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Adrenal gland & paraganglia

Adrenal cortical carcinoma

Myxoid

Author: Maria Tretiakova, M.D., Ph.D.

Editorial Board Members: Debra L. Zynger, M.D., Bonnie Choy, M.D.

Last author update: 16 February 2022

Last staff update: 2 December 2022

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PubMed Search: Myxoid[TIAB] carcinoma adrenal

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Table of Contents

Cite this page: Tretiakova M. Myxoid . PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/adrenocorticalcarcinomamyxoid.html. Accessed April 19th, 2024.

Definition / general

Rare variant of malignant epithelial tumor of adrenal cortical cells with extracellular myxoid component

Essential features

Uncommon variant of adrenal cortical carcinoma (ACC), ~50 cases reported
Characterized by the presence of variably abundant extracellular myxoid component (5 - 90%) resembling carcinomas with extracellular mucin secretions or myxoid tumors (Am J Surg Pathol 2010;34:973, Am J Clin Pathol 2011;136:783, Histopathology 2018;72:82)
Compared with conventional ACC, myxoid variant has slightly more aggressive clinical behavior and shorter overall survival on univariate and multivariate analyses (Hum Pathol 2014;45:1555, Am J Clin Pathol 2011;136:783, J Korean Med Sci 2017;32:764)
Positive for Alcian blue, inhibin, calretinin, MelanA, synaptophysin; negative for keratins and other epithelial markers

Terminology

Adrenal cortical carcinoma (ACC), myxoid variant
Adrenocortical carcinoma, myxoid type
Myxoid adrenocortical carcinoma

ICD coding

ICD-O: 8370/3 - adrenal cortical carcinoma

Epidemiology

Accounts for 10 - 12% of ACC cases in 2 large studies (Arkh Patol 2021;83:10, Am J Surg Pathol 2010;34:973)
Mean age: 48; age range: 16 - 82 (Am J Clin Pathol 2011;136:783, J Korean Med Sci 2017;32:764, Virchows Arch 2012;460:9)
Unlike conventional ACC, no gender predilection (Biomedicines 2021;9:175)

Sites

Left adrenal more commonly affected: left to right ratio = 1.5:1 (Biomedicines 2021;9:175)

Pathophysiology

Molecular evidence for an adenoma to carcinoma progression (Virchows Arch 2012;460:9, PLoS One 2013;8:e73959)

Etiology

Sporadic with no established risk factors
Acquired genetic mutations of several driver genes (i.e. IGF2, CDKN2A, TERT, RB, ZNRF3, CDK4), similar to conventional ACC (Cancer Cell 2016;29:723, Endocrinol Metab Clin North Am 2015;44:399, Biomedicines 2021;9:174, Turk Patoloji Derg 2015;31:98, Mod Pathol 2018;31:1257)
2 case reports of myxoid ACC in patients with MEN1 syndrome (Biomedicines 2021;9:175)

Diagrams / tables

Images hosted on other servers:

Survival analysis comparing myxoid ACC to other variants

Clinical features

Hormone production in 57 - 70% of tumors (Am J Surg Pathol 2010;34:973, Virchows Arch 2012;460:9, Biomedicines 2021;9:175)
- Cortisol with Cushing syndrome in ~70% of functional tumors
- Hyperaldosteronism (~10%)
- Sex hormone or multiple hormones (~20%)
In nonfunctional tumors, symptoms related to large size of abdominal mass include
- Pain, discomfort, vomiting
- Loss of weight, weakness
Majority of myxoid ACC present with advanced tumor stage III / IV (J Korean Med Sci 2017;32:764)
Metastases eventually developed in 68 - 88% of patients, most commonly to liver and lungs / pleura (J Korean Med Sci 2017;32:764, Biomedicines 2021;9:175)
Tumor recurrence was documented in 43% of cases with median time of recurrence after surgery being 4.8 months (Biomedicines 2021;9:175)
- High incidence of postoperative recurrence, even in nonmetastatic disease, was postulated to be caused by micrometastases at the time of surgery (World J Surg 2010;34:1380)

Diagnosis

Only definitive criteria for malignancy are distant metastasis or local invasion
Myxoid ACC on imaging characterized by large size, irregular contours and significant signal heterogeneity (Endocr J 2019;66:739)
Loss / disruption of reticulin framework (J Korean Med Sci 2017;32:764)
Mean Weiss score in myxoid ACC is 5 - 7 (J Korean Med Sci 2017;32:764, Am J Surg Pathol 2010;34:973)

Laboratory

Same as conventional adrenal cortical carcinoma

Radiology description

Same as conventional adrenal cortical carcinoma

Radiology images

Images hosted on other servers:

Myxoid ACC on CT, MRI and PET / CT imaging

Prognostic factors

Myxoid ACC has slightly worse prognosis than conventional ACC (Horm Cancer 2011;2:333)
Overall median survival for myxoid ACC is 29 months (Biomedicines 2021;9:175)
Behavior of myxoid ACC is difficult to predict: even tumors with low Weiss score could have fatal outcome (Histopathology 2018;72:82)
p53 / Rb1 pathway activation was associated with high tumor stage, high Ki67 index, aggressive disease status and shorter disease free survival
Overexpression of miR-483-3p, miR483-5p and miR-210 indicate poor prognosis (similar to conventional ACC) and are associated with male sex, presence of necrosis, high Ki67 proliferation index, mitotic count and increased SF1 expression on IHC (Hum Pathol 2014;45:1555)

Case reports

38 year old man with myxoid ACC and extensive lipomatous metaplasia (Arch Pathol Lab Med 2003;127:227)
38 year old woman who underwent robot assisted laparoscopic adrenalectomy for myxoid ACC (Case Rep Urol 2019;2019:9794345)
68 year old woman with myxoid ACC and MEN1 syndrome (Endocr J 2019;66:739)
82 year old woman with myxoid ACC presenting as primary hyperaldosteronism (Int J Surg Pathol 2011;19:803)

Treatment

Surgical: radical resection, treatment mainstay (Surgery 2019;166:524)
Guidelines for adjuvant treatment with mitotane, cytotoxic chemotherapy and radiation therapy are similar to conventional ACC

Clinical images

Images hosted on other servers:

Robot assisted laparoscopic adrenalectomy

Gross description

Median tumor size is 12 - 19.8 cm (range: 7 - 24 cm) (Am J Clin Pathol 2011;136:783, Biomedicines 2021;9:175)
Median weight is 552 - 707 g (range: 38 - 3200 g) (Am J Clin Pathol 2011;136:783, J Korean Med Sci 2017;32:764, Biomedicines 2021;9:175)
Partially encapsulated yellow-brown with gelatinous myxoid areas, hemorrhage and necrosis (Am J Clin Pathol 2011;136:783, Biomedicines 2021;9:175)

Gross images

Images hosted on other servers:

Gelatinous and solid whitish appearance

Obvious areas of hemorrhage and necrosis

Microscopic (histologic) description

Variable amounts (5 - 90%) of light basophilic, amorphous, mucinous material (Am J Surg Pathol 2010;34:973)
2 distinct morphologic groups (Am J Surg Pathol 2010;34:973, Ann Diagn Pathol 2008;12:344, Am J Clin Pathol 2011;136:783):
- Group 1: predominant myxoid stromal component with pools of copious mucin; tumor cells are small, uniform, mildly atypical and arranged in delicate arborizing cords, pseudoglands or microcysts (may resemble adenoid cystic carcinoma)
- Group 2: focal myxoid changes (< 20%) in tumors otherwise similar to conventional ACC with large atypical eosinophilic cells with diffuse, trabecular or alveolar architecture
Group 1 may represent true myxoid ACC as a distinctive variant, whereas group 2 may be result of myxoid degenerative changes of conventional ACC (Virchows Arch 2012;460:9, Am J Surg Pathol 2010;34:973)
Histochemical mucin staining pattern favors acid mucopolysaccharides of connective tissue type, not intracellular (Int J Surg Pathol 2011;19:803)
Capsular invasion, sinusoidal invasion and necrosis are present in 80 - 90% of cases (Am J Clin Pathol 2011;136:783, J Korean Med Sci 2017;32:764)

Microscopic (histologic) images

Contributed by Maria Tretiakova, M.D., Ph.D.

ACC with predominant myxoid component

Delicate arborizing cords

Mucin pools with floating cells

Pseudoglandular architecture

Complex architecture

Adjacent benign adrenal

Focal myxoid pattern

Transition to myxoid area

Microcystic architecture

Positive margin

pT3 myxoid ACC

Mitoses

Normal reticulin network

Loss of reticulin framework

Positive stains

Alcian blue uniformly positive highlighting extracellular acidic mucosubstance
Inhibin, MelanA, calretinin, vimentin, synaptophysin, CD56: uniform expression
EGFR (membranous), SF1, neurofilament: variable expression
Disrupted reticulin network
Ki67 proliferation rates are very high (18 - 32%) (Ann Diagn Pathol 2008;12:344, Am J Clin Pathol 2011;136:783)

Negative stains

Negative or focal weak staining with PAS and mucicarmine
Cytokeratins and EMA typically negative
HMB45, S100, SMA, chromogranin
References: Am J Surg Pathol 2013;37:1433, Ann Diagn Pathol 2008;12:344, Int J Surg Pathol 2011;19:803, Hum Pathol 2014;45:1555, Am J Surg Pathol 2010;34:973, Am J Clin Pathol 2011;136:783, Virchows Arch 2012;460:9

Electron microscopy description

Same as conventional adrenal cortical carcinoma

Molecular / cytogenetics description

Molecular alterations are similar to conventional ACC, including high mutation burden and massive DNA loss followed by whole genome doubling (Histopathology 2018;72:82)
Most frequently affected by somatic mutations, copy number alterations and epigenetic silencing were p53 (21%), ZNRF3 (19%), CDKN2A (15%), CTNNB1 (16%), TERT (14%) and PRKAR1A (11%) (Cancer Cell 2016;30:363)
Another study of 7 myxoid ACC showed very frequent gain of TERT (43%) and CDK4 (86%) and loss of RB1 (28%), CDKN2A (28%), ZNRF3 (14%) (Mod Pathol 2018;31:1257)
High expression of miR-483-3p, miR483-5p and miR-210 was similar to conventional ACC (Hum Pathol 2014;45:1555)
EGFR protein overexpression without mutations or amplification; increased EGFR copy number in one case (Am J Clin Pathol 2011;136:783)

Sample pathology report

Adrenal gland, left, adrenalectomy:
- Adrenal cortical carcinoma with the following features:
  - Tumor size: 12 cm x 10 cm x 9 cm
  - Tumor (gland) weight: 300 g
  - Tumor extent: capsular invasion
  - Histologic type: myxoid variant (30% tumor)
  - Histologic grade: high grade
  - Necrosis: present
  - Lymphovascular invasion: present
  - Margins: positive
  - pTNM, AJCC 8th Edition: pT3 NX MX
- Ancillary studies: Ki67 mitotic rate 25%
- Reticulin stain: disruption of reticulin framework

Differential diagnosis

Adrenal cortical carcinoma, conventional:
- No myxoid component
Metastatic mucin producing carcinomas:
- More likely to be bilateral; check clinical history
- Carcinoma with myxoid areas, especially adenoid cystic (cytokeratin+, p63+)
Other myxoid neoplasms in retroperitoneum:
- Chordoma:
  - S100+
  - ACC markers-
- Benign or malignant nerve sheath tumor:
  - S100+
- Myxoid leiomyoma and leiomyosarcoma
  - SMA+
- Myxoid malignant fibrous histiocytoma
- Extraskeletal myxoid chondrosarcoma

Board review style question #1

Which of the following features is characteristic for myxoid variant of adrenocortical carcinoma (ACC), shown in the picture?

Has unique immunohistochemical, molecular and genomic profiles
More common than other variants of ACC
More indolent than conventional ACC
Must have ≥ 50% extracellular mucinous component
Should be distinguished from metastatic mucin producing carcinoma

Board review style answer #1

E. Should be distinguished from metastatic mucin producing carcinoma. Myxoid variant of adrenocortical carcinoma (ACC) is characterized by the presence of extracellular myxoid component. In some cases, tumors exhibit striking resemblance with myxoid tumors, adenoid cystic and other mucin producing carcinomas, which have to be ruled out in the right clinical context. Answer A is incorrect because there is a substantial overlap in immunohistochemical, molecular and genomic profiles of myxoid and conventional ACC variants. Answer B is incorrect because myxoid ACC is less common than conventional or oncocytic variants of ACC with only ~50 cases reported to date. Answer C is incorrect because compared with conventional ACC, myxoid variant has more aggressive clinical behavior with higher rate of tumor recurrence, metastases and shorter overall survival. Answer D is incorrect because myxoid extracellular matrix is variably abundant from 5 - 90% of tumor volume.

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Reference: Adrenal cortical carcinoma - Myxoid variant

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