Adrenal gland & paraganglia

Adrenal cortical carcinoma

Adrenal cortical carcinoma



Last author update: 13 December 2021
Last staff update: 13 December 2021

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Maria Tretiakova, M.D., Ph.D.
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Cite this page: Tretiakova M. Adrenal cortical carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/adrenocorticalcarcinoma.html. Accessed December 9th, 2022.
Definition / general
  • Malignant epithelial tumor of adrenal cortical cells
Essential features
  • Malignant epithelial tumor of adrenal cortex
  • Adrenocortical carcinoma (ACC) is a rare endocrine tumor with high mortality
  • IGF2 overexpression is a major event in adrenal cortical carcinoma tumorigenesis
  • Vast majority are sporadic but could present in different syndromic settings
  • Heterogeneous group of tumors with prognosis dependent on patient age, clinical presentation, stage, histologic variant and molecular / genomic characteristics
  • Positive for SF1, inhibin, calretinin, MelanA, synaptophysin
Terminology
  • Adrenal cortical carcinoma (ACC)
  • Adrenocortical carcinoma, conventional type
  • Adrenal cortical adenocarcinoma
  • Adrenocortical carcinoma
  • Adrenal cortical tumor, malignant
ICD coding
  • ICD-O: 8370/3 - adrenal cortical carcinoma
Epidemiology
Sites
Pathophysiology
Etiology
Diagrams / tables

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Diagnostic algorithm for ACC stratification

Diagnostic algorithm for ACC stratification

Clinical features
  • ~50% are functional and ~50% are nonfunctional (J Clin Endocrinol Metab 2006;91:2027, N Engl J Med 1990;322:1195)
  • Functional adrenal cortical carcinomas have the following symptoms related to hormone production:
    • 50% cortisol excess (Cushing syndrome, rapid onset)
    • 20% sex hormone secretion (mainly androgens causing hirsutism, virilization and menstrual irregularities)
    • 8% aldosterone (hypertension, hypokalemia)
    • 15 - 25% mixed hormone production
    • Patients are younger, more likely females and present with metastatic disease
  • Nonfunctional adrenal cortical carcinomas could present in 2 ways:
    • 80% create a mass effect (gastrointestinal symptoms, organ compression or back pain) or mimic an infectious process (localized pain, fever due to cytokines from highly necrotic tumors)
    • 20% discovered incidentally during unrelated imaging procedures
  • Tumors often displace and invade adjacent organs (kidneys, liver, pancreas), adrenal vein, vena cava and retroperitoneum
  • Common metastatic sites are liver (60%), lymph nodes (40%), lungs (40%), peritoneal and pleural surfaces, bone, skin (anaplastic tumors) or retroperitoneum (Endocr Rev 2014;35:282)
Diagnosis

Weiss criteria: ≥ 3 for adrenal cortical carcinoma (Am J Surg Pathol 1984;8:163, Am J Surg Pathol 2002;26:1612)
1 Nuclear grade III or IV (Fuhrman)
2 > 5 mitotic figures/50 high power fields*
3 Atypical mitotic figures*
4 Clear or vacuolated cells ≤ 25% tumor
5 Diffuse architecture (> 33% of tumor)
6 Necrosis
7 Venous invasion* (of smooth muscle walled vessels)
8 Sinusoidal invasion
9 Capsular invasion
* = major criteria; 1 is required to diagnose adrenal cortical carcinoma (Virchows Arch 2012;460:9)
Laboratory
  • Hormone quantification in serum or urine (free cortisol, ACTH, DHEA sulfate, 17-OH, 17-hydroxy, testosterone, 17-beta-estradiol, 17-deoxycortison)
  • Dexamethasone suppression test
  • Potassium
  • Steroid metabolome profiling by mass spectrometry (Biomedicines 2021;9:174)
Radiology description
Radiology images

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Heterogeneous enhancing mass with lymphadenopathy

Heterogeneous enhancing mass with lymphadenopathy

CT imaging of advanced ACC

CT imaging of advanced ACC

Prognostic factors
Case reports
Treatment
Gross description
Gross images

Contributed by Debra Zynger, M.D.
Organ confined, ≤ 5 cm (pT1)

Organ confined, ≤ 5 cm (pT1)

Organ confined, > 5 cm (pT2)

Organ confined, > 5 cm (pT2)

Extra-adrenal invasion (pT3)

Extra-adrenal invasion (pT3)

Liver invasion (pT4)

Liver invasion (pT4)



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250 g, 10 cm tumor

250 g, 10 cm tumor

Large tumor compressing kidney

Large tumor compressing kidney

Large tumor dwarfing kidney

Large tumor dwarfing kidney

Microscopic (histologic) description
  • Encapsulated tumor composed of variably sized nests, large sheets and trabeculae
  • Invasion of thick fibrous capsule
  • Lymphovascular invasion (venous or sinusoidal)
  • Areas of necrosis, hemorrhage, degeneration are common
  • Large cells with granular clear to eosinophilic cytoplasm, often pleomorphic
  • Frequent intranuclear inclusions, mitoses, atypical mitoses
  • Grade defined by mitotic frequency:
    • Low grade: ≤ 20 mitoses/50 high power fields
    • High grade: > 20 mitoses/50 high power fields
  • Morphologic subtypes:
    • Conventional (vast majority, 70 - 90% of cases)
    • Oncocytic (> 75% oncocytic cells; second most common subtype)
    • Myxoid (abundant extracellular mucin)
    • Sarcomatoid (mesenchymal differentiation)
  • Loss of continuity of the reticular fibers or basement membrane network (> 33% lesion)
  • References: Am J Surg Pathol 1989;13:202, Am J Surg Pathol 2002;26:1612, Am J Surg Pathol 2018;42:201, Histopathology 2018;72:82
Microscopic (histologic) images

Contributed by Maria Tretiakova, M.D., Ph.D.
High nuclear grade

High nuclear grade

Pleomorphic ACC

Pleomorphic ACC

Necrosis

Necrosis

Capsule / fat invasion

Capsule / fat invasion

Positive margin

Positive margin


Reticulin loss

Reticulin loss

Diffuse growth

Diffuse growth

Ki67

Ki67

MelanA

MelanA

Inhibin

Inhibin



Contributed by Debra Zynger, M.D.
High mitotic rate

High mitotic rate

Lymphovascular invasion

Lymphovascular invasion

Extra-adrenal adipose invasion

Extra-adrenal adipose invasion

Liver involvement

Liver involvement

Cytology description
  • Single cells, poorly cohesive cell clusters in necrotic background
  • Cytoplasm is vacuolated to densely eosinophilic
  • Often marked nuclear atypia and mitotic activity
  • Reference: Diagn Cytopathol 2018;46:1064
Cytology images

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Discohesive, round to polygonal tumor cells showing moderate nuclear pleomorphism

Discohesive, round to polygonal tumor cells

Electron microscopy description
  • Abundant rough and smooth endoplasmic reticulum
  • Intracytoplasmic droplets of lipids
  • Many mitochondria with tubular cristae
  • Occasionally dense core granules (associated with neuroendocrine immunostains)
  • Reference: Int J Surg Pathol 2004;12:231
Molecular / cytogenetics description
  • Most frequent significantly mutated driver genes: IGF2, CTNNB1, TP53, TERT, ZNRF3, PRKAR1A, RPL22, TERF2, CCNE1, NF1 (Cancer Cell 2016;29:723)
  • Often harbors massive DNA loss, followed by whole genome duplication associated with aggressive clinical course / hallmark of disease progression (Cancer Cell 2016;29:723)
  • Increased TERT expression, decreased telomere length and activation of cell cycle programs (Cancer Cell 2016;29:723)
  • DNA methylation signatures identified 3 adrenocortical carcinoma molecular subtypes with distinct clinical outcomes with disease progression rates of 7%, 56% and 96% (Cancer Cell 2016;29:723)
Molecular / cytogenetics images

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Hallmark molecular features

Hallmark molecular features

Sample pathology report
  • Adrenal gland, left, adrenalectomy:
    • Adrenal cortical carcinoma with the following features:
      • Tumor size: 8.5 cm x 7.5 cm x 7 cm
      • Tumor (gland) weight: 228 g
      • Tumor extent: tumor invades through the adrenal capsule
      • Histologic type: focal myxoid and oncocytic features
      • Histologic grade: low grade
      • Lymphovascular invasion: small vessel (capillary lymphatic)
      • Margins: involved circumferential margin (blue ink)
      • pTNM, AJCC 8th edition: pT3 NX
    • Ancillary studies: Ki67 mitotic rate 20%
    • Reticulin stain: disruption of reticulin framework
Differential diagnosis
Board review style question #1

A 54 year old woman presents to clinic complaining of recent onset of hot flashes, headaches, weight gain and muscle weakness. On exam, she has hypertension, acne, facial plethora and mild abdominal distension. A noncontrast CT of the abdomen reveals a heterogeneous enhancing 9.3 cm mass in the left adrenal gland. An adrenalectomy was done and is shown in the photo. Which of the gross features will be most predictive of a malignant diagnosis?

  1. Areas of necrosis
  2. Fibrous capsule
  3. Size (9.3 cm)
  4. Tan-yellow color
  5. Weight 205 g
Board review style answer #1
A. Areas of necrosis. Macroscopically, adrenal cortical carcinomas (ACC) tend to be large, lobulated, yellow masses with heterogeneous cut surface and fibrous capsule; however, in organ confined disease, only the presence of confluent necrosis would be consistent with either borderline or malignant tumor. Further microscopic examination will be essential to further substantiate ACC diagnosis with overtly malignant features (diffuse architecture with loss of reticulin continuity, high mitotic activity, atypical mitoses or lymphovascular invasion).

Comment Here

Reference: Adrenal cortical carcinoma
Board review style question #2

Which stains should be performed for precise characterization and prognostication of this adrenal of this tumor?

  1. AE1 / AE3, CK7, TTF1
  2. Chromogranin, synaptophysin, CD56
  3. MelanA, inhibin, calretinin
  4. PAX8, CAIX, TFE3
  5. SF1, reticulin, Ki67
Board review style answer #2
E. SF1, reticulin stain, Ki67. This is an adrenal cortical carcinoma. The clinical presentation and image are suggestive of functional (cortisol producing) adrenocortical tumor. Expression of SF1 will confirm adrenocortical origin. Reticulin will be useful to highlight disrupted reticulin framework supporting malignant diagnosis of adrenal cortical carcinoma (ACC). Adrenal cortical carcinomas can be stratified in prognostic groups based on mitotic activity and proliferation index by Ki67. Chromogranin, synaptophysin and CD56 could be useful in distinguishing pheochromocytoma from an adrenocortical tumor. AE1 / AE3, CK7 and TTF1 expression will be consistent with metastatic lung cancer. PAX8, CAIX and TFE3 expression panel will be helpful to confirm and classify renal cell carcinoma. MelanA, inhibin and calretinin are expressed in benign and malignant adrenocortical tumors, thus not ideal for precise diagnosis and prognostication of this neoplasm.

Comment Here

Reference: Adrenal cortical carcinoma
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