Getting the GIST cutaneous hyperpigmentation disease

By Warren R. Heymann, MD
Nov. 6, 2019
Vol. 1, No. 35

Gastrointestinal stromal tumors (GISTs) are mesenchymal malignancies arising from the interstitial cells of Cajal (cells that create bioelectrical slow wave potential, leading to smooth muscle contraction, thereby aiding peristalsis). GISTs were initially recognized by identification of KIT (CD117) expression, c-KIT mutations. Twenty years after the discovery of KIT in GISTs, the diagnosis of GISTs has become more accurate by using the gold standard immunohistochemical (IHC) panel (CD117/DOG1) and molecular analysis (KIT/PDGFRA). (1) Up to 15% of adults and most children (85%) with GIST have no mutations in the KIT or PDGFRA genes. These GISTs are referred to as wild-type GISTs with mutations in the succinate dehydrogenase (SDH) gene. (2)

According to Campbell et al, c-kit and its ligand stem cell factor (SCF) regulate the development, migration, and survival of melanocytes, interstitial cells of Cajal, and many other cells. The gain-of-function c-kit mutation in exon 11 causes most GISTs because it promotes continued activation of the receptor, which can lead to an increased cellular proliferation, decreased apoptosis, and ultimately neoplasia. (3) In 1998, the tyrosine kinase inhibitor imatinib revolutionized GIST therapy. Unfortunately, GIST patients on imatinib eventually fail due to imatinib resistance. Even though sunitinib and regorafenib have demonstrated efficacy as second- and third-line treatments, both have limited effects. Fortunately, ongoing pharmacologic and surgical trials appear promising. (2)

Why should you know about GISTs? Although it is unlikely that you will ever encounter GIST cutaneous hyperpigmentation disease — if you recognize it, you may be saving a life.

Images from JAAD Case Rep 2019; 5: 170-172.

The majority of GISTs occur sporadically. In 2001, Maeyama et al reported 2 sisters with multiple GISTs and cutaneous hyperpigmentation first observed in their early teens. Both had a point mutation of the c-kit gene. The diagnosis of multiple GISTs, which proved to be fatal, was not made until they were 41 and 45 years old. Both had a point mutation of the c-kit gene. Direct sequencing analysis showed that the point mutation occurred at codon 559 of exon 11 (Val3Ala). The same single-point mutation was detected in DNA extracted from peripheral leukocytes obtained from the younger sister and her 2 children (who had similar general hyperpigmentation) as well as in DNA from a skin biopsy specimen taken from the older sister. The germline mutation at codon 559 of the c-kit gene found in the present familial GISTs differed from that in a previously reported case of familial GISTs. The authors proposed that GISTs caused by a germline mutation of the c-kit gene should be referred to as GIST — cutaneous hyperpigmentation disease (GCHD). (4)

Despite the rarity of the syndrome, multiple kindreds with GCHD have been described with autosomal dominant inheritance. Cutaneous include variable hyperpigmentation, multiple lentigines, vitiligo, and urticarial pigmentosas. As stated by Wali et al: “The association of cutaneous hyperpigmentation and GIST tumors is not surprising given the role of c-kit in development of both melanocytes and interstitial cells of Cajal.” (5)

There have now been multiple reports of patients with GCHD where imatinib treatment showed long-term regression of GISTs and rapid diminution of the cutaneous hyperpigmentation, such as the case of a 52-year-old man harboring a de novo KIT germline mutation; his 2 daughters had the mutation and similar hyperpigmentation. His 23-year-old daughter with the syndrome also had multiple small intestinal GISTs treated by resection and imatinib administration, resulting in prompt regression of the cutaneous hyperpigmentation. (6) Coleman et al presented the case of a 20+-year-old man with speckled lentiginous nevi that may have been a manifestation of aberrant c-kit expression resulting in both GISTs and hyperpigmentation. Although his constellation of multiple GISTs in association with hyperpigmentation suggested GCHD, his genetic analysis failed to detect a germline mutation in c-kit or other genes linked to familial GISTs. Regardless, his speckled lentiginous nevi, presumably due to mosaicism, disappeared with imatinib therapy. As noted by the authors, it is possible that genetic sequencing of melanocytes before imatinib treatment may have detected the same c-kit mutation found in our patient’s GISTs, or perhaps these melanocytes harbored another c-kit mutation. (7)

It is impossible to diagnose rare disorders if you do not consider them in your differential diagnosis. These cases of GCHD underscore the need to inquire about a family history of GISTs when confronted patients with unusual hyperpigmentation and/or letinigines.

Point to Remember: GIST cutaneous hyperpigmentation disease, while rare, beautifully demonstrates the marriage of clinical phenotype and molecular analysis, leading to life-saving targeted therapy.

Our Expert’s Viewpoint

Moise Levy, MD
Physician-in-Chief and Chief, Pediatric Dermatology
Dell Children’s Medical Center

KIT is involved in mast cells, melanocytes, and interstitial cells of Cajal. Gastrointestinal stromal tumors (GIST) derive from the latter. Reports have cited the relationship of disorders of each of these in some individuals diagnosed with GIST. While exon 11 mutations in KIT relate to GIST (which usually presents in the 60s), and exon 17 mutations are related to mastocytosis, there is clearly overlap between KIT mutations (and others that have been described) in some families and individuals, allowing for mastocytosis, pigmentary anomalies, and GIST to occur. As noted, signal transduction inhibitors such as imatinib are useful for management of some cases of GIST. We should keep these associations in mind!

1. Wu CE, Tzen CY, Wang SY, Yeh CN. Clinical diagnosis of gastrointestinal stromal tumor (GIST): From the molecular genetic point of view. Cancers; 2019; 11: 679.

2. Khoshnood A. Gastrointestinal stromal tumor – A review of clinical studies. J Oncol Pharm Pract 2019 May 8:1078155219846955. doi: 10.1177/1078155219846955. [Epub ahead of print].

3. Campbell T, Feelsten L, Moore J. Disappearance of lentigines in a patient receiving imatinib treatment for familial gastrointestinal stromal tumor syndrome. Arch Dermatol 2009; 145: 1313-1316.

4. Maeyama H, Hidaka E, Ota H, Minami S, et al. Familial gastrointestinal stromal tumor with hyperpigmentation: Association with a germline mutation in the c-kit gene. Gastroenterology 2001 Jan; 120(1): 210-5.

5. Wali GN, Halliday D, Jua J, Ieremia E, et al. Cutaneous hyperpigmentation and familial gastrointestinal stromal tumor associated with KIT mutation. Clin Exp Dermatol 2019; 44: 418-421.

6. Farag S, van der Kolk LEW, van Boven HH, Akkooi ACJ, et al. Remarkable effects of imatinib in a family with young onset gastrointestinal stromal tumors and cutaneous hyperpigmentation associated with a germline KIT-Trp557Arg mutation: Case report and literature review. Fam Cancer 2018; 17: 247-253.

7. Coleman E, Panse G, Cowper S, Lacy J, Leventhal J. Disappearing pigmentary mosaicism during imatinib treatment for gastrointestinal stromal tumors. JAAD Case Rep 2019; 5: 170-172.