Get to grips with these commonly seen high-yield pathology images – curated by Megan C. Smith, MPH.

Microscopic pathology can be a challenge to decipher. Professionals spend years learning to analyze seas of pink and blue shapes, interpreting select images to diagnose disease. Thankfully, the USMLE board uses straightforward imagery as evidence to support the diagnosis suggested by the vignette. The differential diagnosis gleaned from the question stem can be narrowed down by practiced recognition and the understanding of pathological images. This article highlights some of the types of microscopic images most frequently seen on the USMLE Step 1 exam and explains the pathology behind the findings.

Musculoskeletal Pathology

Gout versus pseudogout

Gout and pseudogout are both diseases caused by crystal deposition in the joints. Clinically, they present similarly. In questions surrounding these topics, a visual analysis of synovial fluid from the affected joint may be provided in order to help the examinee make the diagnosis.

Gout - Monosodium Urate Crystals

Image credit: View image source on wikipedia.org

In gout, microscopy under polarized light shows needle-shaped crystals of monosodium urate. These crystals demonstrate negative birefringence. Birefringence is a property involving the differing refractive indices of a material, dependent on light polarization. The details of this property are not tested on the USMLE. Just keep an eye out for these needle-shaped crystals in the context of acute joint pain.

Pseudogout - Calcium Pyrophosphate Dihydrate Crystals

Image credit: DIEPPE P, SWAN A. Identification of crystals in synovial fluid Annals of the Rheumatic Diseases 1999;58:261-263.
View image source on the NCBI Website

The crystals of pseudogout are comprised of calcium pyrophosphate dihydrate (CPPD). In contrast to gout, pseudogout crystals are rhomboid in shape and demonstrate weakly positive birefringence.

Infectious Disease Pathology

Giardiasis – Giardia trophozoites

Image credit: Gulwani H. Giardia lamblia. Accessed July 9th, 2019.
View image source on pathologyoutlines.com

Giardiasis presents with fatty, foul-smelling diarrhea. The condition is self-limiting and stool is not frequently examined for ova or parasites.  However, microscopic examination would reveal Giardia parasites in their trophozoite form. They are teardrop-shaped with a short tail and two distinct nuclei.

Candidiasis – Candida albicans

Image credit: View image source on biotrans.uni.wroc.pl

Candidiasis is a fungal infection that may impact the mouth, esophagus, or vagina. The genus of fungi known as Candida appears microscopically in its yeast form or filamentous form, as it is a dimorphic fungus. Candida albicans is the most common species causing infection in humans. Normally, Candida harmlessly colonizes the mouth, GI tract, or vagina and is kept under control by native bacteria. Disruptions to normal flora may lead to uncontrolled growth of Candida and reveal symptoms. Most commonly, the stringy, dark purple, filamentous form will be shown with a USMLE vignette. Round yeasts, as in the photo, may be seen as well. When these microscopic findings are seen with a white plaque on the affected mucous membrane, candidiasis should be suspected.

Bacterial vaginosis – Clue cells

Image credit: Microbicide Trials Network. Training Instructions for Reading Vaginal Wet Mounts for Clue Cells. (Presentation Slides)
View image source on the Microbicide Trials Network Website

Lactobacillus is part of the normal vaginal bacterial flora. Bacterial vaginosis is a genitourinary condition resulting in overgrowth of other bacteria, often resulting in vaginal odor and discharge concerning to the patient. Vaginal discharge may be examined under the microscope to aid in diagnosis. A swab will sample vaginal epithelial cells and Gram staining will highlight bacterial morphology. In bacterial vaginosis, the epithelial cells are visibly coated in a variety of bacteria. The surface of the cell appears extensively stippled and the edges of the cells are obscured. These are known as “clue cells”.

Normal vaginal epithelial cells are shown below, for reference. Note the presence of rod-shaped Lactobacilli, normal vaginal flora.


Image credit: Microbicide Trials Network. Training Instructions for Reading Vaginal Wet Mounts for Clue Cells. (Presentation Slides) 
View image source on the Microbicide Trials Network Website

Hematopathology

Leukemia

When a vignette suggests a clinical picture of hematologic malignancy (fevers/chills, chronic fatigue, weight loss), it can be difficult to narrow down the diagnosis. It is helpful when an image of a peripheral blood smear or bone marrow aspirate is included. A few leukemias have distinct microscopic findings to bear in mind when evaluating a patient.

Acute Myeloid Leukemia – Auer Rods

Image credit: Gordon, SW and Krystal GW. (2017). Images in Clinical Medicine: Auer Rods. N Engl J Med, 376(2062). DOI: 10.1056/NEJMicm1612344
View image source from the New England Journal of Medicine (@NEJM) on Twitter

In acute myeloid leukemia (AML), bone marrow biopsy will show immature myeloid cells known as blasts. The presence of Auer rods in these cells is a known feature of AML. Auer rods (indicated by arrows) are needle-shaped clusters of primary granules that form in the cytoplasm. Demonstration of Auer rods in a bone marrow sample is indicative of AML.

Chronic Lymphocytic Leukemia – Smudge Cells

Image credit: Yun, H. D., & Waller, E. K. (2013). Smudge cells following treatment with pentostatin in a patient with B-cell prolymphocytic leukemia. Blood, 122(4), 474-474. doi:10.1182/blood-2013-02-481697
View image source on bloodjournal.org

Indicated by the thin arrow, “smudge cells” can be seen on peripheral blood smear in chronic lymphocytic leukemia (CLL). Smudge cells appear as poorly defined, “crushed” cytoplasm without distinguishable nuclei. These are fragile lymphocytes, produced by a poorly functioning leukemic bone marrow. They are crushed during slide preparation when the coverslip is placed over the blood sample on the glass slide. Smudge cells on microscopy in combination with the symptoms of leukemia suggests CLL.

Hairy Cell Leukemia – Hairy Cells

Image credit: American Society of Hematology.
View image source on the ASH Website

Hairy cell leukemia is named after these characteristic cells. They appear “hairy” under the microscope due to threadlike or stringy cytoplasmic projections, while the cytoplasm of a normal lymphocyte appears smoothly rounded. When hairy cells are seen in conjunction with the symptoms of leukemia, the examinee can confidently diagnose this malignancy.

Sickle Cell Anemia – Sickle Cells

Image credit: Sickle Cells Open Online Topics and Educational Resources (SCOOTER).
View image source on sicklecellanaemia.org

Sickle cells are among the most recognizable features in hematology. In sickle cell anemia, hydrophilic glutamic acid is replaced by hydrophobic valine in the β chain of hemoglobin. Under conditions of hypoxia, infection, dehydration or acidosis, this results in inappropriate polymerization of hemoglobin, leading to deformed and rigid red blood cells. When these cells pass through delicate capillaries, they suffer membrane damage and are hemolyzed intravascularly or in the reticuloendothelial system. They can also occlude small vessels in the hands/feet, pulmonary microcirculation, kidney, or spleen leading to painful vaso-occlusive crises. Patients with sickle cell trait are heterozygous for the autosomal recessive mutation, and have less than 50% mutated hemoglobin. Interestingly, patients with sickle cell trait often exhibit resistance to malaria.

Multiple Myeloma – Rouleaux Formation

Image credit: Peter Maslak. (2005). Rouleaux. Blood, 105(3), 919. Accessed July 13th, 2019. 
View image source on bloodjournal.org

Multiple myeloma is a plasma cell disorder characterized by the presence of M protein in serum or urine. The mnemonic “CRAB” is often used to remember the common symptoms of multiple myeloma: Calcium elevation, Renal Complications, Anemia, and Bone pain. On peripheral blood smear, red blood cells may be seen in the “rouleaux” formation, meaning that the cells appear as a “stack of coins”. In multiple myeloma, the heightened level of serum proteins (including fibrinogen) helps to stabilizes clusters like these. This feature is nonspecific, also seen in diabetes and other malignancies. However, when seen together with the CRAB symptoms, multiple myeloma may be suspected.

Gastrointestinal Pathology

Whipple Disease – Foamy, PAS positive macrophages

Image credit: Mathis, D and Rodriguez, R in Gulwani H. Whipple disease. Accessed July 13, 2019. 
View image source on pathologyoutlines.com

Whipple disease (also known as intestinal lipodystrophy) is a condition of systemic tissue damage caused by infection with Tropheryma whippelii. Symptoms include migratory joint pain (often chronic) and chronic diarrhea/malabsorption. It may impact multiple other systems as well, demonstrating cerebellar ataxia, endocarditis, pleural effusion, and uveitis, for example. The classic vignette for Whipple disease may describe a male patient over age 40, undergoing a small bowel biopsy after other gastrointestinal workup has been noncontributory. The biopsy will demonstrate foamy macrophages in the lamina propria (connective tissue layer beneath epithelium) that stain positive for PAS (periodic acid-Schiff; detects structures with high carbohydrate content). Due to staining, the macrophages appear as deep pink, granular structures. These can be especially difficult for the inexperienced histologist to identify. However, if you see deep pink in a small bowel biopsy from an older male patient with joint pain and diarrhea, Whipple disease is a strong possibility.

This is a rare condition, but the microscopic findings are so classic that it will be an easy point if you can make an identification.

Conclusion

These are some common examples of images that you might expect to see on the USMLE Step 1 exam, but this list is not exhaustive. Keep an eye out for unique images like these while reviewing material. Consider making flashcards of the images in order to quiz yourself on what the image demonstrates, what diagnostic clues it provides, and how the finding contributes to the disease process. Recognizing a high-yield image can clinch the diagnosis (and the extra exam point) when the clinical picture is unclear.

Happy studying!

This blog was authored by Megan C. Smith, MPH, a Fourth-Year Medical Student at Wright State University Boonshoft School of Medicine. Megan is applying to residency in pathology this year.

Test your knowledge with over 800 pathology questions in the Pastest USMLE Step 1 Qbank – try full, free access for 48 hours! No credit card required.

Looking for more USMLE Step 1 guidance? Check out our Ultimate Guide to the USMLE Step 1 Exam for everything you need to know.