Download Supplementary Table 1. Ostensible explanations and potential

Supplementary Table 1. Ostensible explanations and potential mechanisms for neglect in seeking medical attention (i.e., in
cutaneous and other malignancies).
General
Specific
Mechanism
Mechanisms/reasons
Psychologic
Denial
Mediators
Examples
Refere
nces
Patients (with NMSC/other malignancies) thought
1, 2
tumor would go away; it wasn’t important; too busy;
thought could self-treat; afraid it was something
dangerous
Major mental illness
Schizophrenia, dementia, paranoid delusions, major
2
depression
Substance abuse
Alcoholics and poly-substance abusers were ultralate
3
referrals for kidney replacement therapy
Social situation
Distrust/lack of
Patients (with giant NMSC/other malignancies)
confidence in
believed if prior treatment did not work, nothing
healthcare system
would
Isolation
Living alone most significant risk factor for thick
2, 4
5
primary melanoma
Poverty (health
Poor socioeconomic status major contributor to
insurance status)
delayed treatment in patients with giant NMSC and
3, 4, 6
those in need of renal replacement therapy
Poverty strong predictor for clustering of late-stage
melanoma. Medicaid coverage associated with higher
odds for late-stage melanoma
Competing priorities
Patients (with NMSC/giant NMSC) afraid of lost time
1, 4
from work and/or caring for others
Community-level
Hispanic ethnicity strong predictor for clustering of
barriers
late-stage melanoma, independent of poverty and
6
insurance status
Other (host)
Age
Larger cutaneous SCC sizes associated with male sex,
1, 5, 7,
factors
Sex
tumors located on not easily visible sites, and tumors
8
Tumor location
arising in chronic lesions (larger sizes in turn
Pre-existing
associated with delayed treatment)
dermatoses
History of skin
Patients younger than 65 years, with
cancer
a skin cancer history, with major life problems, and
with a history of any cancer were most likely to wait
to see a doctor for NMSC
Older age/male sex risk factors for thick primary
melanoma
Tumor biology
Analgesia Loss of/no tumor
innervation
Tumor-nerve
Innervation and pain related in pancreatic carcinoma
9-11
cytokine interactions
No innervation of colonic tumors/oral SCC suspected
to account for silent presentation
Activation of sensory
Cannabinoids,
Activation of sensory receptors in the brain or spinal
receptors
opioids, endorphins
cord and neurons will inhibit other neurons
12-16
Mood alterations Autocrine/paracrine
analgesia
Cannabinoids,
Exercise-induced endogenous analgesia
12-17
opioids, endorphins,
Endomorphins
Inflammation Anti-inflammatory
POMC peptides
18
effects
Tumor kinetics Faster growth rate in
Growth rate (diameter/year) of common BCC:
19
<1.0mm for tumors ≤10years of age
giant BCC
1-1.3mm for tumors >10ears
0.48mm based in this study
By comparison, giant BCC grew at a much faster rate
based on this study (See supplemental figures S1 and
S2).
Antimicrobial Absence of infection
in tumor ulcers
Antimicrobial
13-16,
peptides,
20
antimicrobial action
of opioid and POMC
peptides
Immunity Escape from immune
surveillance
Cancer associated
Cytokines produced in head and neck SCC result in
fibroblasts
suppression of T cell proliferation, induction of T cell
apoptosis, and induction of regulatory T cells
NMSC: non-melanoma skin cancer; BCC: basal cell carcinoma; PM: primary melanoma. POMC: proopiomelanocortin; SCC:
squamous cell carcinoma.
21
REFERENCES
1.
Alam M, Goldberg LH, Silapunt S, Gardner ES, Strom SS, Rademaker AW, et al. Delayed treatment and continued growth of
nonmelanoma skin cancer. Journal of the American Academy of Dermatology. 2011 May;64(5):839-48. PubMed PMID: 21055843.
Epub 2010/11/09. eng.
2.
Kunkel EJ, Woods CM, Rodgers C, Myers RE. Consultations for 'maladaptive denial of illness' in patients with cancer:
psychiatric disorders that result in noncompliance. Psycho-oncology. 1997 Jun;6(2):139-49. PubMed PMID: 9205971. Epub
1997/06/01. eng.
3.
Obialo CI, Ofili EO, Quarshie A, Martin PC. Ultralate referral and presentation for renal replacement therapy: socioeconomic
implications. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2005 Nov;46(5):881-6.
PubMed PMID: 16253728. Epub 2005/10/29. eng.
4.
Robinson JK, Altman JS, Rademaker AW. Socioeconomic status and attitudes of 51 patients with giant basal and squamous
cell carcinoma and paired controls. Archives of dermatology. 1995 Apr;131(4):428-31. PubMed PMID: 7726584. Epub 1995/04/01.
eng.
5.
Grange F, Barbe C, Aubin F, Lipsker D, Granel-Brocard F, Velten M, et al. Clinical and Sociodemographic Characteristics
Associated With Thick Melanomas: A Population-Based, Case-Case Study in France. Archives of Dermatology. 2012 Sep 17:1-7.
PubMed PMID: 22986518. Epub 2012/09/19. Eng.
6. Hu S, Sherman R, Arheart K, Kirsner RS. Predictors of neighborhood risk for late-stage melanoma: addressing disparities through
spatial analysis and area-based measures. J Invest Dermatol 2014;134:937-45.
7.
Archontaki M, Stavrianos SD, Korkolis DP, Arnogiannaki N, Vassiliadis V, Liapakis IE, et al. Giant Basal cell carcinoma:
clinicopathological analysis of 51 cases and review of the literature. Anticancer Res. 2009 Jul;29(7):2655-63. PubMed PMID:
19596942. Epub 2009/07/15. eng.
8.
Renzi C, Mastroeni S, Passarelli F, Mannooranparampil TJ, Caggiati A, Potenza C, et al. Factors associated with large
cutaneous squamous cell carcinomas. Journal of the American Academy of Dermatology. 2010 Sep;63(3):404-11. PubMed PMID:
20598396. Epub 2010/07/06. eng.
9.
Ceyhan GO, Demir IE, Rauch U, Bergmann F, Muller MW, Buchler MW, et al. Pancreatic neuropathy results in "neural
remodeling" and altered pancreatic innervation in chronic pancreatitis and pancreatic cancer. Am J Gastroenterol. 2009
Oct;104(10):2555-65. PubMed PMID: 19568227. Epub 2009/07/02. eng.
10.
Tomita T. Localization of nerve fibers in colonic polyps, adenomas, and adenocarcinomas by immunocytochemical staining
for PGP 9.5. Dig Dis Sci. 2011 Feb;57(2):364-70. PubMed PMID: 21928069. Epub 2011/09/20. eng.
11.
Habash FS, Hantash RO, Yunis MA. Assessment of the innervation pattern of oral squamous cell carcinoma using neural
protein gene product (9.5)-An immunocytochemical study. J Oral Maxillofac Pathol. 2012 Jan;16(1):16-21. PubMed PMID:
22434940. Pubmed Central PMCID: 3303516. Epub 2012/03/22. eng.
12.
Biro T, Toth BI, Hasko G, Paus R, Pacher P. The endocannabinoid system of the skin in health and disease: novel perspectives
and therapeutic opportunities. Trends Pharmacol Sci. 2009 Aug;30(8):411-20. PubMed PMID: 19608284. Pubmed Central PMCID:
2757311. Epub 2009/07/18. eng.
13.
Slominski AT, Zmijewski MA, Zbytek B, Brozyna AA, Granese J, Pisarchik A, et al. Regulated proenkephalin expression in
human skin and cultured skin cells. J Invest Dermatol. 2011 Mar;131(3):613-22. PubMed PMID: 21191404. Pubmed Central PMCID:
3074970. Epub 2010/12/31. eng.
14.
Slominski A, Wortsman J. Neuroendocrinology of the skin. Endocrine reviews. 2000 Oct;21(5):457-87. PubMed PMID:
11041445.
15.
Slominski A, Wortsman J, Luger T, Paus R, Solomon S. Corticotropin releasing hormone and proopiomelanocortin
involvement in the cutaneous response to stress. Physiol Rev. 2000 Jul;80(3):979-1020. PubMed PMID: 10893429.
16.
Slominski AT, Zmijewski MA, Skobowiat C, Zbytek B, Slominski RM, Steketee JD. Sensing the Environment: Regulation of
Local and Global Homeostasis by the Skin's Neuroendocrine System. Advances in Anatomy, Embryology and Cell Biology.
2012;212:1-115.
17.
Laux-Biehlmann A, Mouheiche J, Veriepe J, Goumon Y. Endogenous morphine and its metabolites in mammals: History,
synthesis, localization and perspectives. Neuroscience. 2012 Dec 21;233C:95-117. PubMed PMID: 23266549. Epub 2012/12/26. Eng.
18.
Slominski A, Heasley D, Mazurkiewicz JE, Ermak G, Baker J, Carlson JA. Expression of proopiomelanocortin (POMC)-
derived melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) peptides in skin of basal cell carcinoma
patients. Human pathology. 1999 Feb;30(2):208-15. PubMed PMID: 10029451. Epub 1999/02/24. eng.
19.
Ono T, Kitoh M, Kuriya N. Characterization of basal cell epithelioma in the Japanese. J Dermatol. 1982 Aug;9(4):291-300.
20.
Gallo RL, Hooper LV. Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol. 2012 Jul;12(7):503-16.
PubMed PMID: 22728527. Epub 2012/06/26. eng.
21.
Takahashi H, Sakakura K, Kawabata-Iwakawa R, Rokudai S, Toyoda M, Nishiyama M, Chikamatsu K. Immunosuppressive
activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma. Cancer Immunol Immunother. 2015 Jul 23. [Epub
ahead of print]