Anemia in a Heavy Smoker

Medscape

a day ago

Editor's Note:
The Case Challenge series includes difficult-to-diagnose conditions, some of which are not frequently encountered by most clinicians, but are nonetheless important to accurately recognize. Test your diagnostic and treatment skills using the following patient scenario and corresponding questions. If you have a case that you would like to suggest for a future Case Challenge, please email us at [e-mail] with the subject line "Case Challenge Suggestion." We look forward to hearing from you.
Background and Initial Presentation
A 40-year-old man presents to the emergency department with complaints of repeated vomiting and dizziness for the past 2 days. He has no fever or diarrhea.
He has been experiencing dyspepsia and abdominal fullness after meals for a month. These symptoms have increased during this time, causing him to decrease his food intake week by week. He has tried over-the-counter drugs, such as antacids and pantoprazole, with no effect. This condition has been associated with epigastric pain; his general practitioner tested him for Helicobacter pylori , which was negative.
The patient has been a heavy smoker for the past 15 years, smoking one pack per day. Since his symptoms began, he has tried to quit smoking using nicotine patches. He attributed his dyspepsia to the use of the nicotine patch, considering his negative H pylori test. He therefore decreased the duration of his nicotine patch use, but his symptoms only minimally improved.
He has also experienced easy fatigability over the past 4 months. He noted that at times during the previous month, his eyes have become yellow.
His family history shows that his father died of colon cancer in his 50s.
The patient's presentation is suspicious for hemolytic anemia, so it will be important to confirm this with a Coombs test and a peripheral blood smear for schistocytes.[1] ESR and CRP and GGT levels will not help diagnose the cause of hemolytic anemia.
Physical Examination and Workup
Examination:
Blood pressure: 100/60 mm Hg
Pulse: 95 beats/min
Temperature: 37.5 °C (99.5 °F)
General examination: Pallor of the inner lips; hand creases apparent, not faded
Abdominal examination: Splenomegaly
Laboratory investigations:
Sodium: 130 mEq/L (range, 135-145)
Potassium: 3 mEq/L (range, 3.5-5.2)
Creatinine: 1.5 mg/dl (range, 0.7-1.3)
Blood urea nitrogen: 50 mg/dL (range, 6-24)
Coombs test: 3+ (range, 0-4)
Hemoglobin: 9 g/dL (range for men, 13.2-16.6)
Calcium level: 9 mg/dL (range, 8.5-10.2)
Complete blood film shows schistocytes count of 6% (range, normal is < 0.5%, although usual values are < 0.2%)
Mean corpuscular volume: 90 fl (range, 80-100)
Platelet: 150,000/µL (range, 150,000-450,000)
White blood cells: 6000/µL (range, 4,500-11,000)
ESR: 120 mm/hr (range for men, < 50 years old: < 15)
CRP: 70 mg/dL (range, < 0.3)
A CT of the abdomen with contrast was taken, showing the lesions in Figure 1.
Figure 1. Abdominal CT with contrast showing lesions.
MAHA as a paraneoplastic syndrome in infiltrative gastric cancer is the most likely diagnosis.
MAHA as a paraneoplastic syndrome is a rare presentation of metastatic gastric cancer, with only about 50 cases documented in the literature. MAHA is caused by tumor-associated thrombotic microangiopathy and is considered an oncologic emergency.[2] It is associated with poor prognosis.[3] In one single-center analysis, most of the patients with MAHA showed infiltrative diffuse gastric cancer with partial or complete signet ring cellular morphology. All patients had metastatic disease at the time of presentation of MAHA, either at first diagnosis or recurrence.[2]
Gastric cancer (GC) is a major cause of cancer-related deaths, mostly due to diagnosis at advanced stages of the disease;[4] it is often asymptomatic in the early stages.[5] Asymptomatic cancers can present with nonspecific paraneoplastic symptoms such as anemia or endocrine disturbances. Rapid development of pernicious anemia due to adenocarcinoma of the stomach has been reported in the literature.[6] Advanced GC symptoms may include iron deficiency anemia.[5]
Anemia due to bleeding in cancers presents as microcytic anemia with low iron and ferritin levels (although ferritin can be elevated as part of the immune response to cancer).[7]
Anemia due to malabsorption is usually due to deficiencies of B12 or folate causing macrocytic anemia or to iron malabsorption causing microcytic anemia.[7,8]
In this patient, the Coombs test result was positive for hemolytic anemia, and the blood smear indicated elevated schistocytes. His anemia is normocytic hemolytic anemia due to destruction of the red blood cells with elevated lactate dehydrogenase and schistocytes. The presence of clear invasive GC provides a cause of his anemia.
In the CT of the abdomen with contrast (Figure 1), circumferential wall thickening up to 15 mm was seen throughout the stomach. Multiple enlarged pathologic lymph nodes were noted perigastric, peripancreatic, within the porta-hepatis, and para-aortic. The largest was seen at porta hepatis measuring 30 x 14 mm. Mild ascites was present. The liver echo pattern was inhomogeneous with multiple bilobar hypodense non-enhancing hepatic focal lesions: one in segment VI/VII measuring 8 x 7 mm and the other in segment III subcapsular exophytic lesion measuring 14 x 12 mm.
An upper GI endoscopy was performed and biopsies were taken. Endoscopy showed thickened mucosa of the stomach with decreased gastric rugae and volume (Figure 2).
Figure 2. Upper GI endoscopy showing thickened stomach mucosa with decreased gastric rugae and volume.
The pathology report of the gastric antral biopsies showed diffuse signet ring cellular morphology stage III.
Of note, in all newly diagnosed patients with GC, testing for microsatellite instability (MSI) status by PCR/next-generation sequencing or mismatch repair status by immunohistochemistry is recommended.[4] Testing for MSI status also should be done in patients with locally advanced and unresectable or metastatic GC to tailor treatment.[5]
Signet ring cell cancer grade 3 usually shows recurrence within 2 years after standard treatment of radical surgery and chemotherapy. Signet ring cell cancer is often chemoresistant; even the use of adjuvant chemotherapy is controversial.[9]
Adequate surgical resection is considered the main therapeutic option for signet ring cell GC;[10] surgery is recommended for appropriate metastatic GC candidates.[4] Advanced GC signet ring cell type is treated with 5-fluorouracil (5-FU);[11] for stage III, the treatment regimen is chemotherapy with a 5-FU-based combination.[2]
For patients who are candidates for treatment with PD-1 inhibitors, PD-L1 testing may be considered. A specimen with a combined positive score ≥ 1 is viewed as exhibiting PD-L1 expression.[4]
The patient was referred to surgery for a radical gastrectomy. After 1 month, he started chemotherapy with a 5-FU-based combination.
After completing his 13-month course of chemotherapy, the patient began to experience cough and dyspnea. He presented to the emergency department with cyanosis and severe dyspnea. On examination, his temperature was normal but his oxygen saturation was 70%, and there was decreased air entry on both sides of the chest. A chest radiograph demonstrated bilateral pleural effusion. Chest CT with contrast was performed to exclude metastasis (Figure 3). The chest CT showed bilateral encysted pleural effusion with mild pericardial effusion. The lungs exhibited areas of atelectasis in relation to the effusion. Lung biopsies confirmed metastasis.
Figure 3. Chest CT with contrast showing bilateral encysted pleural effusion.
The findings indicated recurrence with metastatic presentation. Because of the late stage of disease and the type of tumor, the oncologist recommended personalized palliative immunotherapy to prolong survival and improve the patient's general condition. Immunotherapy options for GC include immunomodulators, checkpoint inhibitors,[4,5,12] and vaccines targeting the tumor.[12]
The patient has recurrent disease following treatment with a 5-FU-containing regimen, and he had received a radical gastrectomy when he presented at stage III. His dyspnea is considered a rare presentation of GC, although it can occur in cases of pulmonary metastasis, pulmonary lymphangitic carcinomatosis, or pulmonary tumor thrombotic microangiopathy.[13]
Immunotherapy for signet ring cell GC includes immune checkpoint inhibitors targeting PD-1 and PD-L1. In selected cases of signet ring cell cancer, where MSI is high with deficient mismatch repair proteins, immunotherapy with PD-1 could be effective.[10] PD-1 and PD-L1 checkpoint inhibitors decrease T-cell tolerance to the tumor cells, enhancing the body's adaptive immune response against cancer cells.[12]
This patient had high MSI and started PD-1 inhibitor immunotherapy. His pulmonary symptoms improved, with decreased dyspnea and fatigue and increased oxygen saturation. Later chest CT showed absence of pleural effusion and pericardial effusion, and the metastatic nodules regressed.
Signet ring cell GC comprises about 17% of primary gastric tumors.[14,15] Patients with signet ring cell gastric carcinoma usually exhibit higher TNM staging at presentation as compared with patients with non-signet ring cell tumors.[15] More patients with signet cell GC receive chemotherapy than those with non-signet cell cancer.
Bone metastasis was higher in patients with signet ring cell cancer as compared with those with non-signet ring cell cancer GC in a large cohort (> 36,000) of GC patients.[15]
First-line treatment for stage IV signet ring cell cancer includes palliative chemotherapy with docetaxel-5-FU-oxaliplatin. If the patient has stage IV disease at diagnosis, radical gastrectomy with chemotherapy (13 months) provides longer survival than chemotherapy alone (7 months).[14] However, in the REGATTA trial, palliative gastrectomy in stage IV disease did not provide any survival benefit over chemotherapy alone.[16]
PD-1 inhibitor immunotherapy may be effective in patients with signet ring cell cancer with high MSI and deficient tumor mismatch repair.[10] As noted previously, PD-1 and PD-L1 checkpoint inhibitors decrease T-cell tolerance to the tumor cells, enhancing the body's adaptive immune response against cancer cells.[12]
Although the patient's chest CT showed bilateral pleural effusion, that is not a prognostic marker for PD-1 inhibitor response. As noted earlier, signet ring cell cancer is often chemoresistant, and grade 3 usually shows recurrence within 2 years after the standard treatment of radical surgery and chemotherapy,[17] neither of which are prognostic markers for PD-1 inhibitor response.