|Year : 2020 | Volume
| Issue : 2 | Page : 57-62
Cutaneous squamous cell carcinoma of the neck: Dramatic response to cytotoxic chemotherapy or spontaneous regression?
M Daniyan1, MM Dauda1, AA Liman2, SE Nwabuoku1, M Abubakar1
1 Department of Surgery, A.B.U. Teaching Hospital, Zaria, Nigeria
2 Department of Pathology and Morbid Anatomy, A.B.U. Teaching Hospital, Zaria, Nigeria
|Date of Submission||13-Jun-2020|
|Date of Acceptance||23-Sep-2020|
|Date of Web Publication||20-May-2021|
Dr. M Daniyan
Department of Surgery, A.B.U. Teaching Hospital, Zaria
Source of Support: None, Conflict of Interest: None
Skin cancers are common worldwide though incidence is higher among Caucasians. While basal cell carcinoma (BCC) is more common among Caucasians, squamous cell carcinoma (SCC) is the most common non-melanoma skin cancer in Nigeria as well as in other African countries.The Standard of care remains surgical resection with preservation of function and cosmesis, followed by adjuvant radiotherapy. Occasionally, however, systemic chemotherapy may be indicated. When it is, Cisplatin-based regimen has been the standard of care. We hereby report two cases of high risk cutaneous SCC with a dramatic response to preoperative Cisplatin/Methotrexate combination chemotherapy and highlight the possibility of spontaneous regression of SCC.
Keywords: Chemotherapy, cisplatin, metastasis, methotrexate, neoadjuvant, squamous cell carcinoma
|How to cite this article:|
Daniyan M, Dauda M M, Liman A A, Nwabuoku S E, Abubakar M. Cutaneous squamous cell carcinoma of the neck: Dramatic response to cytotoxic chemotherapy or spontaneous regression?. Arch Int Surg 2020;10:57-62
|How to cite this URL:|
Daniyan M, Dauda M M, Liman A A, Nwabuoku S E, Abubakar M. Cutaneous squamous cell carcinoma of the neck: Dramatic response to cytotoxic chemotherapy or spontaneous regression?. Arch Int Surg [serial online] 2020 [cited 2021 Aug 2];10:57-62. Available from: https://www.archintsurg.org/text.asp?2020/10/2/57/316490
| Introduction|| |
Skin cancers are common worldwide though incidence is higher among Caucasians., Non-melanoma skin cancers (NMSC) represent the most common malignancy worldwide, with the United States of America (USA) reporting over 2 million cases annually. While basal cell carcinoma (BCC) is more common among Caucasians, squamous cell carcinoma (SCC) is the most common NMSC in Nigeria as in other African countries.,,, The skin of the black Africans by virtue of its higher content of melanin absorbs ultraviolet B radiation, a major risk factor for cutaneous cancers among Caucasians. In the absence of albinism, post-burn scar is the most important risk factor for SCC in the African subcontinent.,
Cutaneous squamous cell carcinoma (cSCC) rarely metastases, hence local therapy has remained the mainstay of treatment with cure rates of 90–95% reported. Occasionally, systemic therapy may be indicated in the rare cases of metastatic diseases, deeply invasive primary tumor, high-risk primary tumor, or patients with operable disease who refused surgery, and those with residual disease after surgery., This is commonly in a multimodality fashion with surgery and radiotherapy employed as necessary.,, Cisplatin-based regimen has been the standard of care when indicated., Agents commonly combined include 5 fluorouracil, bleomycin, paclitaxel, and Adriamycin. Methotrexate when employed is usually used as an intralesional cytotoxic. Not only are published studies guiding systemic therapy in this regards scanty, but they are also largely case reports and case series. We hereby report two cases of high-risk cSCC with good response to preoperative cisplatin/methotrexate combination chemotherapy while considering the possibility of spontaneous regression.
Malignancies including cSCC are known to spontaneously regress, though rarely. The famous mechanisms put forward for such occurrence is immunologic. This may exist in the form of modulation, modification, manipulation, or stimulation of the immune system against the tumor.
| Case Reports|| |
Case No. 1
A 55-year-old male farmer presented with 4 months history of a progressively increasing, painless, left-sided neck mass. No compressive symptoms. No lumps in other parts of the body and no history of trauma. No previous neck wound or scar. No history was suggestive of tuberculosis. No previous exposure to irradiation and no family history of similar illness. No symptom was referable to the nasopharynx. Two (2) months into the illness, he consulted a trado-medical practitioner who incised the mass with a hot knife. The wound created got infected and bled on contact. The mass increased in size progressively and the ulcer failed to heal.
When examined, he was found to be pale, moderately dehydrated, with an exophytic mass in the region of the left anterior triangle of the neck. It measured 16 × 12 cm and harbors multiple ulcers, the largest measuring 4 × 6 cm [Figure 1]. Its edges were everted with an indistinct border and a necrotic fleshy floor discharging purulent exudate. There was contact bleeding. The mass was fixed to the skin and the stenocleidomastoid. There were transmitted pulsations and a mobile ipsilateral supraclavicular lymphadenopathy 4 cm in diameter. The intraoral examination was normal.
A diagnosis of superficial squamous cell carcinoma T3N2aM0 was made. A differential diagnosis of soft tissue sarcoma was entertained. Admitting packed cell volume was 17% (despite haemoconcentration). Histopathological analysis of a wedge biopsy specimen revealed moderately differentiated squamous cell carcinoma with marked lymphocytic infiltration. Immunohistochemical analysis was unavailable for further characterization. Plain cervical X-ray revealed soft tissue shadow compressing on the pharynx. Plain chest X-ray and abdominopelvic ultrasound were within normal. He had a normal renal function test and a non-reactive retroviral screening. His performance status was ECOG 1. He was resuscitated with 3 units of whole blood and double dose hematinics, antibiotics, tetanus prophylaxis, and wound care. He was thereafter counseled and subsequently worked up for neoadjuvant cytotoxic chemotherapy, aimed at down-staging the tumor. Cisplatin and methotrexate combination were instituted; IV Methotrexate 40 mg/m2 on day 1, then 60 mg/m2 on days 8 and 15; IV Cisplatin 50 mg/m2 on days 1 and 8. The cycle was repeated every 4 weeks. The response was dramatic with about 80% and over 95% regression in tumor size after the first and second cycles respectively [Figure 2] and [Figure 3]. The medication was well-tolerated and only required oral hematinics to maintain a hemogram above 30%. He suffered alopecia and mild diarrhea consistent with Clavien Dindo grade I.
While been worked up for wide local excision after the second cycle of cisplatin/methotrexate combination chemotherapy, the patient was lost to follow up.
Case No. 2
A 57-year-old man presented with a 6 months history of a mass in the left parotid region. The mass progressively increased in size until 3 months before presentation when it spontaneously ulcerated with associated contact bleeding. The mass had progressively increased in size despite the application of traditional herbs. The patient did not give a history of trauma and no previous exposure to irradiation. He had no systemic complaints.
Examination revealed a fungating ulcer in the left parotid region which measured 14 × 8 × 1 cm, with raised and everted edges. The floor was hard, nodular, and bled on contact, with a lot of necrotic debris [Figure 4]. There was no facial nerve palsy and no intraoral extension. Other systemic examinations were unremarkable. A diagnosis of fungating parotid gland tumor was made (T3N0M0). Incisional biopsy was taken for histopathological examinations. It was reported as poorly differentiated squamous cell carcinoma. Chest X-ray and abdominopelvic ultrasound were free of metastatic deposits. Other baseline investigations were within normal limits. On account of financial constraints, CT scan or MRI was not done. He was counseled and a decision to downstage the tumor with combination chemotherapy was reached with the patient. He had the same cisplatin/methotrexate combination chemotherapy protocol as for case 1 above.
Following the commencement of chemotherapy, the tumor shrank by over 60% after the second cycle of chemotherapy. The ulcer floor has become soft and nodules have disappeared [Figure 5], [Figure 6]. He however developed oral thrush and had to be managed with Nystatin oral drops. The third course of chemotherapy was delayed for two additional days for the oral thrush to improve. While the patient was been prepared for wide local excision and further (adjuvant) chemotherapy, he was reported to have died in an RTA on his way to the hospital.
| Discussion|| |
In the United States, an estimated 5 million patients with non-melanoma skin cancers (keratinocyte cancer) were treated in 2012, 50% of whom were cSCC. Cutaneous SCC constituted 20 − 30% of all cutaneous cancers among Caucasians. In Nigeria and other African countries, it has remained the most common malignant skin tumor,,, In Yakubu et al's report from Zaria, cutaneous SCC constituted 67% of all skin cancers. This is similar to studies by Rafindadi (68.3%) and Olasupo (60.9%)., In contrast, Ganiyu and Olu-Eddo reported that malignant melanoma has been the most common cutaneous malignancy in our subregion.,
Although the standard of care for cSCC remains surgical resection and adjuvant radiotherapy, systemic chemotherapy continues to play a major role in Sub-Saharan Africa, owing to the late presentation of its patients and non-availability of uninterrupted radiotherapy services. Where radiotherapy services are available, forbidden costs make access unattainable for many. Such preoperative systemic cytotoxic chemotherapy is aimed to downstage the tumor such that a functional, cosmetic, and oncologic local tumor control with surgery and/or radiotherapy can be achieved. The two cases presented above presented late with an extensive local tumor burden, thus not amenable to surgical extirpation without incurring significant morbidities. Thus, mutilating, cosmetically, functionally, and often oncologically unacceptable surgical adventure can be avoided.
Randomized controlled trials pertaining to cytotoxic chemotherapy regimen are largely unavailable due to the few pockets of high-risk cSCC for which systemic therapy is indicated. Only a few of these agents have been investigated with adequately powered prospective studies. Therefore, most evidence is derived from case reports and case series., However, with the unending industrialization in both developed and developing nations like ours, and its accompanying destruction of the ozone layer, our skin will continue to be exposed to increasing quantum of ultraviolet rays. Consequently, the incidence of cSCC and that of advanced, high-risk cases will be expected to rise. Hence the call for more RCTs to enquire about the most efficient cytotoxic chemotherapy regimen with the longest disease-free and overall survival for this special group of patients with high-risk cSCC in our sub-region.
Cisplatin-based chemotherapy has for long been the first-line agent in combination with either 5-fluorouracil, docetacel, bleomycin, Adriamycin, taxanes, gemcitabine, methotrexate, or ifosfamide in the management of regional or metastatic cSCC. A recent NCCN guideline recommends cisplatin and 5 fluorouracil combination. Other systemic therapies with promising results from case reports and case series include Cetuximab (EGFR inhibitor), Nivolumab (programmed death receptor 1 antibody), and Ipilimumab (anti-CTLA-4).
Considering the high-risk nature of the tumors in both cases presented based on their location, perceived depth of invasion on clinical grounds, and the extensive loco-regional involvement, the Authors wanted a potent cytotoxic agent yet with an acceptable toxicity profile. Cisplatin and methotrexate have both been used in the management of cSCC with a good response in the past., Given their tolerable non-overlapping side effects profile, established anecdotal efficacy against cSCC, availability, and affordability, this drug combination protocol was selected for use in our institution for these patients. The published literature concerning this regimen is largely limited. Hence our attempt to contribute to the pool of literature in this regard.
Both patients (more so in case 1) presented had a dramatic response to cisplatin/methotrexate combination with regression in tumor burden in excess of 95% just after 2 cycles. Although literature abounds with case reports and case series reporting good response to other cytotoxic regimens, most are rarely of this magnitude. The poor degree of differentiation reported in case 2 may be responsible for the lower magnitude of response observed.
Spontaneous regression of cancers are generally rare, more so for cSCC. They are estimated to occur in 1 in every 140,000 cases of cancers. Everson and Cole defined spontaneous regression as “the complete or partial, permanent or temporary disappearance of all or at least a significant portion of a well diagnosed malignant tumor in the absence of all treatment or in the presence of therapy which is considered inadequate to exert a significant influence on the neoplastic disease. Such remissions are to last at least one month. Of the several mechanisms put forward to explain its occurrence,, immunological factors appear the most rational. Successes recorded with targeted therapy using monoclonal antibodies further buttress this observation. In the first patient, the marked host response as seen in [Figure 7], below may partly be responsible for the dramatic response observed following commencement of cytotoxic chemotherapy. Though on treatment, such treatment is not known to give such a dramatic response. A similar observation was made by Bhardwaj et al. Whether or not spontaneous regression played a role in the response observed in case 1 may be difficult to profess. Furthermore, immunosuppressed patients have also been known to be at risk for advanced disease and poor outcomes. The absence of any obvious immunosuppressive state in these two patients might have contributed also to the observed response.
|Figure 7: Moderately differentiated, SCC with marked lymphocytic infiltration (patient 1)|
Click here to view
Late presentation with the attendant dismal outcome is a common occurrence in our subregion. Most patients would have consulted spiritual houses and trado-medical practitioners like these patients before presenting for orthodox medical care. Superstitious beliefs about cancers and fear of ablative surgeries are partly responsible for this behavior. Following the presentation, another issue to contend with is patient's refusal to accept adjuvant ablative therapy after noticing a dramatic response to cytotoxic chemotherapy administered in a neoadjuvant setting as was seen in case 1. This calls for proper and adequate pre-treatment counseling.
| Conclusion|| |
Cutaneous SCC remains the most common non-melanoma skin cancer in the African sub-continent. Its incidence is expected to continue to increase due to the continued destruction of the ozone layer and increasing exposure to ultraviolet rays. The goal of treatment is to ensure complete removal of the tumor with negative lateral and deep margins, while optimally preserving function and cosmesis where applicable. Although a larger study preferably RCT is required to validate the role of cisplatin/methotrexate combination for cSCC, these cases presented demonstrate the usefulness of this regimen in chemo-reduction of high-risk cSCC in the head and neck region, especially among the indigent patients in our sub-region.
A written consent was obtained from the patients after counseling.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yakubu A, Mabogunje OA. Skin cancers in Zaria, Nigeria. Trol Doc 1995;25:63-7.
Kimbrough CW, Urist MM, McMasters KM. Melanoma and cutaneous malignant neoplasms. In: Courteny MT Jr. Beauchamp RD, Evers RM, Mattox KL, editors. Sabiston Textbook of Surgery; The Biological Basis of Modern Surgical Practice. 20th
ed.. Philadelphia: Elsevier Saunders; 2016. p. 724-53.
Olu-Eddo AN, Forae GD. Patterns of non-melanoma skin cancer in Benin City, Nigeria: A teaching hospital experience. Niger J Surg Sci 2013;23:2-5. [Full text]
Harris RB, Griffith K, Moon TE. Trend in the incidence of non-melanoma skin cancer in South-Easter Arizona, 1985-1996. J Am Acad Dermatol 2001;45:528-36.
Asuquo ME, Udosen AM, Ikpeme IA, Ngim NE, Otei OO, Ebughe G, et al
. Cutaneous squamous cell carcinoma in Calabar, southern Nigeria. Clin Exp Dermatol 2009;34:870-3.
Iregbulem LM. Post-burn squamous cell cancers in Nigerians. Br J Plast Surg I987;40:488-93.
Ranfidadi AH, Samaila MO. Histopathologic analysis of epidermal skin tumour and tumour-like lesions in Ahmadu Bello University Teaching Hospital, Zaria. Niger Postgrad Med J 2006;13:354-6.
Dennis KE, Kim-Singa C, Laskinb J. Locally advanced cutaneous squamous cell carcinoma: Two case reports of dramatic responses to sequential cisplatin, docetaxel and radiotherapy. World J Oncol 2011;2:199-203.
Squamous cell skin cancer. National comprehensive cancer network practice guidelines in oncology. Version 2.2018.
Yanagi T, Kitamura S, Hata H. Novel therapeutic targets in cutaneous squamous cell carcinoma. Front Onco 2018;8:1-5.
Gurudutt VV, Genden EM. Cutaneous squamous cell carcinoma of the head and neck. J Skin Cancer 2011:50;23-7.
Potenza C, Bernardini N, Balduzzi V, Losco L, Mambrin A, Marchesiello A, et al. A review of the literature of surgical and nonsurgical treatments of invasive squamous cells carcinoma. Biomed Res Int 2018:94;89-163.
Sengupta S, Arocho J, Windham TC.Spontaneous regression of a histologically proven cutaneous squamous cell carcinoma. J Cancer Ther2013;4:546-8.
Chang WYM. Complete spontaneous regression of cancer: Four case reports, review of literature, and discussion of possible mechanisms involved. Hawaii Med J 2000;59:379-87.
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13.
Olasupo AO, Emmanuel E, Eshiobo I, Clifford O. Cutaneous cancers in Irrua, Edo State, Nigeria: A six year review. J Adv Med Med Res 2017;23:1-6.
Oseni GO, Olaitan PB, Komolafe AO, Olaofe OO, Akinyemi HAM, Suleiman OA. Malignant skin lesions in Oshogbo, Nigeria. Pan Afr Med J 2015;20:253.
Stratigos A, Garbe C, Lebbe C, Malvehy J, del Marmol V, Pehamberger H, et al
. Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer 2015;51:1989-2007.
Ribero S, Stucci LS, Daniels GA, Borradori L. Drug therapy of advanced cutaneous squamous cell carcinoma: is there any evidence? Curr Opin Oncol 2017;29:129-35.
Chen A, Ali N, Boasberg P, Ho AS. Clinical remission of cutaneous squamous cell carcinoma of the auricle with cetuximab and nivolumab. J Clin Med 2018;7:1-8.
Vogl SE, Schoenfeld DA, Kaplan BH, Lerner HJ, Engstrom PF, Horton J. A randomized prospective comparison of methotrexate with a combination of methotrexate, bleomycin, and cisplatin in head and neck cancer. Cancer 1985;56:432-42.
Clavel M, Cognetti F, Dodion P, Wildiers J, Rosso R, Rossi A, et al
. combination chemotherapy with methotrexate, bleomycin, and vincristine with or without cisplatin in advanced squamous cell carcinoma of the head and neck. Cancer 1987;60:1173-7.
Bhardwaj VM, Jain PK. Spontaneous regression of supraglottic squamous cell carcinoma: A clinical case report. J Head Neck Physicians Surg 2018;6:93-96. [Full text]
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]