Paraneoplastic Syndromes in Patients with Keratinocyte Skin Cancer: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Ioannis BASSUKAS.

A variety of well-characterized cutaneous paraneoplastic syndromes (PNS) are diagnosed during internal malignancies; however, the spectrum of keratinocyte skin neoplasms (KSC) related to PNS is still obscure. Aim of the present research synthesis was to provide a typology of the spectrum of these PNS based on a focused literature search.

  • paraneoplasia
  • keratinocyte skin cancer
  • basal cell carcinoma
  • cutaneous squamous cell carcinoma
  • hypercalcemia
  • hidradenitis suppurativa

1. Introduction

Paraneoplastic syndromes (PNS) are nonmetastatic tumor-associated findings caused by malignancies in remote body sites [1,2][1][2]. PNS are found in a considerable fraction of tumor patients and may primarily affect the neuromuscular/musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, endocrine or renal systems [2]. Moreover, in some cases PNS may be even the first or most prominent manifestation of an underlying cancer, so their timely identification can guide the search for a still unrecognized malignancy. From a pathophysiologic point of view, most PNS are attributed to either endocrine phenomena (induced by tumor secreted biomolecules) or auto-immunity mediated immunological mechanisms [3,4][3][4]. Although the skin is a frequent target organ of PNS [5[5][6],6], PNS have been rather rarely reported in the course of skin neoplasms, even in relation to the biologically more aggressive ones, like malignant melanoma and Merkel cell carcinoma [7,8][7][8].

2. Discussion

Malignancy associated hypercalcemia (MAH) [50,51,52][9][10][11] was the PNS most frequently reported in patients with KSC. Serum calcium levels are rigorously regulated in health (normal range: 8.2–10.6 mg/dL), and depending on the degree of hypercalcemia a plethora of clinical findings may result, ranging from non-specific symptoms like asthenia, nausea, and loss of appetite for mild hypercalcemia to more specific presentations for calcium levels >12.0 mg/dL (confusion, lethargy, coma) and finally to shock and death for extremely high serum calcium levels (>18.0 mg/dL) [50][9]. Immediate medical attention is necessary in these cases to reduce serum calcium levels, restore the glomerular filtration rate, and treat the underlying KSC to allow for the resolution of the crisis.
Almost all KSC-associated MAH cases presented with laboratory profiles consistent with the diagnosis of humoral hypercalcemia of malignancy (HHM), a PNS seen in up to 20% of cancer patients in the course of their disease [50,51,52][9][10][11]. HHM is caused by ectopic secretion of PTHrP, an immunologically distinct member of the PTH polypeptides hormone family [51][10] that acts through the PTH receptor to induce ubiquitous bone resorption and to reduce renal calcium clearance and phosphorus reabsorption. Increased PTHrP serum levels were also reported in most MAH cases (including two hypercalcemia-leukocytosis cases) with relevant information in the presently compiled material (Table 1). PTHrP is secreted by normal and malignant human keratinocytes and seems to act as a paracrine factor during normal growth and differentiation of the epidermis [53][12]. It is worth noting that the scarcity of reports identified herein seems to confirm the clinical experience that hypercalcemia is only occasionally diagnosed in association with SCC of epidermal origin, and this contrasts with the fact that SCC arising in extracutaneous sites accounts for a substantial fraction of all MAH cases [51,54][10][13]. This latter finding is in accordance with the conclusion of a former study that hypercalcemia is rare in patients with KSC [47][14]. Remarkably, although a cSCC complicating a severe hidradenitis suppurativa case is a rather exceptional event, ref. [10][15] a substantial fraction of the present PNS cases (8/41 cases), particularly MAH (7/41 or 17% of all cases), were observed within this patient setting. As MAH may develop on the background of concurrency with some other hypercalcemia-predisposing condition, like a granulomatous disease [50][9], it is worth inquiring whether a granulomatous hidradenitis suppurativa variant [55][16] underlies the development of this PNS.
Table 1. Malignancy associated hypercalcemia in KSC patients: Core demographic and laboratory findings. No (%): Number (% cases with available data).
Demographics    
Age, median [range], y   58 [5–83]
Sex, No (%) Women 5 (16)
Men 27 (84)
Tumor, No (%) SCC 30 (94)
Other 2 (6)
Laboratory findings    
Hypercalcemia a, Νο (%) mild 4 (13)
moderate 9 (28)
severe 19 (59)
Phosphorus b, Νο (%) decreased 5 (25)
norm 14 (70)
increased 1 (5)
N/A 12 (38)
Parathormone b, PTH, Νο (%) decreased 15 (54)
norm 13 (46)
increased 0 (0)
N/A 4 (12)
Parathormone related protein, PTHrP b,Νο(%) decreased 0 (0)
norm 1 (5)
increased 20 (95)
N/A 11 (34)
Vitamin D3 b, No (%) decreased 5 (31)
norm 10 (63)
increased 1 (6)
N/A 16 (50)
The background color highlights the data that refer to one factor. a Mild: 10.7—11.9 mg/dL; moderate: 12.0–13.9 mg/dL; severe: ≥14 mg/dL. b Explanations. norm: within normal range; increased: above norm range; decreased: below norm range; N/A: value not available. Abbreviations. D3: 1,25 (OH)2 D3; KSC: Keratinocyte Skin Cancer; PLM: pilomatrixoma; PTH: parathormone; PTHrP: parathormone related protein; SCC: cutaneous Squamous Cell Carcinoma; TRC: trichilemmal carcinoma.
 
 
With four cases, anemia was the second most frequent PNS reported in patients with KSC. Anemia is probably the most common systemic finding of patients with solid tumors [56][17]. It is caused by either a functional iron deficiency (anemia of inflammation or chronic disease) or by iron sequestration. It is worth noting that most anemia cases were found in association with advanced BCC. Chronic bleeding from the large erosive tumor surfaces of advanced BCC could be a plausible anemia explanation; however, in two of the four KSC-associated cases (two of three BCC associated cases) the etiology of anemia was the rather rare pure red cell aplasia syndrome [57][18].
Bazex syndrome (acrokeratosis paraneoplastica), a rare obligate cutaneous PNS, [58][19] was the third more frequently reported PNS in association with a KSC. It is worth noting that although most cases in the literature are related to SCC of upper aerodigestive mucosae, cases compiled here are associated with cSCC of the extremities: a lower leg and a forearm tumor with axillary lymph node metastases.

References

  1. Hobbs, C.B.; Miller, A.L. Review of Endocrine Syndromes Associated with Tumours of Non-Endocrine Origin. J. Clin. Pathol. 1966, 19, 119–127.
  2. Bilynsky, B.T.; Dzhus, M.B.; Litvinyak, R.I. The Conceptual and Clinical Problems of Paraneoplastic Syndrome in Oncology and Internal Medicine. Exp. Oncol. 2015, 37, 82–88.
  3. Dimitriadis, G.K.; Angelousi, A.; Weickert, M.O.; Randeva, H.S.; Kaltsas, G.; Grossman, A. Paraneoplastic Endocrine Syndromes. Endocr.-Relat. Cancer 2017, 24, R173–R190.
  4. Maverakis, E.; Goodarzi, H.; Wehrli, L.N.; Ono, Y.; Garcia, M.S. The Etiology of Paraneoplastic Autoimmunity. Clin. Rev. Allergy Immunol. 2012, 42, 135–144.
  5. Thiers, B.H.; Sahn, R.E.; Callen, J.P. Cutaneous Manifestations of Internal Malignancy. CA Cancer J. Clin. 2009, 59, 73–98.
  6. Ehst, B.D.; Minzer-Conzetti, K.; Swerdlin, A.; Devere, T.S. Cutaneous Manifestations of Internal Malignancy. Curr. Probl. Surg. 2010, 47, 384–445.
  7. Vyas, R.; Selph, J.; Gerstenblith, M.R. Cutaneous Manifestations Associated with Melanoma. Semin. Oncol. 2016, 43, 384–389.
  8. Iyer, J.G.; Parvathaneni, K.; Bhatia, S.; Tarabadkar, E.S.; Blom, A.; Doumani, R.; McKenzie, J.; Asgari, M.M.; Nghiem, P. Paraneoplastic Syndromes (PNS) Associated with Merkel Cell Carcinoma (MCC): A Case Series of 8 Patients Highlighting Different Clinical Manifestations. J. Am. Acad. Derm. 2016, 75, 541–547.
  9. Goltzman, D. Approach to Hypercalcemia. In Endotext; Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., de Herder, W.W., Dhatariya, K., Dungan, K., Grossman, A., Hershman, J.M., et al., Eds.; MDText.com, Inc.: South Dartmouth, MA, USA, 2000.
  10. Zagzag, J.; Hu, M.I.; Fisher, S.B.; Perrier, N.D. Hypercalcemia and Cancer: Differential Diagnosis and Treatment. CA Cancer J. Clin. 2018, 68, 377–386.
  11. Stewart, A.F. Clinical Practice. Hypercalcemia Associated with Cancer. N. Engl. J. Med. 2005, 352, 373–379.
  12. Weckmann, M.T.; Gröne, A.; Capen, C.C.; Rosol, T.J. Regulation of Parathyroid Hormone-Related Protein Secretion and MRNA Expression in Normal Human Keratinocytes and a Squamous Carcinoma Cell Line. Exp. Cell Res. 1997, 232, 79–89.
  13. Burt, M.E.; Brennan, M.F. Incidence of Hypercalcemia and Malignant Neoplasm. Arch. Surg. 1980, 115, 704–707.
  14. Nicolae, I.; Schipor, S. PTH-Independent Hypercalcaemia and Non-Melanoma Skin Cancer. J. Eur. Acad. Derm. Venereol. 2010, 24, 449–452.
  15. Hakkou, J.; Rostom, S.; Bahiri, R.; Hajjaj-Hassouni, N. Paraneoplastic rheumatic syndromes: Report of eight cases and review of literature. Rheumatol. Int. 2012, 32, 1485–1489.
  16. Attanoos, R.L.; Appleton, M.A.; Hughes, L.E.; Ansell, I.D.; Douglas-Jones, A.G.; Williams, G.T. Granulomatous Hidradenitis Suppurativa and Cutaneous Crohn’s Disease. Histopathology 1993, 23, 111–115.
  17. Gaspar, B.L.; Sharma, P.; Das, R. Anemia in Malignancies: Pathogenetic and Diagnostic Considerations. Hematology 2015, 20, 18–25.
  18. Means, R.T. Pure Red Cell Aplasia. Blood 2016, 128, 2504–2509.
  19. Räßler, F.; Goetze, S.; Elsner, P. Acrokeratosis Paraneoplastica (Bazex Syndrome)—A Systematic Review on Risk Factors, Diagnosis, Prognosis and Management. J. Eur. Acad. Derm. Venereol. 2017, 31, 1119–1136.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback