Uterus
Undifferentiated / dedifferentiated carcinoma
Minor changes: 14 December 2020
Copyright: 2020, PathologyOutlines.com, Inc.
PubMed Search: (Undifferentiated[TI] OR dedifferentiated[TI]) carcinoma uterus
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Immunofluorescence description | Immunofluorescence images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Molecular / cytogenetics images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Al-Loh Ashi S, Al-Hussaini M. Undifferentiated / dedifferentiated carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusundifferentiateddedifferentiatedcarcinoma.html. Accessed March 4th, 2021.
Definition / general
- Endometrial carcinoma lacking any evidence of differentiation (Tavassoéli: Pathology and Genetics of Tumours of the Breast and Female Genital Organs, 1st Edition, 2003)
Essential features
- Can be pure undifferentiated endometrial carcinoma (UEC) or associated with a better differentiated endometrial carcinoma component: dedifferentiated endometrial carcinoma
- Frequently involves the lower uterine segment or the cervix and usually presents with advanced stage
- Predominant dyscohesive monotonous medium to large sized cells, with complete absence of glandular differentiation
- Characterized by frequent microsatellite instability sporadically but also can be associated with hereditary nonpolyposis colorectal carcinoma / Lynch syndrome
Terminology
- Dedifferentiated endometrial carcinoma
- Dedifferentiating endometrial carcinoma
- Combined endometrial carcinoma, mixed endometrial carcinoma
ICD coding
Epidemiology
- Uncommon; 1.1 - 1.6% of all endometrial carcinoma
- Reported incidence of 9% of endometrial carcinoma (Pathology 2007;39:134)
Sites
- Uterine cavity, with frequent involvement of the lower uterine segment
- Similar tumors can originate from the ovary
Pathophysiology
- Can be associated with hereditary nonpolyposis colorectal carcinoma / Lynch syndrome (Cancer 2006;106:87)
- Microsatellite instability: loss of 1 or more of the DNA mismatch repair (MMR) genes reported in 47% of the tested cases, most frequently MLH1 and PMS2
- Loss was demonstrated in both differentiated and undifferentiated components in tested combined cases, supporting the common origin of both components' dedifferentiation
- MLH1 promoter hypermethylation has been described in sporadic cases
- Association between MMR deficient endometrial carcinoma and the increased expression of PDL1 when compared with MMR retained cases suggests that MMR deficiency may be a better predictor of response to PD1 / PDL1 inhibitor therapy than tumor grade in endometrial carcinoma (Am J Surg Pathol 2017;41:326)
- MMR deficiency should promote testing for PDL1
- Loss of either INI1 / BAF47 / SMARCB2, BRG1 / SMARCA4 or SMARCA2 immunostains in a few tumors support their undifferentiated nature and suggest a possible relation with rhabdoid tumors
Etiology
- No information provided
Diagrams / tables
- None provided
Clinical features
- Median age (50 and 59); 40% are younger than 50 years (Arch Pathol Lab Med 2013;137:438)
- 7% of endometrial carcinomas in patients younger than 40 years (Arch Pathol Lab Med 2013;137:438)
- Risk factors similar to endometrioid carcinoma (hypertension, diabetes and obesity) (Am J Surg Pathol 2005;29:1316)
- Presentation: postmenopausal bleeding (most common), abdominal pain, a mass protruding from the vagina, vaginal discharge (Int J Gynecol Pathol 2018;37:564)
- Incidental finding of thickened endometrium during pelvic ultrasound check up led to the diagnosis (Int J Gynecol Pathol 2018;37:564)
- Most patients (64.7%) present with an advanced stage; FIGO stage III and IV disease (Int J Gynecol Pathol 2018;37:564)
- Pelvic and paraaortic lymph nodes are the most common sites of metastasis (Int J Gynecol Pathol 2018;37:564)
Diagnosis
- Diagnosis can only be made on tissue biopsy, dilation and curettage material but more often on hysterectomy specimen
Laboratory
- No information provided
Radiology description
- No information provided
Radiology images
- None provided
Prognostic factors
- Stage: 54% of undifferentiated endometrial carcinomas present as high stage disease (stage III or IV), as compared to 30% of endometrioid adenocarcinomas FIGO grade 3 (Am J Surg Pathol 2005;29:1316)
- In cases of combined histologic appearance, the presence of undifferentiated component appears to carry a poor clinical outcome, while the presence of a better differentiated component, irrespective of its extent, does not appear to confer improved clinical outcome (Int J Gynecol Pathol 2006;25:52, Mod Pathol 2010;23:781)
- No association was found between age, stage, presence and number of tumor infiltrating lymphocytes, rhabdoid cell morphology and clinical outcome (Int J Gynecol Pathol 2006;25:52, Mod Pathol 2010;23:781)
- Median overall survival was 11 months (range: 1 - 30) (Int J Gynecol Pathol 2018;37:564)
- Disease related death rate (41 - 75%), mostly in the first 5 years after diagnosis (Arch Pathol Lab Med 2013;137:438)
Case reports
- 33 year old woman with dedifferentiated endometrioid adenocarcinoma with trophoblastic components and elevated serum alpha fetoprotein (Medicine (Baltimore) 2018;97:e0551)
- 41 year old woman with stage IVB dedifferentiated adenocarcinoma that clinically showed resistance to several regimens of chemotherapy (Eur J Gynaecol Oncol 2016;37:426)
- 47 year old woman with menorrhagia and 71 year old woman with postmenopausal bleeding, both diagnosed with endometrial adenocarcinoma, FIGO grade 1 and 2 respectively, on biopsy and dedifferentiated carcinoma on hysterectomy (Pol J Pathol 2018;69:195)
- 58 year old woman with dedifferentiated endometrial carcinoma with clear cell carcinoma (Pathol Int 2017;67:472)
- 61 year old woman with endometrial dedifferentiated adenocarcinoma associated with MLH1 promotor hypermethylation and microsatellite instability (Pathol Res Pract 2018;214:1904)
- 80 year old woman developed spontaneous regression of recurrent undifferentiated carcinoma of the endometrium (Intern Med 2019;58:1649)
- 4 cases of dedifferentiated endometrial carcinoma of undifferentiated carcinoma and low grade endometrioid carcinoma (World J Surg Oncol 2017;15:17)
Treatment
- Total hysterectomy with bilateral salpingo-oophorectomy, pelvic and paraaortic lymph nodes dissection, adjuvant chemotherapy or radiotherapy
Clinical images
- None provided
Gross description
- Friable fungating / polypoid masses with evident necrosis (Mod Pathol 2010;23:781, Arch Pathol Lab Med 2013;137:438, Int J Gynecol Pathol 2018;37:564)
- Tumor tends to involve the lower uterine segment and the cervix (Mod Pathol 2010;23:781, Arch Pathol Lab Med 2013;137:438, Int J Gynecol Pathol 2018;37:564)
Gross images
- None provided
Frozen section description
- No information provided
Frozen section images
- None provided
Microscopic (histologic) description
- Predominant dyscohesive monotonous medium to large sized cells, with complete absence of glandular differentiation
- Vesicular nuclei with prominent eosinophilic nucleoli, occasional hyperchromasia, marked nuclear pleomorphism and multinucleation
- Variation of cellular size; small cells with scanty basophilic cytoplasm, large cells with clear or vacuolated cytoplasm
- Patternless growth pattern; solid sheet-like growth with total absence of nests, papillae, glands or trabeculae
- Solid and alveolar (delicate fibrovascular septae segregating tumor cells into an alveolar pattern)
- Solid with focal nesting pattern
- Focal vague cords and trabeculae
- Large areas of geographic necrosis with viable perivascular tumor cells
- Focal rhabdoid cells morphology
- Myxoid background
- Abundant mitotic and apoptotic figures
- Prominent tumor infiltrating lymphocytes
- Should not show squamous differentiation, mucinous differentiation or spindled growth pattern
- Foci of vague spindling and abrupt keratinization is allowed
- Usually deeply invasive, infiltrating more than half of the myometrial thickness
- Lymphovascular invasion is common
- Could be:
- Pure undifferentiated endometrial carcinoma
- Mixed form, combined carcinoma or dedifferentiated carcinoma is undifferentiated endometrial carcinoma combined with
- Endometrioid carcinoma (DEC) of various FIGO grades (1, 2 and 3)
- Carcinosarcoma in which the epithelial component showed at least focal undifferentiated endometrial carcinoma were identified and a mixed cell type with serous carcinoma
- Less frequently serous carcinoma or a minor squamous component
- Interface between the differentiated and the undifferentiated components is abrupt (sharply demarcated), with a more superficial location for the differentiated component and a deep location for the undifferentiated carcinoma
- Undifferentiated endometrial carcinoma may be detected asynchronously in the recurrence or metastasis of an otherwise previously confirmed and treated endometrial endometrioid adenocarcinoma (Int J Gynecol Pathol 2006;25:52)
Microscopic (histologic) images
Contributed by Maysa Al-Hussaini, M.D.
Dyscohesive cells
CAM 5.2
Pancytokeratin MNF 116
Vimentin
MLH1
PMS2
Dyshesive cells resembling lymphoma
PAX8
SMARCB1 / BAF47 / INI1
Patternless sheets
p53
Glandular and alveolar growth patterns
p16
Biphasic tumor
SMARCA4 / BRG1
Synaptophysin
E-cadherin in undifferentiated carcinoma
TTF1 in undifferentiated carcinoma
Virtual slides
Images hosted on other servers:
H&E
CD10
CKCKTL
H&E
p16
p53
Cytology description
- No information provided
Cytology images
- None provided
Immunofluorescence description
- No information provided
Immunofluorescence images
- None provided
Positive stains
- Focal strong pancytokeratin (CAM 5.2, less frequently AE1 / AE3, MNF 116) and EMA (Mod Pathol 2010;23:781, Int J Gynecol Pathol 2018;37:564)
- The better differentiated component is diffusely and strongly positive
- Cytokeratin 18 is the most helpful stain for epithelial differentiation
- p53, p16 (50%) and cyclin D1 (Int J Gynecol Pathol 2012;31:57, Am J Surg Pathol 2015;39:722)
- Neuroendocrine markers (chromogranin, synaptophysin or CD56) (< 10% positivity in 41%) (Int J Gynecol Pathol 2009;28:142)
- Vimentin, fascin, S100 protein, CD10, estrogen receptor / ER, progesterone receptor / PR (Mod Pathol 2013;26:1514, Int J Gynecol Pathol 2018;37:564)
Negative stains
- PAX8 (20% of cases can show patchy or diffuse staining) (Int J Gynecol Pathol 2016;35:410)
- Loss of one or more of the mismatch repair proteins: MLH1, PMS2, less commonly MSH2 and MSH6
- Actin - alpha smooth muscle, desmin and HMB45
- E-cadherin lost (~50%)
Electron microscopy description
- No information provided
Electron microscopy images
- None provided
Molecular / cytogenetics description
- Mismatch repair proteins are described to be lost in undifferentiated endometrial carcinoma, mostly secondary to hypermethylation of MLH1 and occasionally due to germ line mutations
Molecular / cytogenetics images
- None provided
Videos
- None provided
Sample pathology report
- Endometrial, total abdominal hysterectomy and bilateral salpingo-oophorectomy:
- Undifferentiated endometrial carcinoma (see comment)
- Comment: There is a hypercellular tumor composed of proliferation of largely dyscohesive cells with focal rhabdoid morphology and alveolar pattern. No evidence of a better differentiated component despite extensive sampling. The tumor is invading throughout the full thickness of the myometrium and is involving the lower uterine segment and the cervical stroma (pT2 / FIGO II).
- Immunohistochemically the tumor cells show strong focal expression of CAM 5.2 cytokeratin and EMA, with focal positivity for synaptophysin (< 10.0% of cells). E-cadherin immunostain is lost and PAX8 immunostain is negative. SMARCA4 / BRG1 shows loss of the nuclear stain (internal tissue control is positive), while SMARCB1 / INI01 / BAF47 nuclear stain is retained. MLH1 and PMS2 mismatch repair proteins show negative nuclear stain, while MSH2 / MSH6 nuclear stain is retained. This constellation of morphological and immunohistochemical features strongly supports the diagnosis of undifferentiated endometrial carcinoma.
Differential diagnosis
- Endometrioid adenocarcinoma FIGO grade 3:
- Most frequent misdiagnosis
- WHO defines grade 3 endometrial carcinoma as composed of 1 - 49% glandular areas
- This feature loses its power in cases of mixed forms of undifferentiated endometrial carcinoma or dedifferentiated carcinoma, because of the presence of a lower grade endometrioid carcinoma in dedifferentiated carcinoma
- Helpful features include cohesive sheets of neoplastic cells in solid areas with comparable cytologic features in the glandular and solid components
- Diffuse immunoreactivity for keratins and EMA in grade 3 endometrioid carcinoma
- Serous carcinoma:
- Especially in serous carcinoma with solid growth pattern
- Distinctive high grade cytologic findings in serous carcinoma
- Papillary or slit-like spaces in serous carcinoma
- Papillary formations are seen frequently in the advancing edge of the tumor
- Frequent lymphovascular invasion
- Psammoma bodies are indentified in 33% of cases of serous carcinoma
- Cytokeratin is diffusely positive
- Malignant mixed Müllerian tumor (carcinosarcoma):
- This is a tumor mostly of elderly females
- Biphasic growth pattern
- High grade carcinomatous component, most frequently serous carcinoma, and a pleomorphic, typically spindle cell sarcomatous component
- Cytokeratin is diffusely positive in the carcinoma component and might be focal in the sarcomatous component
- Endometrial stromal sarcoma, undifferentiated:
- Undifferentiated endometrial sarcoma (UES) should be considered
- A high grade tumor with marked pleomorphism, brisk mitosis and necrosis
- Might show focal staining with CD10
- Other markers, including epithelial markers, are negative
- Extensive sampling to rule out focal areas of differentiation
- Epithelioid leiomyosarcoma:
- Positive staining for muscle markers including desmin, actin - alpha smooth muscle and h-caldesmon
- Pancytokeratin can be positive in epithelioid leiomyosarcomas
- Neuroendocrine carcinoma:
- Can be confused with undifferentiated endometrial carcinoma, especially the large cell variant
- Expression of one or more neuroendocrine markers, including synaptophysin, chromogranin A or CD56 in > 20% of tumor cells
- Hematolymphoid malignancies including lymphoma, plasmacytoma and myeloid sarcoma:
Additional references
- Int J Gynecol Pathol 2009;28:142, J Clin Pathol 2009;62:679, Am J Surg Pathol 2009;33:1869, Am J Surg Pathol 2009;33:925, Mod Pathol 2010;23:781, Int J Surg Pathol 2010;18:21, Int J Gynecol Pathol 2011;30:569, Int J Gynecol Pathol 2012;31:57, Arch Pathol Lab Med 2013;137:438, J Obstet Gynaecol 2015;35:372, Ann Diagn Pathol 2015;19:198, Pathology 2015;47:439, Am J Surg Pathol 2015;39:722, Mod Pathol 2016;29:302, Gynecol Oncol 2018;149:570, Gynecol Oncol 2018;151:401
Board review style question #1
A 46 year old woman presents with abnormal vaginal bleeding. Dilation and curettage was followed by total hysterectomy and bilateral salpingo-oophrectomy. Microscopic examination shows diffuse growth pattern sheets of medium sized cells with round nuclei, prominent nucleoli, focal alveolar pattern of growth and myxoid background. Immunostains show focal strong positive staining for CAM 5.2 and EMA but negative staining for other pancytokeratins like MNF 116 and AE1 / AE3. Synaptophysin was positive in scattered tumor cells not exceeding 10% and SMARCA4 / BRG1 immunostain shows loss of the nuclear stain. Which of the following immunostains would be expected to be expressed by the tumor?
- E-cadherin
- Estrogen receptor / ER
- MLH1
- PAX8
- PMS2
Board review style answer #1
B. Estrogen receptor / ER. These tumors frequently lack expression of PAX8, MLH1, PMS2 and E-cadherin immunostains, while estrogen receptor is typically expressed (positive).
Comment Here
Reference: Undifferentiated / dedifferentiated carcinoma
Comment Here
Reference: Undifferentiated / dedifferentiated carcinoma
Board review style question #2
The best positive immunostain that can help rule out serous carcinoma from undifferentiated endometrial carcinoma in this image is
- Estrogen receptor
- p16
- p53
- PAX8
- Vimentin
Board review style answer #2
