To the Editor:
A healthy 28-year-old mother of 3 referred herself to the hospital because of leg pain and was admitted. Examination and Doppler ultrasound showed only varicose veins, without deep vein thrombosis or plantar fasciitis, and pallor. Hemoglobin (Hb) was 3.9 g/dL (mean corpuscular volume 60.7 fL, mean corpuscular hemoglobin 14.7 pg, red cell distribution width 18.4%), with normal white blood cells/platelets. The previous count was performed on the birth of her youngest son, 1.5 years prior showing Hb 10.8 gr/dL (mean corpuscular volume 89.4 fL). She reported normal diet and menses, had no gastrointestinal complaints and no medications or relevant family history.
Further tests showed microcytosis/anisocytosis on the blood smear, 1.9% reticulocytes (absolute count 49,970, reticulocyte production index 0.28), iron 17 μg/dL, transferrin 315 mg/dL (saturation 3.77%), ferritin 4.1 ng/mL, B12 >2000 pg/mL (N <950), folate 2.1 ng/mL. Serum lactate dehydrogenase (LDH) was consistently 821-991 IU/mL (N <225) but haptoglobin, bilirubin, and all hepatic and muscle enzymes were repeatedly normal, as were C-reactive protein (1.5 mg/dL), albumin (4.1 g/L), glucose, electrolytes, renal function tests, urinalysis, and lipids. Fecal occult blood test was negative.
She received packed cells transfusions and would have been discharged for ambulatory workup of iron deficiency anemia had not the combination of increased serum B12 and LDH suggested an underlying tumor. Computed tomography demonstrated a huge liver mass and a mass in the right colon (Figure). Colonoscopy confirmed a nonobstructing carcinoma and biopsies (both sites) demonstrated adenocarcinoma. Serum carcinoembryonic antigen was >4000 ng/mL. She was referred for oncological treatment and genetic/molecular workup.
Our patient's misfortune saddened us all, but her presentation offers some important insights.
First, we saw once more that young patients can tolerate severe degrees of anemia (in this case, ∼33% of her baseline Hb) developing gradually with no symptoms whatsoever.
Second, an entirely normal biochemistry panel (C-reactive protein, albumin, liver enzymes) cannot rule out stage IV cancer with extensive liver spread.
Third, young age at presentation and absence of risk factors are not incompatible with colorectal cancer. In fact, recent epidemiological trends of increasing diagnosis in younger people has led the US Preventive Services Task Force to recommend starting screening at age 45 years (down from 50) in populations at moderate risk. Young patients 20-39 years old have had the highest increase in incidence (57%-66% increase in the United States in 2015 ± 1 year vs 2001 ± 1 year) and are more likely to be metastatic when diagnosed.
1The same trend was found in Europe.
- Montminy EM
- Zhou M
- Maniscalco L
- et al.
Shifts in the proportion of distant stage early-onset colorectal adenocarcinoma in the United States.
Cancer Epidemiol Biomarkers Prev. 2022; 31: 334-341
2Right-sided colonic lesions are notoriously asymptomatic, and presentation as iron-deficiency anemia is typical through occult bleeding. The single negative occult blood test must have been a sampling-dependent false negative.
- Vuik FER
- Nieuwenburg SAV
- Bardou M
- et al.
Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years.
Gut. 2019; 68: 1820-1826
Fourth, “the devil is in the details,” as the idiom goes. The patient's most unusual telltale findings were the raised LDH and B12 levels. Both are established tumor markers (in the absence of an alternative explanation), and can be seen in myriad malignancies. Serum LDH was found to be frequently increased in cancer patients (hematological, solid tumors) and associated with worse prognosis.
3The mechanism is probably linked to an increased glucose uptake by rapidly proliferating cells, LDH required for its processing, and release through damaged cell membrane. The mechanism of elevated B12 in cancer is poorly understood, but while unexplained high B12 levels (defined as >1000 ng/L) can occur in other conditions, a persistent increase appears to be most strongly associated with solid cancer (hazard ratio 5.90; 95% confidence interval, 2.79-12.45; P < .001),
- Forkasiewicz A
- Dorociak M
- Stach K
- Szelachowski P
- Tabola R
- Augoff K
The usefulness of lactate dehydrogenase measurements in current oncology practice.
Cell Mol Biol Lett. 2020; 25: 35
4and in an appropriate clinical context, as in our patient, suggests the need of further evaluation.
- Lacombe V
- Chabrun F
- Lacout C
- et al.
Persistent elevation of plasma vitamin B12 is strongly associated with solid cancer.
Sci Rep. 2021; 11: 13361
- Shifts in the proportion of distant stage early-onset colorectal adenocarcinoma in the United States.Cancer Epidemiol Biomarkers Prev. 2022; 31: 334-341
- Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years.Gut. 2019; 68: 1820-1826
- The usefulness of lactate dehydrogenase measurements in current oncology practice.Cell Mol Biol Lett. 2020; 25: 35
- Persistent elevation of plasma vitamin B12 is strongly associated with solid cancer.Sci Rep. 2021; 11: 13361
Published online: December 07, 2022
Funding: Not applicable.
Conflicts of Interest: None identified.
Authorship: The paper was written by AS; ID and LU participated in equal parts.
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