Adrenocortical carcinoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Shivali Marketkar, M.B.B.S. [3] Ahmad Al Maradni, M.D. [4] Mohammed Abdelwahed M.D[5]

Overview

On gross pathology, a large tan-yellow surface with areas of hemorrhage and necrosis is a characteristic finding of adrenocortical carcinoma. On microscopic histopathological analysis, sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex are a characteristic finding of adrenocortical carcinoma.

Pathophysiology

Spread can take several forms:[4]  

  • Direct invasion of the tumor capsule, invasion through the tumor capsule into extra-adrenal soft tissue
  • Direct invasion of lymphatic vessels in and around the capsule and nearby blood vessels. Metastatic deposits are largely similar to the primary tumor

ACCs can be graded into low- and high-grade carcinoma groups based on their mitotic rates ( >20 mitoses per 50 high-power fields vs. <20 mitoses per 50 high-power fields)

Mitotic rate was most closely associated with patient outcome.

ACCs in children behave in a more indolent fashion compared with the adult, that is why there are so many pediatric ACCs but few pediatric deaths.[5]

Genetics

The genetic dissection of ACC has revealed genomic aberrations that contribute to neoplastic transformation of adrenocortical cells:

1. Clonality

2. Gene expression arrays

  • Expression levels of BUB1B, PINK1, and DLG7 are identified in ACC.[12]

3. MicroRNAs

  • MicroRNAs are RNAs that are important in the regulation of gene expression.
  • Numerous miRNAs have been identified in the regulation of various cellular processes such as proliferation, apoptosis, and differentiation.[13]
  • Dysregulation of miRNAs, such as overexpression or deletion, plays an important role in diseases.
  • Mistargeting of the miRNAs, resulting in inhibition or activation of various oncogenes, tumor suppressors, and other factors important in tumor angiogenesis.[14]
  • The investigation identified 14 upregulated miRNAs and 9 downregulated miRNAs unique to ACC.[15]
  • Upregulated miRNAs in ACCs included miR-184, miR-210, and miR-503.
  • Downregulated miRNAs included miR-214, miR-375, and miR-511.[16]
  • Levels of miR-184, miR-503, and miR-511 are able to distinguish benign from malignant adrenal tumors.[16]
  • MiR-483 was found to be significantly upregulated in pediatric ACCs.
  • MiR-99a and miR-100 are bioinformatically predicted to target the 3- untranslated regions of IGF1R, RPTOR, and FRAP1 and were experimentally confirmed to target several components of the IGF-1 signaling pathway.[17]

4. Gene mutations

  • TP53 located on 17p13 is the most commonly mutated gene in ACC, present in at least one-third of ACCs.[19]
  • LOH in the gene encoding p16ink/ p14arf, CDKN2A is observed in a subset of ACCs. The tumor suppressor function of this gene has been established in multiple cancers. LOH of 11q13 has been identified in 83% of samples.[20]
  • MEN1 somatic mutations are unusual in sporadic ACC.[21]
  • The canonical Wnt pathway, the catenin gene, and CTNNB1 have been identified as activating point mutations in over 25% of both ACAs and ACCs in children and adults.[22]

5. Chromosomal aberrations

  • ACCs showed complex chromosomal alterations. ACCs contained multiple chromosomal gains or losses with a mean of 10 events.
  • The newest study confirmed increased alterations in ACC (44%) compared with ACAs (10%).
  • In ACCs, the frequently observed chromosomal gains at 5, 7, 12, 16, 19, and 20 and losses at 13 and 22 were confirmed.

6. Epigenetic changes

Cellular signaling pathway

1. IGF pathway

  • In the adult adrenal cortex, both IGF-1 and IGF-2 stimulate basal and ACTH-induced steroidogenesis.[25]
  • Overall, the main role of IGF-2 lies in fetal development and growth, whereas IGF-1 acts mainly postnatally.[26]
  • Prominent overexpression of IGF2 and alterations of the IGF2/H19 locus have been identified in sporadic ACC.[27]
  • The IGF2 gene is located on 11p15, which also includes a noncoding H19 gene and a cyclin-dependent kinase inhibitor, CDKN1C (p57KIP2) (216, 217), and 80% to 90% of all ACCs show very high IGF2 expression. Pediatric ACCs reveal a 20-fold overexpression of IGF2.[28][29]
  • Patients with high IGF2 expression levels and 11p15 LOH are associated with a 5-fold increased risk for recurrence and a shorter disease-free survival.[30]
  • loss of maternally expressed CDKN1C and H19, may contribute to adrenal tumorigenesis.[31]
  • The combination treatment of IGF-1R antagonists and mitotane resulted in a synergistic antiproliferative effect.[32]

2. WNT signaling pathway

  • The pathway is differentiated into 3 diverging signaling cascades dependent on signal conduction through:
  • Initial alterations of the WNT/ catenin system/pathway were identified in FAP.[34]
  • Inactivating mutations of AXIN2 (a component of the catenin destruction complex) have also been described in some adrenocortical tumors.[36]
  • Both nuclear catenin accumulation and activating CTNNB1 mutations are present in ACCs suggests that WNT activation is a part of ACA tumorigenesis.

3. Vascular endothelial growth factor

Hormones biosynthesis in adrenal cortex

source: By David Richfield (User:Slashme) and Mikael Häggström. Derived from previous version by Hoffmeier and Settersr.In external use, this diagram may be cited as:Häggström M, Richfield D (2014). "Diagram of the pathways of human steroidogenesis". Wikiversity Journal of Medicine 1 (1). DOI:10.15347/wjm/2014.005. ISSN 20018762. - Self-made using bkchem and inkscape, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=6355511

Associated Conditions

Associated diseases with adrenocortical carcinoma are:

Gross Pathology

  • On gross pathology, adrenocortical carcinomas are often large (>5 cm in largest diameter), with a tan-yellow cut surface and areas of hemorrhage and necrosis.
  • Their cut surface ranges from brown to orange to yellow depending on the lipid content of their cells. Necrosis is almost always present.
  • Typical ACC with a hypercellular population of cells with the earliest form of tumor necrosis.
  • A typical ACC with a solid growth pattern and abundant eosinophilic cytoplasm with focal clear areas, consistent with lipid.
A large adrenal cortical carcinoma resected from a 27-year-old woman. The tumor measured 17 cm in diameter and invaded kidney and spleen which necessitated en bloc removal of these organs with the tumor.

Shown above is a large adrenal cortical carcinoma resected from a 27-year-old woman. The tumor measured 17 cm in diameter and invaded kidney and spleen which necessitated en bloc removal of these organs with tumor. Patient had evidence of virilization.

Microscopic Pathology

On microscopic examination, the tumor usually displays sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex. The presence of invasion and mitotic activity helps differentiate small cancers from adrenocortical adenomas.[42]

The Weiss criteria is the most reliable histopathological scoring system differentiating ACC from adrenocortical adenoma.

ACC can be diagnosed by the presence of at least 3 of the 9 Weiss criteria:

  • Nuclear grade III or IV
  • More than 5 mitotic figures/50 HPF, counting 10 random fields in area of greatest number of mitotic figures on 5 slides with the greatest number of mitosis
  • Presence of atypical mitotic figures (abnormal distribution of chromosomes or excessive number of mitotic spindles)
  • Clear or vacuolated cells comprising 25% or less of tumor
  • Diffuse architecture (more than 1/3 of tumor forms patternless sheets of cells; trabecular, cord, columnar, alveolar or nesting pattern is not considered to be diffuse)
  • Microscopic necrosis
  • Venous invasion (veins must have smooth muscles in wall; tumor cell clusters or sheets forming polypoid projections into vessel lumen or polypoid tumor thrombi covered by endothelial layer)
  • Sinusoidal invasion (sinusoid is endothelial lined vessel in adrenal gland with little supportive tissue; consider only sinusoids within tumor)
  • Capsular invasion (nests or cords of tumor extending into or through capsule with a stromal reaction); either incomplete or complete

Modified Weiss criteria (score of 3 or more suggests malignancy):

Micrograph of an adrenocortical carcinoma (left of image - dark blue) and the adrenal cortex it arose from (right-top of image - pink/light blue). Benign adrenal medulla is present (right-middle of image - gray/blue). H&E stain.

Video

Shown below is a video explaining the histology of adrenocortical carcinoma

{{#ev:youtube|7jMFENhPaOM}}

References

  1. ↑ Johnson PT, Horton KM, Fishman EK (2009). "Adrenal mass imaging with multidetector CT: pathologic conditions, pearls, and pitfalls". Radiographics. 29 (5): 1333–51. doi:10.1148/rg.295095027. PMID 19755599.
  2. ↑ Dunnick NR, Heaston D, Halvorsen R, Moore AV, Korobkin M (1982). "CT appearance of adrenal cortical carcinoma". J Comput Assist Tomogr. 6 (5): 978–82. PMID 7142516.
  3. ↑ Bharwani N, Rockall AG, Sahdev A, Gueorguiev M, Drake W, Grossman AB; et al. (2011). "Adrenocortical carcinoma: the range of appearances on CT and MRI". AJR Am J Roentgenol. 196 (6): W706–14. doi:10.2214/AJR.10.5540. PMID 21606258.
  4. ↑ Dehner LP, Hill DA (2009). "Adrenal cortical neoplasms in children: why so many carcinomas and yet so many survivors?". Pediatr Dev Pathol. 12 (4): 284–91. doi:10.2350/08-06-0489.1. PMID 19326954.
  5. ↑ Cagle PT, Hough AJ, Pysher TJ, Page DL, Johnson EH, Kirkland RT; et al. (1986). "Comparison of adrenal cortical tumors in children and adults". Cancer. 57 (11): 2235–7. PMID 3697922.
  6. ↑ Beuschlein F, Reincke M, Karl M, Travis WD, Jaursch-Hancke C, Abdelhamid S; et al. (1994). "Clonal composition of human adrenocortical neoplasms". Cancer Res. 54 (18): 4927–32. PMID 7915195.
  7. ↑ Gicquel C, Leblond-Francillard M, Bertagna X, Louvel A, Chapuis Y, Luton JP; et al. (1994). "Clonal analysis of human adrenocortical carcinomas and secreting adenomas". Clin Endocrinol (Oxf). 40 (4): 465–77. PMID 7910530.
  8. ↑ Amberson JB, Vaughan ED, Gray GF, Naus GJ (1987). "Flow cytometric determination of nuclear DNA content in benign adrenal pheochromocytomas". Urology. 30 (2): 102–4. PMID 3617290.
  9. ↑ Cibas ES, Medeiros LJ, Weinberg DS, Gelb AB, Weiss LM (1990). "Cellular DNA profiles of benign and malignant adrenocortical tumors". Am J Surg Pathol. 14 (10): 948–55. PMID 2403197.
  10. ↑ de Fraipont F, El Atifi M, Cherradi N, Le Moigne G, Defaye G, Houlgatte R; et al. (2005). "Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy". J Clin Endocrinol Metab. 90 (3): 1819–29. doi:10.1210/jc.2004-1075. PMID 15613424.
  11. ↑ Giordano TJ, Kuick R, Else T, Gauger PG, Vinco M, Bauersfeld J; et al. (2009). "Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling". Clin Cancer Res. 15 (2): 668–76. doi:10.1158/1078-0432.CCR-08-1067. PMC 2629378. PMID 19147773.
  12. ↑ de Reyniès A, Assié G, Rickman DS, Tissier F, Groussin L, René-Corail F; et al. (2009). "Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival". J Clin Oncol. 27 (7): 1108–15. doi:10.1200/JCO.2008.18.5678. PMID 19139432.
  13. ↑ Czech B, Hannon GJ (2011). "Small RNA sorting: matchmaking for Argonautes". Nat Rev Genet. 12 (1): 19–31. doi:10.1038/nrg2916. PMC 3703915. PMID 21116305.
  14. ↑ Lujambio A, Lowe SW (2012). "The microcosmos of cancer". Nature. 482 (7385): 347–55. doi:10.1038/nature10888. PMC 3509753. PMID 22337054.
  15. ↑ Soon PS, Tacon LJ, Gill AJ, Bambach CP, Sywak MS, Campbell PR; et al. (2009). "miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer". Clin Cancer Res. 15 (24): 7684–7692. doi:10.1158/1078-0432.CCR-09-1587. PMID 19996210.
  16. ↑ 16.0 16.1 Tömböl Z, Szabó PM, Molnár V, Wiener Z, Tölgyesi G, Horányi J; et al. (2009). "Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis". Endocr Relat Cancer. 16 (3): 895–906. doi:10.1677/ERC-09-0096. PMID 19546168.
  17. ↑ Doghman M, El Wakil A, Cardinaud B, Thomas E, Wang J, Zhao W; et al. (2010). "Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors". Cancer Res. 70 (11): 4666–75. doi:10.1158/0008-5472.CAN-09-3970. PMC 2880211. PMID 20484036.
  18. ↑ Barzon L, Chilosi M, Fallo F, Martignoni G, Montagna L, Palù G; et al. (2001). "Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors". Eur J Endocrinol. 145 (2): 207–12. PMID 11454518.
  19. ↑ Jain M, Rechache N, Kebebew E (2012). "Molecular markers of adrenocortical tumors". J Surg Oncol. 106 (5): 549–56. doi:10.1002/jso.23119. PMID 22504887.
  20. ↑ Kjellman M, Roshani L, Teh BT, Kallioniemi OP, Höög A, Gray S; et al. (1999). "Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16". J Clin Endocrinol Metab. 84 (2): 730–5. doi:10.1210/jcem.84.2.5506. PMID 10022445.
  21. ↑ Tadjine M, Lampron A, Ouadi L, Bourdeau I (2008). "Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas". Clin Endocrinol (Oxf). 68 (2): 264–70. doi:10.1111/j.1365-2265.2007.03033.x. PMID 17854394.
  22. ↑ Gaujoux S, Tissier F, Groussin L, Libé R, Ragazzon B, Launay P; et al. (2008). "Wnt/beta-catenin and 3',5'-cyclic adenosine 5'-monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors". J Clin Endocrinol Metab. 93 (10): 4135–40. doi:10.1210/jc.2008-0631. PMID 18647815.
  23. ↑ Barreau O, Assié G, Wilmot-Roussel H, Ragazzon B, Baudry C, Perlemoine K; et al. (2013). "Identification of a CpG island methylator phenotype in adrenocortical carcinomas". J Clin Endocrinol Metab. 98 (1): E174–84. doi:10.1210/jc.2012-2993. PMID 23093492.
  24. ↑ Hofland J, Steenbergen J, Voorsluijs JM, Verbiest MM, de Krijger RR, Hofland LJ; et al. (2014). "Inhibin alpha-subunit (INHA) expression in adrenocortical cancer is linked to genetic and epigenetic INHA promoter variation". PLoS One. 9 (8): e104944. doi:10.1371/journal.pone.0104944. PMC 4128726. PMID 25111790.
  25. ↑ Voutilainen R, Miller WL (1987). "Coordinate tropic hormone regulation of mRNAs for insulin-like growth factor II and the cholesterol side-chain-cleavage enzyme, P450scc [corrected], in human steroidogenic tissues". Proc Natl Acad Sci U S A. 84 (6): 1590–4. PMC 304481. PMID 3031644.
  26. ↑ Han VK, Lu F, Bassett N, Yang KP, Delhanty PJ, Challis JR (1992). "Insulin-like growth factor-II (IGF-II) messenger ribonucleic acid is expressed in steroidogenic cells of the developing ovine adrenal gland: evidence of an autocrine/paracrine role for IGF-II". Endocrinology. 131 (6): 3100–9. doi:10.1210/endo.131.6.1446644. PMID 1446644.
  27. ↑ Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL; et al. (2003). "Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis". Am J Pathol. 162 (2): 521–31. doi:10.1016/S0002-9440(10)63846-1. PMC 1851158. PMID 12547710.
  28. ↑ Gaston V, Le Bouc Y, Soupre V, Burglen L, Donadieu J, Oro H; et al. (2001). "Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome". Eur J Hum Genet. 9 (6): 409–18. doi:10.1038/sj.ejhg.5200649. PMID 11436121.
  29. ↑ Ilvesmäki V, Kahri AI, Miettinen PJ, Voutilainen R (1993). "Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas". J Clin Endocrinol Metab. 77 (3): 852–8. doi:10.1210/jcem.77.3.8370710. PMID 8370710.
  30. ↑ Barlaskar FM, Spalding AC, Heaton JH, Kuick R, Kim AC, Thomas DG; et al. (2009). "Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma". J Clin Endocrinol Metab. 94 (1): 204–12. doi:10.1210/jc.2008-1456. PMC 2630877. PMID 18854392.
  31. ↑ Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E; et al. (2001). "Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors". Cancer Res. 61 (18): 6762–7. PMID 11559548.
  32. ↑ Almeida MQ, Fragoso MC, Lotfi CF, Santos MG, Nishi MY, Costa MH; et al. (2008). "Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors". J Clin Endocrinol Metab. 93 (9): 3524–31. doi:10.1210/jc.2008-0065. PMID 18611974.
  33. ↑ Kim AC, Reuter AL, Zubair M, Else T, Serecky K, Bingham NC; et al. (2008). "Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex". Development. 135 (15): 2593–602. doi:10.1242/dev.021493. PMID 18599507.
  34. ↑ Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB; et al. (1991). "Identification of FAP locus genes from chromosome 5q21". Science. 253 (5020): 661–5. PMID 1651562.
  35. ↑ Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H; et al. (1991). "Identification and characterization of the familial adenomatous polyposis coli gene". Cell. 66 (3): 589–600. PMID 1651174.
  36. ↑ Chapman A, Durand J, Ouadi L, Bourdeau I (2011). "Identification of genetic alterations of AXIN2 gene in adrenocortical tumors". J Clin Endocrinol Metab. 96 (9): E1477–81. doi:10.1210/jc.2010-2987. PMID 21733995.
  37. ↑ Affara NI, Robertson FM (2004). "Vascular endothelial growth factor as a survival factor in tumor-associated angiogenesis". In Vivo. 18 (5): 525–42. PMID 15523889.
  38. ↑ de Fraipont F, El Atifi M, Gicquel C, Bertagna X, Chambaz EM, Feige JJ (2000). "Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations". J Clin Endocrinol Metab. 85 (12): 4734–41. doi:10.1210/jcem.85.12.7012. PMID 11134136.
  39. ↑ Wortmann S, Quinkler M, Ritter C, Kroiss M, Johanssen S, Hahner S; et al. (2010). "Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma". Eur J Endocrinol. 162 (2): 349–56. doi:10.1530/EJE-09-0804. PMID 19903796.
  40. ↑ Giordano TJ, Kuick R, Else T, Gauger PG, Vinco M, Bauersfeld J; et al. (2009). "Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling". Clin Cancer Res. 15 (2): 668–76. doi:10.1158/1078-0432.CCR-08-1067. PMC 2629378. PMID 19147773.
  41. ↑ Bagri A, Kouros-Mehr H, Leong KG, Plowman GD (2010). "Use of anti-VEGF adjuvant therapy in cancer: challenges and rationale". Trends Mol Med. 16 (3): 122–32. doi:10.1016/j.molmed.2010.01.004. PMID 20189876.
  42. ↑ Richard Cote, Saul Suster, Lawrence Weiss, Noel Weidner (Editor). Modern Surgical Pathology (2 Volume Set). London: W B Saunders. ISBN 0-7216-7253-1.

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