic pathway involves factors VIII, IX, XI, and XII, prekallikrein, and high-molecular weight- kininogen. The extrinsic pathway involves factor VII. The common pathway involves factors II, V, and X and fibrinogen (Figure 8-9).
54
Which laboratory tests help differentiate DIC from thrombocytopenia?
DIC is classically diagnosed from an elevated PT, elevated PTT, low fibrinogen, and high D-dimer. Thrombocytopenia would not show elevated coagulation tests.
55
What is the prognosis and treatment of Disseminated intravascular coagulation (DIC)?
DIC mortality ranges from 40%–80% if it is associated with sepsis, burns, or trauma. Treatment of the underlying condition causing DIC is essential. Hemodynamic support is the mainstay of treatment, but correction of coagulopathy with platelet or coagulation factor replacement may be necessary if there is a serious risk of bleeding (eg, recent surgery or fibrinogen < 100). Fresh frozen plasma can be used to correct the PT/PTT while cryoprecipitate is used if the fibrinogen < 100.
56
What is the most likely diagnosis?What is the differential diagnosis of a brain lesion?
Glioblastoma multiforme (GBM). MRI is the definitive test for a brain mass. Gliomas appear hypointense on T1-weighted imaging (Figure 8-10) and hyperintense on T2-weighted imaging. They also heterogeneously enhance with contrast and can be distinguished from the surrounding edema. The rapidity of onset of this patient’s symptoms without signs of infarct suggests a malignant process.
57
What are some characteristics of Glioblastoma multiforme (GBM)?
- GBM is the most commonly diagnosed primary brain tumor. It is a grade IV astrocytoma that is most commonly found in adults, in contrast to the peak childhood prevalence of low-grade (pilocytic) astrocytoma. GBM is typically found in the cerebral hemispheres and can cross the corpus callosum to form the characteristic “butterfly glioma.”
- Symptoms of GBM include headache (73%–86% of cases) and seizures (26%–32% of cases).
- Signs of GBM include paraparesis, papilledema, confusion, and aphasia.
58
What is the appropriate treatment for Glioblastoma multiforme (GBM)?
The prognosis for GBM is poor; most patients do not survive beyond 1 year of diagnosis. The initial treatment is resection. Adjuvant radiation therapy with chemotherapy (with nitrosoureas and temozolomide) is the current standard of care. Dexamethasone is used to alleviate the vasogenic edema that that is caused by blood-brain barrier disruption that occurs in the area around many brain tumors. Dexamethasone is preferred over other steroids because its relative lack of mineralocorticoid activity decreases the risk of fluid retention.
59
What is the most likely diagnosis?
What is the pathophysiology of this condition?
What are the typical PBS findings in this condition?
**Glucose-6-phospate dehydrogenase (G6PD) deficiency.**
**Pathophysiology**: G6PD protects cells from oxidative damage by converting nicotinamide adenine dinucleotide phosphate (NADP+) to its reduced form (NADPH). Patients with a deficiency in this enzyme are less able to cope with oxidative stresses, such as those that are caused by ingestion of a sulfa drug (ie, trimethoprim- sulfamethoxazole).
**Histology**: PBS will likely reveal bite cells and ghost cells, implying intravascular hemolytic anemia.
60
How is Glucose-6-phospate dehydrogenase (G6PD) deficiency acquired?
G6PD deficiency is an X-linked recessive trait and affects males predominantly. Heterozygous females are usually normal. Patients with G6PD deficiency are normal in the absence of oxidative stress. However, exposure to oxidative stress triggers the disease. G6PD in Mediterranean pedigrees results in favism, or hemolysis induced by the ingestion of fava beans.
61
How are anemias classified in terms of cell volume? What is the appropriate treatment for this condition?
Treatment is generally supportive with removal of the offending agent.
62
What conditions should be considered in the differential diagnosis of a neck mass?
What is the most likely diagnosis?
What risk factors increase this patient’s likelihood of disease?
63
Which procedures can help confirm the diagnosis of a head/neck mass?
Diagnostic procedures include biopsy via fine-needle aspiration of the mass, and CT and/or MRI to determine the stage and possible vascular involvement and resectability. If lymphoma is suspected, excisional biopsy should be performed (Figure 8-11).
64
Where are the lesions of Squamous cell tumor of the head and neck commonly located?
What are the appropriate treatments for this condition?
65
What is the most likely diagnosis?
Hereditary hemochromatosis (HH) is an autosomal recessive disease (with variable penetrance), resulting in excessive iron absorption. Excess iron gradually accumulates at a rate of approximately 0.5–1.0 g/year. Normal body iron content is approximately 3–4 g, and symptoms are noticeable at a body iron content exceeding 20 g. As a result, most men are not diagnosed until after 40 years of age, and women are not diagnosed until after cessation of their menstrual periods. Normal iron loss is 1 mg/day in men and 1.5 mg/day in menstruating women.
66
What is the pathophysiology of Hereditary hemochromatosis?
What signs and symptoms are commonly associated with Hereditary hemochromatosis?
67
What are the typical laboratory findings in Hereditary hemochromatosis?
Iron saturation of > 60% in men and > 50% in women suggests HH 90% of the time. A cutoff of 45% for both men and women is typically used for simplicity. If you suspect hemochromatosis, genetic testing (a simple blood test) for the HH gene should be performed (see Figure 8-12 for screening algorithm). Other typical laboratory findings include hyperglycemia, elevated liver enzyme levels, elevated serum iron levels, decreased total iron binding capacity, and elevated ferritin levels.
68
What is the appropriate treatment for Hereditary hemochromatosis?
Treatment for HH includes serial phlebotomy with the possible use of deferoxamine, an iron-binding agent, especially for patients with homozygous HFE mutations (C282Y) and iron overload. Compound heterozygotes with iron overload should also be treated. Deferoxamine, an iron-binding agent, can be used for severe iron overload or in those patients who cannot tolerate phlebotomy (eg, anemia or cardiac disease).
69
What type of cell is depicted in Figure 8-13? What is the most likely diagnosis?
This is the classic Reed-Sternberg cell, characterized by large size, bilobed nucleus, and nucleolar inclusion bodies (“owl’s eyes”). Classically, these cells, formed from germinal B cell centers, also display a common set of markers, including CD15+ and CD30+.
Hodgkin lymphoma. Most patients present with nontender asymptomatic palpable lymphadenopathy, often in the neck and supraclavicular area. Alternatively, many patients will present with a fairly large asymptomatic mediastinal mass on routine x-ray of the chest. Approximately one-third of patients experience fever, night sweats, weight loss, fatigue, and pruritus. There are five main classes of Hodgkin lymphoma (Table 8-3).
70
What are B symptoms?
Classic B symptoms are unexplained weight loss, persistent or recurrent fevers, and drenching night sweats. These symptoms generally correlate with an advanced stage of disease and tumor burden and a slightly worse prognosis independent of stage.
71
What is the appropriate treatment for Hodgkin lymphoma?
More than 90% of patients with early-stage localized disease are cured with excision and localized radiotherapy. Patients with more advanced disease typically undergo the ABVD chemotherapy regimen consisting of doxorubicin (adriamycin), bleomycin, vinblastine, and dacarbazine. Cure rates are very high, even with advanced, stage 4 disease.
72
What is the most likely diagnosis? What are the variants of this condition?
How is this condition inherited?
- Hemophilia is due to deficiencies in the intrinsic coagulation pathway (factor VIII in hemophilia A and factor IX in hemophilia B). Therefore, this disease is characterized by normal bleeding time, platelet count, and prothrombin time but an elevated PTT.
- Von Willebrand disease is the most common hereditary bleeding disorder. It is distinguished from hemophilia by its prolonged bleeding time and usually a modest prolongation of the PTT.
- Both disease variants are X-linked recessive.
73
What are the possible complications of Hemophilia?
- Complications include deep and delayed bleeding into joints (hemarthrosis), muscles (hematoma), and the gastrointestinal tract. The most concerning complications are bleeds in the central nervous system and oropharynx.
- Mucosal or cutaneous bleeding is uncommon and more characteristic of platelet dysfunction or von Willebrand disease.
- Transmission of blood-borne infection (specifically HIV and hepatitis C) through transfusion has been significantly reduced through modern screening technology and recombinant factors.
74
What are the appropriate treatments for Hemophilia?
75
What is the most likely diagnosis?
Teratoma, the most common type of germ cell tumor. The component tissues in a teratoma arise from all three germ layers and vary from immature to well differentiated. Additionally, these tissues are foreign to the anatomic site in which they are found.
76
What are the three types of Teratoma?
77
What are the typical imaging findings in Teratoma?
How are these masses graded?
- Ultrasound is the most common modality for pelvic imaging, especially for suspected teratomata. Mixed cystic and solid lesions with fat-fluid and hair-fluid levels are commonly found.
- Only malignant teratomata are graded, and the grade of differentiation is based upon the proportion of tissue containing immature neuroepithelium. This is an important prognostic indicator of extra-ovarian spread.
78
What is the appropriate treatment for a teratoma?
Complete surgical excision is the standard of care. Higher-grade malignant teratomata are additionally managed with chemotherapy such as methotrexate, with a high rate of cure.
79
What is the most likely diagnosis? What clinical findings are commonly associated with this condition?
Idiopathic thrombocytopenic purpura (ITP), a disease that is associated with antiplatelet antibodies, is the most likely diagnosis. The patient presents with isolated thrombocytopenia (normal WBC and Hct), no coagulopathy, and given her age, ITP is the most common cause of thrombocytopenia.
80
How is the etiology of Idiopathic thrombocytopenic purpura (ITP) determined?
Thrombocytopenia can have a number of etiologies, which can be differentiated according to Figure 8-16.
81
What are the appropriate treatments for Idiopathic thrombocytopenic purpura (ITP)?
First-line treatment is high-dose steroids. Second-line treatment includes intravenous IgG, anti-Rh, splenectomy, or rituximab (anti-CD20). Thrombopoietin receptor agonists (romiplostim) have been shown to be highly effective in raising platelets counts for long-term control, but long-term safety data and cost of therapy are limiting factors in using these modalities as first-line therapy. Acute bleeding in ITP is treated with intravenous IgG followed by platelets and pulse methylprednisolone.
82
What are the three main mechanisms of low platelet counts?
Thrombocytopenia may be caused by:
1. Splenic sequestration.
2. Decreased production (stem cell failure, leukemia, aplastic anemia, EtOH, aspirin, clopidogrel).
3. Increased destruction (ITP, thrombotic thrombocytopenic purpura, heparin, quinidine).
83
What conditions can cause basophilic stippling? What is the most likely diagnosis?
Lead poisoning is suggested by the blue pigmentation of the gums (Burton lines), microcytic anemia, and characteristic basophilic stippling.
84
What are other common signs and symptoms of Lead poisoning?
Common signs and symptoms of lead poisoning include: colicky abdominal pain; constipation; irritability; difficulty concentrating; depression/psychosis; decreased short-term memory; arthralgias and myalgias; headache; decreased libido; and peripheral neuropathy, often presenting as extensor weakness (eg, wrist drop) due to segmental demyelination and degeneration of motor axons.
85
What is the cause of anaemia in patient's with lead poisoning?
Lead poisoning is an environmental cause of porphyria through inhibition of aminolevulinate dehydratase, which converts δ-aminolevulinic acid to porphobilinogen in one of the first steps of heme synthesis. It also inhibits ferrochelatase to inhibit the conversion of protoporphyrin IX to heme in the last step of synthesis (Figure 8-17). This impairment results in decreased hemoglobin production and a microcytic, hypochromic anemia.
86
What do increased serum lead levels and increased free erythrocyte protoporphyrin (FEP) levels indicate about the duration of lead poisoning?
Increased serum lead levels indicate lead exposure within the past 3 weeks. FEP levels are a measure of intoxication in the past 120 days (the average lifetime of an RBC). Chelation therapy with succimer can be useful in severe cases after removing the source of the lead.
87
What is the most likely diagnosis?
What are the major clinical features of this condition?
Lung cancer (with Pancoast syndrome). This condition is caused by a tumor of the upper lobe of the lung, which causes pain in the ipsilateral arm and Horner syndrome (ptosis, miosis, and ipsilateral anhidrosis). The tumor is often accompanied by ipsilateral pain or weakness/numbness in the ulnar distribution.
88
What are the typical laboratory and imaging findings in Lung cancer?
1. Sputum analysis reveals atypical cells (not sensitive).
2. Anemia of chronic disease.
3. Radiograph and CT typically reveal lung nodules.
4. Positron emission tomography may be useful to evaluate lymph node involvement; this is critical for
staging.
89
What are the primary pathologic types of lung cancer?
90
What are the appropriate treatments for lung cancer?
Surgery is considered for lesions without distant metastasis if the patient has sufficient cardiopulmonary reserve. Radiotherapy is used to treat unresectable tumors. Adjuvant chemotherapy is also used with some patients undergoing surgery. For patients with metastatic disease, palliative chemotherapy is often used.
91
What is the most likely diagnosis? What other laboratory test could be used to determine the diagnosis?
- The tests indicate a macrocytic anemia. However, macrocytic anemia is not a diagnosis in itself, and a cause for the anemia must be determined.
- In this patient we are suspecting B12 deficiency (megaloblastic anemias) given the high MCV and neurologic findings. In megaloblastic anemias, a peripheral blood smear reveals the presence of hypersegmented neutrophils (more than five nuclei) (Figure 8-18).
92
What are 6 possible etiologies for macrocytic anaemia?
Etiologies of macrocytic anemia include the following:
1. Alcoholism
2. Folate deficiency.
3. Vitamin B12 deficiency.
4. Hypothyroidism.
5. Myelodysplastic syndrome or myeloma.
6. Pharmaceutical agents (especially antimetabolites such as methotrexate or chemotherapeutic agents).
93
What findings distinguish vitamin B12 from folate deficiency?
Vitamin B12 deficiency results in subacute combined degeneration of the dorsal columns of the spinal cord, causing loss of vibration and position sense. Also, methylmalonic acid is elevated in the urine of patients with B12 deficiency.
In folate deficiency, there are no neurologic findings and no rise in methylmalonic acid levels in the urine.
94
What is the most likely diagnosis? What factors can lead to this condition?
Iron deficiency anemia. This diagnosis would be supported by laboratory studies demonstrating a
decreased iron concentration, increased total iron binding capacity, and decreased ferritin levels.
The cause for a patient’s iron deficiency, however, needs to be further pursued. In addition, comorbid inflammatory conditions can raise serum ferritin, resulting in values within the normal range.
95
Why are total iron binding capacity (TIBC) measurements important in iron deficiency anaemia?
TIBC is high in iron deficiency anemia and low in anemia of chronic disease. Both illnesses have decreased serum iron levels. A low ferritin (< 41 ng/mL) is sensitive and specific for iron deficiency anemia. The normal iron/TIBC ratio is typically 0.25–0.45, and levels < 0.12 indicate iron deficiency. Anemia of chronic disease often has a normal iron/TIBC ratio because of the concomitant decrease of TIBC and serum iron.
96
What other conditions are patients with iron deficiency anaemia at greatly increased risk for developing?
Because of the extreme lack of iron, this patient is at risk for Plummer-Vinson syndrome. This syndrome is characterized by atrophic glossitis, esophageal webs, and anemia.
97
What are the common causes of microcytic, hypochromic anemia?
Microcytic anemia results from either decreased hemoglobin production or faulty hemoglobin function. Common causes include iron deficiency, thalassemia, sideroblastic anemia, and lead poisoning.
98
What is the most common tumor in infants?
Neuroblastoma is a malignancy of the sympathetic nervous system that arises during embryonic development. In the embryo, neuroblasts (pluripotent sympathetic stem cells) invaginate and migrate along the neuraxis to the adrenal medulla, the sympathetic ganglia, and various other sites. Figure 8-20 shows a large neuroblastoma occupying the right flank in an older child. The site of disease presentation depends on the area of neuroblast migration.
99
What are the 7 types of small, round, blue-cell tumors?
1. **Neuroblastoma** is a common tumor of the adrenal medulla in children. It is characterized by homovanillic acid (dopamine breakdown product) present in urine. It is associated with the N-myc oncogene.
2. **Wilms tumor** is the most common childhood renal malignancy and presents with flank mass and hematuria. It is associated with deletion of WT1 on chromosome 11.
3. **Acute leukemia** is caused by unregulated growth of leukocytes in the bone marrow.
4. **Mesothelioma** is associated with smoking and asbestos exposure.
5. **Rhabdomyosarcoma** is a tumor of skeletal muscle.
6. **Medulloblastoma** is a highly malignant cerebellar tumor. It often compresses the 4th ventricle to cause hydrocephalus.
7. **Retinoblastoma** is associated with 13q mutation of Rb gene.
100
What prognostic factors are important in Neuroblastoma?
Tumor stage and the patient’s age at diagnosis are the two most important prognostic factors. Patients with localized disease, regardless of age, have a favorable prognosis (5-year survival rate: 80%–90%). Overall, younger age at diagnosis carries a more favorable prognos
101
What are the likely biopsy findings in Neuroblastoma?
Histologically, neuroblastoma presents as dense nests of small, round, blue tumor cells with hyperchromatic nuclei. Homer-Wright pseudorosettes are seen in 10%–15% of cases. These pseudorosettes are composed of neuroblasts surrounding neuritic processes and are pathognomonic for neuroblastoma.
102
What are the appropriate treatments for neuroblastoma?
For patients with localized disease, surgical excision is curative. For more advanced disease, treatment consists of surgical excision followed by chemotherapy. Chemotherapy for neuroblastoma consists of combination regimens, typically vincristine, cyclophosphamide, and doxorubicin. Other regimens include etoposide in combination with either cisplatin or carboplatin.
103
What is the most likely diagnosis? What is the pathophysiology of this condition?
- Back pain, increased recent susceptibility to infection, and elevated serum calcium and creatinine levels strongly suggest multiple myeloma.
- Multiple myeloma is a clonal proliferation of B cells that have differentiated into plasma cells. These mature B cells cause lytic lesions in the bones, called punched-out lesions. These cells produce massive quantities of identical immunoglobulin molecules, usually IgG or IgA, that are either κ or λ light chain (κ more common than λ). Rarely, IgD or nonsecretory myeloma is diagnosed.
104
What renal complications are associated with Multiple myeloma?
The large amount of Bence Jones proteins (free immunoglobulin light chains) found in the urine of patients with multiple myeloma causes azotemia. Other renal complications include inflammation with potential giant cell formation and metastatic calcification.
105
What other tests can be used to confirm the diagnosis of Multiple myeloma?
A complete blood count should be ordered. Patients with multiple myeloma may be anemic as a result of tumor cells overcrowding myeloid precursor cells. Electrophoresis with immunofixation will demonstrate M protein, the term given to the massively produced immunoglobulin. Urinalysis of a 24-hour collection may reveal the presence of a Bence Jones protein. Bone marrow biopsy shows a two- to fourfold increase in plasma cells; biopsy results are essential for the diagnosis of multiple myeloma. Other immunoglobulins may be low, which can add to the risk of infection. Due to hyperglobulinemia, RBCs on peripheral blood smear will clump in a rouleaux formation (Figure 8-21).
106
What is MGUS?
Monoclonal gammopathy of undetermined significance (MGUS) is a precursor (premalignant) lesion if the M protein level is < 3 g/dL, there is < 10% plasma cells in the bone marrow, and there are no clinical manifestations of multiple myeloma present. The CRAB mnemonic can be used to remember the clinical characteristics that are not present in MGUS but are present in multiple myeloma: elevated Calcium, Renal failure, Anemia, and Bone lesions. Twenty-five percent to 30% of those with MGUS may go on to develop a lymphoproliferative disorder in their lifetime.
107
What is the most likely diagnosis? Where do the tumors of this condition typically occur?
- **Oligodendroglioma**. These relatively rare, slow-growing tumors are responsible for 2%–4% of primary brain tumors. They occur with equal incidence in women and men. They originate from glial cells, which myelinate central nervous system axons.
- Oligodendrogliomas almost always (92% of cases) occur supratentorially and are most often found in the frontal lobes. Lesions are typically peripheral. Most oligodendrogliomas arise in the cortex and extend into the white matter of the cerebral hemispheres.
108
What symptoms are typically associated with this condition?
The clinical presentation of oligodendrogliomas is typically attributable to compression of adjacent structures by the tumor:
1. Headache.
2. Mental status changes.
3. Paresis.
4. Seizures.
Because they are slow-growing tumors, they may have a more insidious presentation, whereas the anaplastic forms present with more rapid neurologic decline.
109
What are the likely histology findings in Oligodendroglioma?
“Fried egg” cells are typically seen on histologic section. These cells have characteristic round nuclei with clear cytoplasm. The tumors often calcify (30% of cases), and calcifications may be apparent on histologic section.
110
What is the prognosis for patients with Oligodendroglioma?
About 50% of patients with oligodendrogliomas survive > 5 years, and the 10-year survival rate is 25%–34%. Mortality increases with features of increasing nuclear atypia, necrosis, and mitosis. Some oligodendrogliomas contain astrocytic components and are termed mixed gliomas. Patients with highly anaplastic oligodendrogliomas have a median survival of < 2 years.
111
What is the most likely diagnosis? From what cell line does the tumor involved in this condition originate?
A palpable adnexal mass in conjunction with abdominal swelling suggests ovarian cancer, which is often accompanied by ascites. The patient’s irregular periods may simply be normal menopause, but the triad of irregular periods, facial hair, and acne suggest androgen excess. The Sertoli-Leydig ovarian tumor is an androgen-producing neoplasm that presents with hirsutism in 50% of patients.
112
What do Sertoli and Leydig cells produce?
- Sertoli cells contain aromatase and convert testosterone to estrogen. In men, follicle-stimulating hormone stimulates Sertoli cells in spermatogenesis.
- Leydig cells, which are stimulated by luteinizing hormone, secrete testosterone.
113
What 3 other tumors have the same origin as Sertoli-Leydig cell tumors?
Other stromal ovarian tumors include:
1. **Fibromas**, solid tumors consisting of cells that resemble fibroblasts.
2. **Thecoma** tumors, which contain fibroblasts plus lipid-containing cells.
3. **Granulosa cell tumors**, which consist of estrogen-secreting granulosa cells and may present with abnormal vaginal bleeding or endometrial hyperplasia.
114
What are the likely histology findings in Sertoli-Leydig cell tumor?
The Sertoli-Leydig cell tumor is usually composed of large cells with eosinophilic cytoplasm arranged into tubules and surrounded by a fibrous stroma. Sertoli cells are found lining the tubules, and Leydig cells may be found in the stroma.
115
What is the lymphatic drainage of the ovaries?
Like that of the testicles, the ovaries’ lymphatic drainage is to the lumbar and para-aortic lymph nodes. The ovarian lymph vessels travel with the venous drainage in the broad ligament.
116
What is the treatment and prognosis of Sertoli-Leydig cell tumors?
These tumors are almost always benign and have an excellent long-term prognosis; treatment with unilateral oophorectomy is highly successful.
117
What is the most likely diagnosis?
What is the classic presentation of this condition?
What is the pathophysiology of this condition?
Pancreatic cancer.
- The classic presentation of pancreatic cancer is painless jaundice. Weight loss, abdominal pain, and pruritus are also common.
- Pancreatic tumors form mostly in the head and neck of the pancreas from the endocrine and exocrine portions of the pancreas. The majority of pancreatic cancers are exocrine in origin.
118
What 6 risk factors are associated with Pancreatic cancer?
1. African American race.
2. Cigarette smoking.
3. History of chronic pancreatitis.
4. History of diabetes mellitus.
5. Male gender.
6. Diet high in fried meats.
119
What are the common sites of invasion for pancreatic cancer?
What are the common sites of metastasis?
- Pancreatic cancer can invade the duodenum, the ampulla of Vater, and the common bile duct. Figure 8-22 shows a pancreatic adenocarcinoma, which appears as a large, heterogeneously enhancing mass at the head of the pancreas.
- Metastasis often begins in the regional lymph nodes and spreads to the liver or, less often, to the lungs. Pancreatic cancer can also directly invade the duodenum, stomach, and colon.
120
What is the most common form/location of pancreatic cancer?
With treatment, what is the prognosis of this condition?
- More than 80% of pancreatic tumors are adenocarcinomas, and 60% are found in the head of the pancreas. Notably, with pancreatic adenocarcinoma, the tumor marker CA19-9 is often elevated.
- Approximately 90% of patients die within 1 year of diagnosis; however, if resection of the cancer is possible and the cancer is caught in an early stage, 5-year survival increases to 30%. For a cancer in the head/neck of the pancreas, resection is performed with a Whipple procedure; for a cancer in the tail, resection is performed with a distal pancreatectomy. In a Whipple procedure, the stomach antrum, part of the duodenum, head of the pancreas, common bile duct, and gallbladder are removed. The remaining pancreas, common hepatic duct, and remaining stomach are all sewn into the jejunum.
121
What is the most likely diagnosis?
Levels of which hormone should be measured to establish the diagnosis?
Polycythemia vera, also known as primary erythrocytosis. This patient’s elevated hemoglobin concentration is a sign of an increased RBC count. An increased RBC mass (> 32 mL/kg in women and > 36 mL/kg in men) is diagnostic of polycythemia vera absent of secondary causes. Polycythemia vera is one of the myeloproliferative syndromes, which also include essential thrombocytosis, CML, and myeloid metaplasia.
122
Which two types of carcinoma are associated with Polycythemia vera?
Renal cell carcinoma and hepatocellular carcinoma. In a healthy adult, the kidneys produce a majority of the body’s erythropoietin, and the liver is a secondary source.
123
What is a myeloproliferative disorder?
It is a disorder in which there is clinical expansion of multipotent hematopoietic stem cells. Isolated cell lines may be affected; if megakaryocyte expansion occurs, an essential thrombocytosis is seen.
124
How can an uncorrected ventricular septal defect (VSD) lead to Polycythemia vera?
In patients with uncorrected VSD, atrial septal defect, or patent ductus arteriosus, blood is shunted from the left side of the heart to the right side, which exposes the pulmonary vasculature to systemic blood pressures. Over time, the pulmonary vasculature adapts by increasing pulmonary resistance, and blood flow through the shunt is reversed to flow from right to left. This reversal of flow is known as Eisenmenger syndrome. Right-to-left shunts cause hypoxemia and cyanosis, a potent stimulus for erythropoietin secretion and a cause of secondary polycythemia.
125
What are the appropriate treatments for Polycythemia vera?
Phlebotomy can reduce the risk of blood clots in patients with polycythemia to that of the normal population. In high-risk patients (the elderly or those with a history of clots), hydroxyurea may be useful for controlling the hematocrit.
126
What are the appropriate treatments for Polycythemia vera?
Phlebotomy can reduce the risk of blood clots in patients with polycythemia to that of the normal population. In high-risk patients (the elderly or those with a history of clots), hydroxyurea may be useful for controlling the hematocrit.
127
What is the most likely diagnosis? What conditions should be considered in the differential diagnosis?
Leukocoria found in a young child suggests retinoblastoma.
Conditions that present similarly to leukocoria include the following:
1. Congenital cataracts.
2. Developmental abnormalities of the vitreous/retina.
3. Inflammatory conditions.
128
What is the pathogenesis of Retinoblastoma?
Retinoblastoma results from mutations of both alleles of the Rb gene, on chromosome 13q14, which codes for a tumor suppressor protein. The Rb protein binds and sequesters transcription factors of the E2F family to prevent the G1-to-S phase transition. Loss of Rb thus promotes deregulation of this transition and increased growth.
129
What is the “two-hit hypothesis”?
The two-hit hypothesis (Knudsen hypothesis) suggests that two separate mutations are required for tumorigenesis involving a suppressor gene. In heritable disease, patients inherit a mutated germline allele from a parent and acquire a second somatic mutation later in development. This often causes binocular and multifocal disease. In noninherited disease, two spontaneous mutations arise in a single retinal cell during development, causing uniocular, unifocal disease.
130
What secondary malignancies are patients with Retinoblastoma at risk of developing?
Osteogenic sarcoma, soft tissue sarcoma, and malignant melanoma commonly develop in patients with retinoblastoma. Metastatic spread occurs rapidly through direct infiltration or via the subarachnoid space, blood, and lymphatics.
131
What is the appropriate treatment for Retinoblastoma?
The treatment of choice for retinoblastoma is enucleation of the affected eye; the goal is to remove a large portion of the optic nerve, as it is the most common path for metastasis to the brain. Other treatment options include external-beam radiation therapy, cryotherapy, and chemotherapy. With treatment, 5-year survival for retinoblastoma is > 90%.
132
What is the most likely diagnosis? What is the typical presentation of this condition?
**Sickle cell anemia** develops at approximately 6 months of age when hemoglobin S (HbS) replaces hemoglobin F (HbF). Painful crises, which are believed to be a result of hypoxic tissue injury from microvascular occlusions, often occur.
133
What is the pathophysiology of sickle cell anaemia?
HbS is the result of a single missense mutation in the beta-globin gene of hemoglobin (negatively charged glutamate is replaced by neutrally charged valine and position 6). This makes hemoglobin susceptible to polymerization in conditions of low oxygen or dehydration (Figure 8-24), dramatically reducing the flexibility of the RBC membrane. Any organ can be affected by the vascular congestion, thrombosis, and infarction caused by sickling cells, so patients tend to have multiple health problems. The combination of sickle cell anemia and β-thalassemia is common and can also result in sickle crises.
134
What 10 complications are common in patients with sickle cell anaemia?
135
What are the typical radiologic findings in sickle cell anaemia?
The marrow expansion caused by the profound anemia can lead to resorption of bone and subsequent new bone formation on the external aspect of the skull. This leads to a “crew cut” appearance on skull radiographs.
136
What is the appropriate treatment for sickle cell anaemia?
Appropriate supportive care, including pain control and intravenous fluids, for acute sickle complications is the mainstay of therapy. Attention to the psychological impact of this disease, with social and psychiatric support, is essential to help patients deal with this disabling, painful disease. Additional medical therapy includes hydroxyurea, which increases HbF production, thereby reducing the number of cells with the potential to sickle. Exchange transfusion with normal RBCs may reduce the sickle RBC percentage and is used to treat the life-threatening complications of acute chest syndrome, stroke, and splenic sequestration.
137
What is the most likely diagnosis?
What risk factors are associated with this condition?
- Small cell lung carcinoma (SCLC). SCLC often presents as a hilar or mediastinal mass.
- Smoking is the major risk factor for the development of most lung cancers. Large cell lung cancer and bronchoalveolar carcinoma, however, are not thought to be related to smoking.
- Exposure to other substances, including asbestos, polycyclic aromatic hydrocarbons, and ionizing radiation also increases the risk for SCLC.
138
What are the most common sites of metastasis for Small cell lung carcinoma (SCLC)?
Small cell lung cancers metastasize to virtually every organ in the body, usually early in the onset of disease. Brain metastases are common, with resulting neurologic deficits. Bone metastases result in bone pain or fractures and can cause spinal cord compression. Liver, supraclavicular lymph nodes, and adrenal metastases are also common.
139
What are the appropriate treatments for Small cell lung carcinoma (SCLC)?
Most patients with SCLC have unresectable disease at the time of presentation. In the rare patient with small peripheral lesions and no metastases, surgical resection may be an option. Treatment for SCLC involves chemotherapy, typically etoposide plus cisplatin, with or without radiotherapy. In patients who do not receive chemotherapy or radiation, mean survival is 6–17 months, while survival for treated patients can average > 24 months.
140
What other syndrome are patients with Small cell lung carcinoma (SCLC) at greatly increased risk for developing?
She is at risk for developing Lambert-Eaton myasthenic syndrome (a paraneoplastic syndrome). This condition, which is similar to myasthenia gravis, is caused by autoantibodies against the P/Q-type calcium channels in the presynaptic neuromuscular junction. It causes weakness of the proximal musculature, especially of the lower limbs. Cranial nerves are commonly affected, which often manifests as ptosis of the eyelids and diplopia.
141
What is the most likely diagnosis? What protein defect causes this condition?
Hereditary spherocytosis, an autosomal dominant form of hemolytic anemia.
- RBC membrane defects are the result of mutations in spectrin or ankyrin (erythrocyte skeletal proteins). This results in a decreased membrane/volume ratio, which makes the cells more fragile. Therefore, a positive result on osmotic fragility testing is typically pathognomonic for the disease. Cells are trapped in the spleen, where they are destroyed.
142
What are the typical peripheral blood smear findings in Hereditary spherocytosis?
What 4 blood tests and findings can help establish the diagnosis of Hereditary spherocytosis?
Small RBCs without central pallor (spherocytes) (Figure 8-26) are seen on a peripheral blood smear.
Tests to Confirm Diagnosis:
1. An osmotic fragility test may confirm the presence of fragile sphere-shaped RBCs.
2. The MCHC is increased because of a reduction in membrane surface area in the setting of a constant hemoglobin concentration.
3. MCV remains normal because the overall volume remains stable.
4. High reticulocyte counts (5%–10%).
Indirect bilirubin levels are elevated.
143
What test could be used to differentiate Hereditary spherocytosis from autoimmune etiologies?
A direct Coombs test is used to distinguish hereditary spherocytosis from warm antibody hemolysis: Hereditary spherocytosis is Coombs negative, whereas warm antibody hemolysis is Coombs positive. A positive result on a direct Coombs test indicates the presence of antibodies on RBCs. A positive result on an indirect Coombs test indicates the presence of antibodies in the serum.
144
What are the appropriate treatments for Hereditary spherocytosis?
Splenectomy is curative and should be considered in patients with severe disease. Surgery also helps prevent gallstone formation. Folate supplementation can be useful.
145
What organ is most likely injured in this case?
The spleen. It is an important organ in immune function and hematopoiesis. The primary function of the spleen is clearance of abnormal RBCs, microorganisms, and particulate matter from the bloodstream. Additionally, it is involved in hematopoiesis (extramedullary hematopoiesis) and synthesis of IgG, properdin, and tuftsin.
146
What is the normal size of the spleen?
A normal spleen weighs 150 g and is nonpalpable. Spleens that are prominent below the costal margin typically weigh 750–1000 g. Figure 8-27A is a CT scan of a man with splenic injury due to blunt trauma. This scan, obtained soon after contrast administration, shows multiple large lacerations of the spleen, hematoma, and perihepatic free fluid. Figure 8-27B, obtained after the contrast had cleared, more clearly shows a large laceration on the posterior surface of the spleen extending anteriorly to the hilum.
147
Where is the spleen located?
The spleen is located under the rib cage in the left upper quadrant of the abdomen, below the diaphragm. Therefore, during palpation, descent of an enlarged spleen is felt on inspiration.
148
Where is the most common site of referred pain in injury to the spleen?
Why is a blunt injury to this organ so concerning?
- Left shoulder and trapezius ridge tenderness (C3–C5 dermatomes, same as the roots of the phrenic nerve) may also be present as a result of subdiaphragmatic phrenic nerve irritation. Referred pain is due to subdiaphragmatic pooling of blood.
- The spleen is a highly vascular organ that filters up to 15% of the total blood volume per minute. The spleen can hold an average of 40–50 mL of RBCs in reserve and can pool significantly more blood.
149
What is the major concern for a patient postsplenectomy?
The major concern is sepsis from encapsulated bacterial organisms. Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae vaccinations are essential since encapsulated organisms are usually cleared by the spleen. Vaccinations are usually given several weeks before splenectomy, if possible, or 2 weeks after in an emergent case. Antibiotic prophylaxis for dental procedures and empiric treatment for fever are also vital given the immunocompromised state of the asplenic patient.
150
What is the most likely diagnosis? What is the differential diagnosis of a scrotal mass?
Testicular tumor, as suggested by the presence of a painless, nontransilluminating testicular mass. In a young man, the most likely diagnosis is a **seminoma**, which has a peak incidence of age 35 years and accounts for approximately 35% of testicular tumors. This diagnosis is further supported by the elevated LDH level, normal hCG level (elevated in 20% of seminomas), and normal AFP level.
151
What is the analogous condition of seminoma in women?
The analogous ovarian tumor is the dysgerminoma, the most common germ cell tumor in women. It is usually malignant and is more common in younger patients. Like seminomas, it can produce LDH. It can also produce alkaline phosphatase.
152
What is the lymphatic drainage of this tumor of the testes?
Understanding the lymphatic drainage of the testicles is important in considering metastases. Because the testicles descend from the abdomen during development, the lymph vessels ascend to the lumbar and para-aortic lymph nodes. This contrasts with the lymph drainage of the scrotum, which is an outpouching of skin. The lymph vessels of the scrotum drain to the superficial inguinal nodes.
153
What conditions, other than seminoma, are characterized by an elevated hCG level?
Only 10%–20% of seminomas present with elevated hCG levels. Tumors in women that are likely to present with an elevated hCG level include hydatidiform moles, choriocarcinomas, and gestational trophoblastic tumors.
154
What is the most likely diagnosis?
Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS).
155
What are the five cardinal symptoms of Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS)?
What is the pathogenesis of these symptoms?
1. Transient neurological problems.
2. Fever.
3. Thrombocytopenia.
4. Microangiopathic hemolytic anemia.
5. Acute renal insufficiency.
TTP/HUS involves the widespread development of hyaline thrombi composed of platelet aggregates in the microcirculation. This consumption of platelets leads to thrombocytopenia and microangiopathic hemolytic anemia, which can cause widespread organ dysfunction.
156
What would this patient’s coagulation studies show?
Coagulation studies will be within normal limits. This is predominantly a thrombocytopenic disease with no coagulation cascade abnormalities.
157
Which inherited risk factor predisposes patients to Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS)?
A deficiency of the von Willebrand metalloproteinase (ADAMTS-13) is an inherited factor that causes very large von Willebrand factor multimers to accumulate in the plasma and promote clot formation.
158
What is the appropriate management for Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS)?
Plasma exchange reverses the platelet consumption that is responsible for the thrombus formation. Severe cases may also require adjunctive immunosuppressive treatment with prednisone. Platelet transfusion is contraindicated because it may lead to new or worsening thrombosis and subsequent neurologic symptoms. Prompt initiation of treatment is essential to avoid irreversible renal failure and possibly death.
159
What is a common cause of Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS) in children?
Typically, TTP/HUS is preceded by severe bloody diarrhea due most often to enterohemorrhagic Escherichia coli O157:H7 infection. This is thought to be due to systemic absorption of a Shiga-like toxin that binds to and damages endothelial cells, inciting platelet activation and thrombosis.
160
What is the most likely diagnosis?
Von Willebrand disease (vWD) is the most common inherited bleeding disorder. It is the result of a quantitative (type 1 or 3) or qualitative (type 2) defect in von Willebrand factor (vWF). vWF is a large protein made by endothelial cells and megakaryocytes. It is a carrier for factor VIII and is a cofactor for platelet adhesion. There are now more specific tests that measure vWF antigen levels and activity (ristocetin cofactor assay) directly.
161
What clinical findings are commonly associated with Von Willebrand disease (vWD)?
vWD disturbs both primary and secondary hemostasis. Its role in adhesion of platelets to exposed subendothelium leads to increased bleeding time and an overall clinical picture of platelet dysfunction (mucous membrane bleeding, petechiae, and purpura) with vWF defects. The role of vWF as a carrier protein for factor VIII means that severe vWF deficiency leads to a clinical picture similar to a coagulation factor deficit (“pseudo-hemophilia”): “deep bleeds” such as hemarthroses (bleeding into joints), easy bruising, and macrohemorrhages. Patients often have a positive family history.
162
What do the PT and PTT values reflect? How would the PT and PTT values differ with the administration of warfarin versus heparin?
- The PT reflects changes in factor II, V, VII, IX, or X. The PTT reflects changes in any of the coagulation factors except factors VII and XIII, and it can be elevated in vWD.
- Heparin affects the intrinsic pathway, causing increased PTT. Warfarin affects the extrinsic pathway, increasing PTT and PT. PT should always be monitored with patients taking warfarin (mnemonic: WEPT = Warfarin affects the Extrinsic pathway, increasing PT.
163
Which coagulation factors require vitamin K for synthesis?
Factors II, VII, IX, and X and proteins C and S require vitamin K for synthesis. Warfarin interferes with vitamin K, leading to a clinical picture that is similar to vitamin K deficiency. The liver is important in the synthesis and metabolism of vitamin K and the coagulation factors (except VIII). Therefore, liver disease can also produce a similar clinical picture.
164
What are the appropriate treatments for Von Willebrand disease (vWD)?
Treatment for mild bleeding in type 1 disease involves the use of desmopressin, which causes release of vWF from endothelial stores. Severe disease may be treated with factor VIII concentrates that contain high vWF antigen. Cryoprecipitate is no longer used as viruses cannot be inactivated (high infection risk).
