Determining the diagnostic significance of eosinophilic
globules for the verification of fumarate-deficient leiomyoma.
TRAINING SET FOR INTEROBSERVER REPRODUCIBILITY STUDY
THIS TRAINING SET COMPILES
Representative slides of uterine leiomyomas with fumarate (dFH-LM) deficiency featuring Eosinophilic globules, drawn from previously published articles and from the archive of the First Department of Pathology, FSBI “National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov,” Ministry of Health of the Russian Federation.
A link to a website hosting scanned histologic slides of dFH-LM on IHC and atypical uterine leiomyomas is provided at the end of the set.
A link to a website hosting scanned histologic slides of dFH-LM on IHC and atypical uterine leiomyomas is provided at the end of the set.
DEFINITION AND METHODOLOGY
Eosinophilic globules
Eosinophilic globules are characteristic intracytoplasmic (within smooth-muscle cells), spherical, homogeneous/glassy eosinophilic structures representing accumulations of protein material (most often glycoproteins).
Staining
H&E– Eosinophilic, dense, occasionally hyaline (i.e., glassy);
Shape
Shape – Round to oval, well-demarcated, with perinucleolar halo, in some cases irregular;
Size
Approximately equal to or slightly larger than the nucleus of a normal spindle-shaped smooth muscle cell;
Quantity
Multiple. The presence of only one or two globules per 10 high-power fields (HPF) is considered as absence of globules;
Surrounding reaction
No associated inflammatory or fibrotic response.
dFH-LM showing prominent eosinophilic nucleoli with perinucleolar halos and Eosinophilic globules.
hematoxylin and eosin, 400×
Reyes C., Karamurzin Y., Frizzell N., et al. Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry. Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 2014 Jul;27(7):1020-1027. DOI: 10.1038/modpathol.2013.215. PMID: 24309325; PMCID: PMC4048336.
https://pubmed.ncbi.nlm.nih.gov/24309325/
https://pubmed.ncbi.nlm.nih.gov/24309325/
dFH-LM showing Eosinophilic globules indicated by arrowhead.
hematoxylin and eosin, 400×
Reyes C., Karamurzin Y., Frizzell N., et al. Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry. Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 2014 Jul;27(7):1020-1027. DOI: 10.1038/modpathol.2013.215. PMID: 24309325; PMCID: PMC4048336.
https://pubmed.ncbi.nlm.nih.gov/24309325/
https://pubmed.ncbi.nlm.nih.gov/24309325/
C. Some nuclei contain pseudoinclusions and eosinophilic cytoplasmic globules are prominent.
D. An example with a focal fascicular pattern and scattered pleomorphic nuclei.
D. An example with a focal fascicular pattern and scattered pleomorphic nuclei.
hematoxylin and eosin, 400×
Miettinen M., Felisiak-Golabek A., Wasag B., Chmara M., Wang Z., Butzow R., Lasota J. Fumarase-deficient Uterine Leiomyomas: An Immunohistochemical, Molecular Genetic, and Clinicopathologic Study of 86 Cases. Am J Surg Pathol. 2016 Dec;40(12):1661-1669. doi: 10.1097/PAS.0000000000000703. PMID: 27454940; PMCID: PMC5106328
https://pubmed.ncbi.nlm.nih.gov/27454940/
https://pubmed.ncbi.nlm.nih.gov/27454940/
Eosinophilic cytoplasmic globules.
hematoxylin and eosin, 400×
Miettinen M., Felisiak-Golabek A., Wasag B., Chmara M., Wang Z., Butzow R., Lasota J. Fumarase-deficient Uterine Leiomyomas: An Immunohistochemical, Molecular Genetic, and Clinicopathologic Study of 86 Cases. Am J Surg Pathol. 2016 Dec;40(12):1661-1669. doi: 10.1097/PAS.0000000000000703. PMID: 27454940; PMCID: PMC5106328
https://pubmed.ncbi.nlm.nih.gov/27454940/
https://pubmed.ncbi.nlm.nih.gov/27454940/
dFH-LM with distinct cytological atypia and cytoplasmic globules.
hematoxylin and eosin, 400×
Batra N., Rekhi B., Menon S., Mittal N., Deodhar K.K. An octad of fumarate hydratase-deficient uterine leiomyomas: Case series with review of literature from a single institution. Indian J Pathol Microbiol. 2025 Jan 1;68(1):69-78. doi: 10.4103/ijpm.ijpm_356_24. Epub 2024 Jul 13. PMID: 39011604.
https://pubmed.ncbi.nlm.nih.gov/39011604/
https://pubmed.ncbi.nlm.nih.gov/39011604/
Mild cellular atypia in tumor cells, with abundant eosinophilic cytoplasm, and hyaline cytoplasmic globules.
hematoxylin and eosin, 400×
Yin X., Wei X., Al Shamsi R. et al. Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases. Virchows Arch 485, 223–231 (2024). https://doi.org/10.1007/s00428-024-03806-8
https://pubmed.ncbi.nlm.nih.gov/38642139/
https://pubmed.ncbi.nlm.nih.gov/38642139/
Features characteristic of dFH-LM and hyaline cytoplasmic globules.
hematoxylin and eosin, 400×
Yin X., Wei X., Al Shamsi R. et al. Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases. Virchows Arch 485, 223–231 (2024). https://doi.org/10.1007/s00428-024-03806-8
https://pubmed.ncbi.nlm.nih.gov/38642139/
https://pubmed.ncbi.nlm.nih.gov/38642139/
Many nuclei contain prominent cherry-red nucleoli with perinucleolar halos.
hematoxylin and eosin, 400×
Ubago J.M., Zhang Q., Kim J.J., Kong B., Wei J.J. Two Subtypes of Atypical Leiomyoma: Clinical, Histologic, and Molecular Analysis. Am J Surg Pathol. 2016 Jul;40(7):923-33. doi: 10.1097/PAS.0000000000000646. PMID: 27015034; PMCID: PMC5777155.
https://pubmed.ncbi.nlm.nih.gov/27015034/
https://pubmed.ncbi.nlm.nih.gov/27015034/
Many intracytoplasmic and extracellular Eosinophilic globules are present.
hematoxylin and eosin, 400×
Ubago J.M., Zhang Q., Kim J.J., Kong B., Wei J.J. Two Subtypes of Atypical Leiomyoma: Clinical, Histologic, and Molecular Analysis. Am J Surg Pathol. 2016 Jul;40(7):923-33. doi: 10.1097/PAS.0000000000000646. PMID: 27015034; PMCID: PMC5777155.
https://pubmed.ncbi.nlm.nih.gov/27015034/
https://pubmed.ncbi.nlm.nih.gov/27015034/
MIMICKERS
Extracellular hyalinized collagen
Apoptotic cells or apoptotic bodies
Red blood cells
Staining artifacts
Extracellular hyalinized collagen.
Sheets/nodules of smooth, eosinophilic “glassy” stroma; often perivascular
hematoxylin and eosin, 200×
Archive of the 1st Department of Pathology, FSBI “National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov,” Ministry of Health of the Russian Federation.
Extracellular hyalinized collagen.
hematoxylin and eosin, 200×
Archive of the 1st Department of Pathology, FSBI “National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov,” Ministry of Health of the Russian Federation.
Apoptotic cells or apoptotic bodies.
How to distinguish from true globules?
Presence of nuclear debris;
-Intracytoplasmic/extracellular debris
-Small (often <10 μm), intensely eosinophilic with karyorrhectic nuclear fragments
How to distinguish from true globules?
Presence of nuclear debris;
True globules lack chromatin fragments.
hematoxylin and eosin, 400×
Archive of the 1st Department of Pathology, FSBI “National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov,” Ministry of Health of the Russian Federation.
Apoptotic cells or apoptotic bodies.
-Irregular borders; heterogeneous density; granularity
hematoxylin and eosin, 400×
Archive of the 1st Department of Pathology, FSBI “National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov,” Ministry of Health of the Russian Federation.
Red blood cells.
How to distinguish from true globules?
Red blood cells:
- Uniform size (≈7 μm)
-Round, biconcave shape
-No nucleus
-Clear central pallor
-Red staining
Eosinophilic globules:
-Variable size, often larger than RBCs
-Homogeneous, glassy appearance
-Strong eosinophilic bright pink staining
How to distinguish from true globules?
Red blood cells:
- Uniform size (≈7 μm)
-Round, biconcave shape
-No nucleus
-Clear central pallor
-Red staining
Eosinophilic globules:
-Variable size, often larger than RBCs
-Homogeneous, glassy appearance
-Strong eosinophilic bright pink staining
hematoxylin and eosin, 400×
Archive of the 1st Department of Pathology, FSBI “National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov,” Ministry of Health of the Russian Federation.
Red blood cells.
hematoxylin and eosin, 400×
Archive of the 1st Department of Pathology, FSBI “National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov,” Ministry of Health of the Russian Federation.
Staining artifacts.
How to distinguish from true globules?
Staining Artifacts
-Irregular size and shape
-Uneven, patchy staining
-Often sharply edged or granular
-Random distribution, no tissue relation
-Can vary in color intensity
How to distinguish from true globules?
Staining Artifacts
-Irregular size and shape
-Uneven, patchy staining
-Often sharply edged or granular
-Random distribution, no tissue relation
-Can vary in color intensity
hematoxylin and eosin, 200×
Archive of the 1st Department of Pathology, FSBI “National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov,” Ministry of Health of the Russian Federation.
View whole-slide images
of dFH-LM on IHC
To familiarize yourself with scoring, please assess the cases below for the presence and extent of Eosinophilic globules.
Quiz
Which are true globules?
Which are true globules?
Incorrect. It's staining artifact
Correct. These are eosinophilic globules.
Incorrect. It's a red blood cell
Incorrect. It’s an apoptotic cell
Which are true globules?
Incorrect. It's a red blood cell
Incorrect. It’s an apoptotic cell
Correct. These are eosinophilic globules.
Incorrect. It's extracellular hyalinized collagen
Which are true globules?
Incorrect. It's extracellular hyalinized collagen
Incorrect. These are staining artifacts
Incorrect. It’s an apoptotic cell
Correct! These are eosinophilic globules.
Which are true globules?
Incorrect. These are staining artifacts
Correct! These are eosinophilic globules.
Incorrect. It's an apoptotic cell
Incorrect. It's extracellular hyalinized collagen
Not bad! Try to take the test again.
Not bad! Try to take the test again.
Great job! Now you are ready to evaluate the presence of eosinophilic globules in leiomyomas.
Great job! Now you are ready to evaluate the presence of eosinophilic globules in leiomyomas.
