Pathways Case Studies: September 2022

A 35-year-old woman with a right kidney mass underwent CT-guided needle core biopsy. Histologic sections show a neoplasm comprised of pleomorphic epithelioid cells with eosinophilic cytoplasm, with occasional bizarre nuclei and variably prominent nucleoli. Mitotic figures are easily appreciated. The neoplastic cells lack expression of PAX8, CK7, CK20, P63, and GATA3. Follow-up immunohistochemical stains show the neoplastic cells are positive for cathepsin-K and Melan-A, and a diagnosis of epithelioid angiomyolipoma (EAML) was made. 

Figure 1
Figure 2
Figure 3

Which of the following can have prognostic value in this case? 

  • Mitotic figures
  • ER/PR status
  • RB/ATRX/TP53
  • KI-67

The correct answer is ...


The morphology and immunophenotypic profile of this neoplasm are consistent with an epithelioid angiomyolipoma (EAML). These account for approximately 5% of angiomyolipoma. The current WHO diagnostic criteria requires at least 80% of the neoplastic cells to have an epithelioid morphology to classify as EAML. These tumors express cathepsin-K and melanocytic markers (HMB45 and Melan-A). Variable expression of smooth muscle markers is also reported. 

The majority of EAML are associated with genetic alterations in mTOR pathway (TSC2 gene more than TSC1 gene) that can arise secondary to somatic or germline alterations. Rare instances can show TFE3 gene rearrangements. Recent studies show metastatic EAML are enriched with alterations of TP53, RB, and ATRX genes.1 Immunohistochemistry can serve as surrogate markers for these genetic alterations and can be of use as prognostic indicators. Mutant patterns include loss of expression of RB, loss of expression of ATRX, and loss or diffuse expression of p53. This case showed loss of RB expression, retained ATRX, and equivocal p53 expression. These results strongly suggest loss of RB gene and raise concern for an EAML with an aggressive clinical behavior. Close follow-up was recommended. 


  1. Mayo Clin Proc. 2021 Jun;96(6):1470-1489. PMID: 33526281.

Sarwat Gilani, M.B.B.S.

Fellow, Genitourinary Pathology
Mayo Clinic

Sounak Gupta, M.B.B.S., Ph.D.

Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Assistant Professor of Pathology
Mayo Clinic College of Medicine and Science

A 71-year-old woman with no significant past medical history presented with postmenopausal bleeding of 4 months of duration. Ultrasound revealed a markedly thickened and enlarged endometrium with free pelvic fluid concerning for endometrial malignancy. Hysteroscopy revealed a vascularized protruding mass through the cervical os. Representative H&E sections of the endometrial biopsies are depicted below, along with selected immunohistochemical stains.

Figure 1: HE Low Power
Figure 2: HE High Power
Figure 3: KRT7
Figure 4: Desmin
Figure 5: Myogenin
Figure 6: MyoD1

What is the most likely diagnosis?

  • Dedifferentiated endometrioid carcinoma
  • Corded and hyalinized endometrial adenocarcinoma
  • Mullerian adenosarcoma
  • Endometrial carcinosarcoma

The correct answer is ...

Endometrial carcinosarcoma.

This tumor is a carcinosarcoma with heterologous rhabdomyoblastic differentiation. Cytokeratin 7 immunohistochemical stain highlights the high-grade carcinoma component. Myogenin and MyoD1 confirm the rhabdomyoblastic heterologous component. 

This is an uncommon, highly aggressive tumor that accounts for less than 5% of uterine malignancies. These tumors usually present in postmenopausal women. It is associated with unopposed estrogens, pelvic irradiation, and prior tamoxifen use. The most common presenting symptom is vaginal bleeding. Some patients present with symptoms related to a pelvic mass or metastatic disease. On gross examination, these tumors are typically large polypoid masses involving the posterior wall, frequently protruding unto the endometrial cavity and may prolapse through the cervical os. Histologically, they are characterized by high-grade malignant epithelial and mesenchymal components of variable proportions and are sharply demarcated. The carcinoma component is high-grade, often serous or endometrioid differentiation, but other components including clear cell and undifferentiated can be seen. The mesenchymal component can be heterologous or homologous. If homologous, this component is frequently high-grade and undifferentiated. The most common heterologous elements are chondrosarcoma followed by rhabdomyosarcoma.

In the appropriate clinical setting, extensive sampling of an undifferentiated sarcoma or pleomorphic rhabdomyosarcoma may reveal areas of epithelial differentiation, rendering the diagnosis of carcinosarcoma. Immunohistochemical stains can aid the diagnosis; however, the epithelial and mesenchymal component should be apparent upon morphological examination. The carcinomatous component is positive for cytokeratins and EMA. The sarcomatous component is positive for vimentin and may show staining for desmin, actin, CD10, and CD34. P16 and p53 are overexpressed in both components. Myogenin and MyoD1 nuclear staining confirms the presence of a rhabdomyoblastic differentiation. Pathologic factors that are associated with poor prognosis include high-grade carcinoma component, heterologous element in the sarcoma component, sarcoma component >50%, increased size (>5 cm), deep myometrial invasion, lymphovascular invasion, malignant peritoneal cytology, lymph node metastasis, as well as local and distant metastatic disease.1-4

  • Dedifferentiated carcinoma: These are uncommon tumors and are characterized by an undifferentiated epithelial component, which is formed by sheets of medium-to-large discohesive round cells that can occur in isolation or in combination with areas of well-differentiated endometrioid adenocarcinoma. There is frequently a sharp demarcation between both components and hence can be mistaken for a carcinosarcoma, as the undifferentiated carcinoma can be misinterpreted as an undifferentiated sarcoma. However, in dedifferentiated endometrioid carcinoma the epithelial component is low-grade while in carcinosarcoma the epithelioid component, when endometrioid is typically high-grade. Immunohistochemical stains can be helpful as the undifferentiated epithelial component formed by non-cohesive cells are focally positive for cytokeratins and EMA. These tumors are also associated with mismatch repair abnormalities, while carcinosarcomas are not.1
  • Corded and hyalinized endometrioid adenocarcinoma: These are low- to intermediate- grade adenocarcinomas with areas of hyalinized stroma containing corder epithelioid and spindled cells. Metastatic osteoid can be present. These features can be mistaken for a malignant stromal component with heterologous differentiation. In contrast to carcinosarcoma, this variant often occurs at a younger age group, is associated with a low- to intermediate-grade, glandular component, and lacks the high-grade pleomorphic malignant stromal component seen in carcinosarcoma.1
  • Mullerian adenosarcoma: This is a mixed epithelial and stromal tumor. The epithelial component, usually endometrioid has a benign appearance, may have a phyllodes like growth pattern. The stromal component shows a “tufting” pattern of hypercellularity beneath the glandular epithelium. The stromal atypia varies from mild to severe. These tumors are usually low-grade but high-grade variants exist.1


  1. McCluggage, W.G., A practical approach to the diagnosis of mixed epithelial and mesenchymal tumours of the uterus. Mod Pathol. 2016;29 Suppl 1:S78-91.
  2. McCluggage, W.G., N. Singh, C.B. Gilks. Key changes to the World Health Organization (WHO) classification of female genital tumours introduced in the 5th edition (2020). Histopathology. 2022;80(5):762-778.
  3. Chen, X., et al., Uterine Carcinosarcomas: Clinical, Histopathologic and Immunohistochemical Characteristics. Int J Gynecol Pathol. 2017;36(5):412-419.
  4. Matsuzaki, S., et al., Uterine carcinosarcoma: Contemporary clinical summary, molecular updates, and future research opportunity. Gynecol Oncol. 2021;160(2):586-601.

Luisa Maria Ricaurte Archila, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

Gary Keeney, M.D.

Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 37-year-old man with a history of multiple endocrine neoplasia 1, Hurthle cell neoplasm, pancreatic neoplasm, and pituitary adenoma, presented after an episode of syncope. Imaging revealed a pituitary mass replacing the clivus, opacifying the right sphenoid sinus and extending into the left sinus and posterior right nasal cavity. His cortisol and adrenocorticotrophic hormone levels were elevated. The histopathologic findings of the pituitary mass are shown below. T-Pit immunostain was also positive, while SF-1 and PIT-1 were negative (not shown). 

Figure 1: A1 ACTH 20x
Figure 2: PIT CAM 5.2.2
Figure 3: Pit 20x

What is best diagnosis for the patient’s pituitary mass?

  • Crooke cell adenoma
  • Sparsely granulated corticotroph adenoma
  • Densely granulated corticotroph adenoma
  • Acidophilic stem cell adenoma

The correct answer is ...

Crooke’s cell adenoma.

The expression of T-PIT transcription factor and adrenocorticotrophic hormone (ACTH) (image above) support the diagnosis of a corticotroph pituitary adenoma. There are three subtypes of corticotroph adenomas: densely granulated, sparsely granulated, and Crooke cell adenoma. The histology shows glassy eosinophilic cytoplasm with granules noted at the periphery, which is characteristic of a Crooke cell adenoma. The CAM 5.2 stain (image above) shows strong perinuclear and ring-like expression of low molecular weight cytokeratin corresponding to the accumulation of hyaline material and is required for diagnosis of the Crooke cell adenoma. Of note, the nomenclature within the 2022 WHO Classification of Tumors, 5th edition, Endocrine and Neuroendocrine Tumors will change from pituitary adenoma to PitNET (pituitary neuroendocrine tumor).

Crooke cell adenomas are a rare subtype of pituitary adenoma, representing <1% of pituitary adenomas, and typically are silent macroadenomas at the time of diagnosis. They can however produce Cushing disease symptoms, and this is a well-known presentation of patients. Crooke cell adenomas show more aggressive behavior with an estimated 60%-66% risk of recurrence. The subtype also typically invades into the cavernous sinus and is resistant to radiotherapy.

Pituitary adenomas can be a manifestation of multiple endocrine neoplasia (MEN) syndrome, which is a hereditary syndrome of the endocrine glands. MEN1 tumors include pituitary gland tumors, parathyroid tumors, and pancreatic neuroendocrine tumors. The most frequent types of pituitary adenoma in MEN1 syndrome are lactotroph, somatotroph, and non-secreting tumors.


  1. Asa SL, Mete O, Perry A, Osamura RY. Overview of the 2022 WHO Classification of Pituitary Tumors. Endocr Pathol. 2022;33(1):6-26. doi:10.1007/s12022-022-09703-7
  2. Azugur M, Grossman A, Yamada S, Casar-Borota O. Corticotroph PitNET/adenoma. In: WHO Classification of Tumours Editorial Board. Endocrine and Neuroendocrine tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol. 8). Available from:
  3. Contributor NT. Endocrine system 2: Hypothalamus and pituitary gland. Nursing Times. Published May 17, 2022. Accessed May 30, 2022. 
  4. Cortez GM, Monteiro A, Agnoletto G, Bit-Ivan EN, Sauvageau E, Hanel RA. Aggressive pituitary tumor with Crooke's cells and invasion of the posterior fossa. World Neurosurgery. 2020;138. doi:10.1016/j.wneu.2020.02.137 
  5. Di Ieva, Antonio, MD, PhD, Davidson, Jennilee, et al. Crooke's cell tumors of the pituitary. Neurosurgery. 2015;76(5):616-622. doi:10.1227/NEU.0000000000000657.
  6. George, David, Scheithauer, Bernd, Kovacs, Kalman, et al. Crooke's cell adenoma of the pituitary: an aggressive variant of corticotroph adenoma. Am J Surg Pathol. 2003;27(10):1330-1336. Cited in: Journals@Ovid Full Text at Accessed May 31, 2022.
  7. Komori, T. The 2021 WHO classification of tumors, 5th edition, central nervous system tumors: the 10 basic principles. Brain Tumor Pathol. 39, 47–50 (2022).
  8. Lopes MB. The 2017 world Health Organization classification of tumors of the pituitary gland: A summary. Acta Neuropathologica. 2017;134(4):521-535. doi:10.1007/s00401-017-1769-8 
  9. Louis DN, Perry A, Wesseling P, et al. (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23:1231–1251
  10. Punsoni M. Pituitary adenoma. Pathology Outlines - Pituitary adenoma. Accessed May 30, 2022. 
  11. Rak B, Maksymowicz M, Pękul M, Zieliński G. Clinical, biological, radiological pathological and immediate post-operative remission of sparsely and densely granulated corticotroph pituitary tumors: A retrospective study of a cohort of 277 patients with Cushing's disease. Front Endocrinol (Lausanne). 2021;12:672178. Published 2021 May 31. doi:10.3389/fendo.2021.672178

Nadarra Stokes, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

Rachael Vaubel, M.D., Ph.D.

Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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This post was developed by our Education and Technical Publications Team.