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{{Palmar plantar erythrodysesthesia}}
{{Palmar plantar erythrodysesthesia}}
{{CMG}}
{{CMG}}; {{AE}} {{MC}}
 
==Overview==
==Overview==
The exact [[pathogenesis]] of palmar plantar erythrodysesthesia (PPE) is not completely understood. It is thought that PPE is caused by direct [[Toxicity|toxic]] effect of the [[Chemotherapeutic agents|chemotherapeutic drugs]] against [[Keratinocyte|keratinocytes]], [[excretion]] of the [[drugs]] in [[eccrine sweat glands]], or [[Type I hypersensitivity reaction|type I allergic reaction]]. The [[pathological]] features of PPE are non-specific. However, since PPE involves a [[Cytotoxicity|cytotoxic]] [[reaction]] primarily affecting [[Keratinocyte|keratinocytes]], the [[Histopathology|histopathologic]] findings are similar to [[Histology|histologic]] manifestation of direct [[Toxicity|toxic]] [[Reaction|reactions]].


==Pathophysiology==
==Pathophysiology==
The cause of PPE is unknown. Existing theories are based on the fact that only the hands and feet are involved and posit the role of temperature differences, vascular anatomy, differences in the types of cells (rapidly dividing epidermal cells and eccrine glands).


The pathophysiologic mechanism of Palmar Plantar Erythrodysesthesia is under active investigation and different mechanisms have been postulated.<ref name="pmid2061446">{{cite journal| author=Baack BR, Burgdorf WH| title=Chemotherapy-induced acral erythema. | journal=J Am Acad Dermatol | year= 1991 | volume= 24 | issue= 3 | pages= 457-61 | pmid=2061446 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2061446  }}</ref> Factors that have been implicated involve rapid cell division in palms and soles, gravitational forces, vascular anatomy peculiar to these areas and temperature gradients that may be present in distal end of extremities. The higher drug concentration in the eccrine glands of palms and soles also play a role in this condition. PPE Biopsies appear histologically nonspecific, but a consistenty toxic reaction is seen.<ref name="pmid2061466">{{cite journal| author=Duvernoy O, Malm T, Thuomas KA, Larsson SG, Hansson HE| title=CT and MR evaluation of pericardial and retrosternal adhesions after cardiac surgery. | journal=J Comput Assist Tomogr | year= 1991 | volume= 15 | issue= 4 | pages= 555-60 | pmid=2061466 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2061466  }}</ref>
=== Pathogenesis ===
 
* The exact [[pathogenesis]] of palmar plantar erythrodysesthesia (PPE) is not completely understood.
* Suggested explanations include:
 
:* Direct [[Toxicity|toxic]] effect of the [[Chemotherapeutic agent|chemotherapeutic drugs]] against [[Keratinocyte|epidermal cells (keratinocytes)]].<ref>{{Cite journal
| author = [[J. E. Fitzpatrick]]
| title = The cutaneous histopathology of chemotherapeutic reactions
| journal = [[Journal of cutaneous pathology]]
| pmid = 8468414
}}</ref>
 
:*[[Concentration]] and [[excretion]] of [[Cytotoxicity|cytotoxic]] [[Drug|drugs]] in [[eccrine sweat glands]] causing damage or architectural insult.<ref name="pmid2061446">{{cite journal| author=Baack BR, Burgdorf WH| title=Chemotherapy-induced acral erythema. | journal=J Am Acad Dermatol | year= 1991 | volume= 24 | issue= 3 | pages= 457-61 | pmid=2061446 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2061446  }} </ref><ref>{{Cite journal
| author = [[Hiromi Tsuboi]], [[Kohzoh Yonemoto]] & [[Kensei Katsuoka]]
| title = A case of bleomycin-induced acral erythema (AE) with eccrine squamous syringometaplasia (ESS) and summary of reports of AE with ESS in the literature
| journal = [[The Journal of dermatology]]
| pmid = 16361756
}}</ref>


In Palmar Plantar Erythrodysesthesia associated with Pegylated liposomal doxorubicin (PLD), it has been determined that the drug is present is deposited in sweat then smeared onto the skin surfaces. The sweat glands are present in high concentration on the palms and soles. The drug then infiltrates the stratum corneum which is a thick layer in the body. This layer acts as a reservoir for the drug leading to the symptoms of PPE.<ref name="pmid23969763">{{cite journal| author=Lademann J, Martschick A, Kluschke F, Richter H, Fluhr JW, Patzelt A et al.| title=Efficient prevention strategy against the development of a palmar-plantar erythrodysesthesia during chemotherapy. | journal=Skin Pharmacol Physiol | year= 2014 | volume= 27 | issue= 2 | pages= 66-70 | pmid=23969763 | doi=10.1159/000351801 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23969763  }}</ref>
:* A [[Type 1 hypersensitivity|type I (immunoglobulin E [IgE]-mediated) allergic reaction]]. This explanation is based on the occasional co-occurrence of [[facial]] [[erythema]]/[[edema]], [[Papule|papular]] [[rash]], and [[fever]].<ref>{{cite book | last = Perry | first = Michael | title = Chemotherapy source book | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins | location = Philadelphia | year = 2012 | isbn = 9781451101454 }}</ref>


==Pathophysiology==
* Unique characteristics of the [[Palms of the hands|palms]] and the [[Sole (foot)|soles]] which justify their involvement as the preferred sites of involvement include:  <ref name="pmid2061446">{{cite journal| author=Baack BR, Burgdorf WH| title=Chemotherapy-induced acral erythema. | journal=J Am Acad Dermatol | year= 1991 | volume= 24 | issue= 3 | pages= 457-61 | pmid=2061446 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2061446  }} </ref> <ref>{{Cite journal
The pathophysiologic mechanism of Palmar Plantar Erythrodysesthesia is under active investigation and different mechanisms have been postulated.<ref name="pmid20614462">{{cite journal| author=Baack BR, Burgdorf WH| title=Chemotherapy-induced acral erythema. | journal=J Am Acad Dermatol | year= 1991 | volume= 24 | issue= 3 | pages= 457-61 | pmid=2061446 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2061446  }}</ref> Factors that have been implicated involve rapid cell division in palms and soles, gravitational forces, vascular anatomy peculiar to these areas and temperature gradients that may be present in distal end of extremities. The higher drug concentration in the eccrine glands of palms and soles also play a role in this condition. PPE Biopsies appear histologically nonspecific, but a consistenty toxic reaction is seen.<ref name="pmid20614463">{{cite journal| author=Baack BR, Burgdorf WH| title=Chemotherapy-induced acral erythema. | journal=J Am Acad Dermatol | year= 1991 | volume= 24 | issue= 3 | pages= 457-61 | pmid=2061446 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2061446 }}</ref>  
| author = [[W. S. Susser]], [[D. L. Whitaker-Worth]] & [[J. M. Grant-Kels]]
| title = Mucocutaneous reactions to chemotherapy
| journal = [[Journal of the American Academy of Dermatology]]
| pmid = 10071309
}}</ref> <ref>{{Cite journal
| author = [[Yvonne Lassere]] & [[Paulo Hoff]]
| title = Management of hand-foot syndrome in patients treated with capecitabine (Xeloda)
| journal = [[European journal of oncology nursing : the official journal of European Oncology Nursing Society]]
| doi = 10.1016/j.ejon.2004.06.007
| pmid = 15341880
}}</ref>
 
:* High density of [[eccrine sweat glands]]<ref name="pmid2947543">{{cite journal| author=Cox GJ, Robertson DB| title=Toxic erythema of palms and soles associated with high-dose mercaptopurine chemotherapy. | journal=Arch Dermatol | year= 1986 | volume= 122 | issue= 12 | pages= 1413-4 | pmid=2947543 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2947543  }} </ref>
 
:* Absence of [[Hair follicle|folliculo]]-[[Sebaceous gland|sebaceous]] units ([[Hair follicle|hair follicles]] and [[Sebaceous gland|sebaceous glands]])<ref name="pmid2947543">{{cite journal| author=Cox GJ, Robertson DB| title=Toxic erythema of palms and soles associated with high-dose mercaptopurine chemotherapy. | journal=Arch Dermatol | year= 1986 | volume= 122 | issue= 12 | pages= 1413-4 | pmid=2947543 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2947543  }} </ref>
:* Thick [[stratum corneum]] <ref name="pmid2947543">{{cite journal| author=Cox GJ, Robertson DB| title=Toxic erythema of palms and soles associated with high-dose mercaptopurine chemotherapy. | journal=Arch Dermatol | year= 1986 | volume= 122 | issue= 12 | pages= 1413-4 | pmid=2947543 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2947543  }} </ref>
:* Wide [[dermal papillae]] <ref name="pmid2947543">{{cite journal| author=Cox GJ, Robertson DB| title=Toxic erythema of palms and soles associated with high-dose mercaptopurine chemotherapy. | journal=Arch Dermatol | year= 1986 | volume= 122 | issue= 12 | pages= 1413-4 | pmid=2947543 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2947543  }} </ref>
:* High [[Cell growth|proliferation]] rate of [[Epidermis (skin)|epidermal]] [[Basal cell|basal cells]]
:* The [[temperature]] and [[pressure gradient]]
:*[[Gravitation]] forces
:*[[Vascular]] [[anatomy]] peculiar to these areas
:* In cases caused by [[capecitabine]], higher [[expression]] of the [[capecitabine]]-activating [[enzyme]] [[thymidine phosphorylase]] in the [[skin]] of the [[Palms of the hands|palms]]<ref name="pmid3855356">{{cite journal| author=Levine LE, Medenica MM, Lorincz AL, Soltani K, Raab B, Ma A| title=Distinctive acral erythema occurring during therapy for severe myelogenous leukemia. | journal=Arch Dermatol | year= 1985 | volume= 121 | issue= 1 | pages= 102-4 | pmid=3855356 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3855356  }} </ref>
 
==Microscopic Pathology==
 
* The [[pathological]] features of PPE are non-specific.
* However, since PPE involves a [[Cytotoxicity|cytotoxic]] [[reaction]] primarily affecting [[Keratinocyte|keratinocytes]], the [[Histopathology|histopathologic]] findings are similar to [[Histology|histologic]] manifestation of direct [[Toxicity|toxic]] [[Reaction|reactions]]:
 
:* Dominantly an interface [[dermatitis]] with a [[Cell (biology)|cell]]-poor infiltrate
:* A variable degree of [[Epidermis (skin)|epidermal]] ([[Keratinocyte|keratinocytes]]) [[necrosis]]<ref name="pmid8468414">{{cite journal| author=Fitzpatrick JE| title=The cutaneous histopathology of chemotherapeutic reactions. | journal=J Cutan Pathol | year= 1993 | volume= 20 | issue= 1 | pages= 1-14 | pmid=8468414 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8468414  }} </ref>
 
* Generally, in mild [[Cytotoxicity|cytotoxic]] [[Reaction|reactions]] (PPE [[World Health Organization|WHO]] [[Grading (tumors)|grades]] 1 and 2), [[necrosis]] is restricted to [[Basal cell|basal keratinocytes]].
* In severe cytotoxic reactions ([[WHO|WHO grades]] 3 and 4) destruction of the entire [[Basal lamina|basal layer]] occurs, and a [[blister]] along with complete [[epidermal]] [[necrosis]] may also be seen.<ref name="pmid9643337">{{cite journal| author=Calista D, Landi C| title=Cytarabine-induced acral erythema: a localized form of toxic epidermal necrolysis? | journal=J Eur Acad Dermatol Venereol | year= 1998 | volume= 10 | issue= 3 | pages= 274-5 | pmid=9643337 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9643337 }} </ref>


In Palmar Plantar Erythrodysesthesia associated with Pegylated liposomal doxorubicin (PLD), it has been determined that the drug is present is deposited in sweat then smeared onto the skin surfaces. The sweat glands are present in high concentration on the palms and soles. The drug then infiltrates the stratum corneum which is a thick layer in the body. This layer acts as a reservoir for the drug leading to the symptoms of PPE.<ref name="pmid239697632">{{cite journal| author=Lademann J, Martschick A, Kluschke F, Richter H, Fluhr JW, Patzelt A et al.| title=Efficient prevention strategy against the development of a palmar-plantar erythrodysesthesia during chemotherapy. | journal=Skin Pharmacol Physiol | year= 2014 | volume= 27 | issue= 2 | pages= 66-70 | pmid=23969763 | doi=10.1159/000351801 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23969763  }}</ref>
* Other [[Histology|histologic]] manifestations in [[Epidermis (skin)|epidermis]] include:
:*[[Vacuole|Vacuolar]] degeneration of the [[Stratum basale|basal cell layer of epidermis]]
:* Mild [[Spongiosum|spongiosis]]
:*[[Hyperkeratosis]]
:* Lymphohistiocytic infiltrates
:*[[Apoptosis]] of [[keratinocytes]]
:* Partial separation of the [[epidermis]] from the [[dermis]]


===Associated Conditions===
*[[Dermal]] changes include:
Palmar Plantar Erythrodysesthesia is commonly associated with chemotherapy that is used for the treatment of different cancers.


===Gross Pathology===
:*[[Superficial]] perivascular [[Infiltration (medical)|infiltration]] of [[dermis]] by [[Lymphocyte|lymphocytes]] and [[eosinophils]]
PPE commonly affects the palms more commonly than the soles. The lesion starts as just a sensation in the palms and soles, progressing to painful, tingling, symmetric, well-demarcated swelling and erythematous plaques. This is then followed by a desquamative phase that happens on resolution.<ref name="urlAcral Erythema - Holland-Frei Cancer Medicine - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK12891/ |title=Acral Erythema - Holland-Frei Cancer Medicine - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
:*[[Papillary]] [[dermal]] [[edema]]
:*[[Neutropenia|Neutrophilic]] [[Eccrine sweat glands|eccrine]] [[hidradenitis]]
:*[[Eccrine sweat glands|Eccrine]] [[squamous]] syringometaplasia, in severe PPE ([[WHO]] grades 3 and 4)


===Microscopic Pathology===
*[[Histological|Histologic]] evidence of small-[[Nerve fiber|fiber]] [[neuropathy]], as shown by reduced [[Epidermis (skin)|epidermal]] [[nerve fiber]] [[density]], has been suggested to be responsible for occurrence of [[neuropathic pain]], [[Dysesthesia|dysesthesias]], [[Paresthesia|paresthesias]], and [[temperature]] intolerance in PPE. <ref name="pmid19078798">{{cite journal| author=Stubblefield MD, Custodio CM, Kaufmann P, Dickler MN| title=Small-Fiber Neuropathy Associated with Capecitabine (Xeloda)-induced Hand-foot Syndrome: A Case Report. | journal=J Clin Neuromuscul Dis | year= 2006 | volume= 7 | issue= 3 | pages= 128-32 | pmid=19078798 | doi=10.1097/01.cnd.0000211401.19995.a2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19078798 }} </ref><br />
On histopathology non-specific features seen in Palmar Plantar Erythrodysesthesia. Features include<ref name="pmid21537373">{{cite journal| author=Farr KP, Safwat A| title=Palmar-plantar erythrodysesthesia associated with chemotherapy and its treatment. | journal=Case Rep Oncol | year= 2011 | volume= 4 | issue= 1 | pages= 229-35 | pmid=21537373 | doi=10.1159/000327767 | pmc=3085037 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21537373 }}</ref>:
* Vacuolar degenration of the basal cell layer
* Mild spongiosis, keratinocytes necrosis
* Papillary dermal edema
* Lymphocytic infiltrates
* Partial separation of epidermis from the dermis
* Dermis shows perivascular infiltrates made up of eosinphils and lymphocytes
* May have presence of eccrine squamous syringometaplasia or netruophilic eccrine hidradenitis.
* Some data suggests that small-fibre neuropathy may cause the pain and dysesthesia.


==References==
==References==
{{reflist|3}}
{{reflist|3}}
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Latest revision as of 19:35, 17 July 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mandana Chitsazan, M.D. [2]

Overview

The exact pathogenesis of palmar plantar erythrodysesthesia (PPE) is not completely understood. It is thought that PPE is caused by direct toxic effect of the chemotherapeutic drugs against keratinocytes, excretion of the drugs in eccrine sweat glands, or type I allergic reaction. The pathological features of PPE are non-specific. However, since PPE involves a cytotoxic reaction primarily affecting keratinocytes, the histopathologic findings are similar to histologic manifestation of direct toxic reactions.

Pathophysiology

Pathogenesis

  • The exact pathogenesis of palmar plantar erythrodysesthesia (PPE) is not completely understood.
  • Suggested explanations include:
  • Unique characteristics of the palms and the soles which justify their involvement as the preferred sites of involvement include: [2] [5] [6]

Microscopic Pathology

References

  1. ↑ J. E. Fitzpatrick. "The cutaneous histopathology of chemotherapeutic reactions". Journal of cutaneous pathology. PMID 8468414.
  2. ↑ 2.0 2.1 Baack BR, Burgdorf WH (1991). "Chemotherapy-induced acral erythema". J Am Acad Dermatol. 24 (3): 457–61. PMID 2061446.
  3. ↑ Hiromi Tsuboi, Kohzoh Yonemoto & Kensei Katsuoka. "A case of bleomycin-induced acral erythema (AE) with eccrine squamous syringometaplasia (ESS) and summary of reports of AE with ESS in the literature". The Journal of dermatology. PMID 16361756.
  4. ↑ Perry, Michael (2012). Chemotherapy source book. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 9781451101454.
  5. ↑ W. S. Susser, D. L. Whitaker-Worth & J. M. Grant-Kels. "Mucocutaneous reactions to chemotherapy". Journal of the American Academy of Dermatology. PMID 10071309.
  6. ↑ Yvonne Lassere & Paulo Hoff. "Management of hand-foot syndrome in patients treated with capecitabine (Xeloda)". European journal of oncology nursing : the official journal of European Oncology Nursing Society. doi:10.1016/j.ejon.2004.06.007. PMID 15341880.
  7. ↑ 7.0 7.1 7.2 7.3 Cox GJ, Robertson DB (1986). "Toxic erythema of palms and soles associated with high-dose mercaptopurine chemotherapy". Arch Dermatol. 122 (12): 1413–4. PMID 2947543.
  8. ↑ Levine LE, Medenica MM, Lorincz AL, Soltani K, Raab B, Ma A (1985). "Distinctive acral erythema occurring during therapy for severe myelogenous leukemia". Arch Dermatol. 121 (1): 102–4. PMID 3855356.
  9. ↑ Fitzpatrick JE (1993). "The cutaneous histopathology of chemotherapeutic reactions". J Cutan Pathol. 20 (1): 1–14. PMID 8468414.
  10. ↑ Calista D, Landi C (1998). "Cytarabine-induced acral erythema: a localized form of toxic epidermal necrolysis?". J Eur Acad Dermatol Venereol. 10 (3): 274–5. PMID 9643337.
  11. ↑ Stubblefield MD, Custodio CM, Kaufmann P, Dickler MN (2006). "Small-Fiber Neuropathy Associated with Capecitabine (Xeloda)-induced Hand-foot Syndrome: A Case Report". J Clin Neuromuscul Dis. 7 (3): 128–32. doi:10.1097/01.cnd.0000211401.19995.a2. PMID 19078798.
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