METASTATIC SQUAMOUS CELL

METASTATIC SQUAMOUS CELL CARCINOMA

213:1492, 19707. Josey WE, Naib ZM, Nahmias AJ: Viral infections of

the female genital tract. J Med 69:1397-1400, 19698. Nahmias AJ, Josey WE, Naib ZM, et al: Perinatal

risks associated with maternal genital herpes simplex viralinfection. Am J Obstet Gynecol 110:825-837, 1971

9. Nahmias AJ: Infection with herpes simplex viruses Iand 11. N EngI J Med 289:781-789, 1973

10. Hensleigh PA, Glover DB, Cannon M: SystemicHerpes virus Hominis in pregnancy. J Reprod Med22(3):171-176, 1979

11. Altschuler G: Pathogenesis of congenital herpesvirus infection-case report including a description of theplacenta. Am J Dis Child 127:427-429, 1974

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25:2731-2733, 197614. Nahmias AJ, Josey WE, Naib ZM: Significance of

herpes simplex virus infection during pregnancy. ClinObstet Gynecol 15:929-938, 1972

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18. Kibrick S: Herpes Simplex in Obstetrics andPerinatal Infections. Philadelphia, Lea and Febiger, 1973

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20. Von Hersen J, Kenirschke K: Unexplained dissemi-nated herpes simplex infection in a newborn. ObstetGynecol 50(6):728-730, 1977

METASTATIC SQUAMOUS CELLCARCINOMA OF THE SKINHillard M. Lazarus, MD, Roger H. Herzig, MD, Richard Bornstein, MD,and Thomas C. Laipply, MDCleveland, OhioSunlight induced squamous cell carcinoma ofthe skin is common and produces low inci-dence of metastases. Non-actinic squamouscell carcinoma, however, possesses a metas-tatic potential even when well differentiated. Arepresentative case of keratinizing squamouscell carcinoma arising in a lower extremitywith development of widespread metastasesis discussed. The prognostic factors associ-ated with metastasizing de novo squamouscell carcinoma of the extremity include: site oforigin, duration of lesion, degree of differ-entiation, sex of patient, and size of the pri-mary lesion. Organs prone to metastasis in-clude: regional lymph nodes, liver, lungs, andbone. As skin cancers of this variety metas-tasize, the clinician must recognize this po-tential when considering therapeutic strategy.

Squamous cell carcinoma of the skin arising insun-damaged areas (actinic or solar carcinoma) isa common lesion in white individuals,13 and

From the Departments of Medicine and Pathology, CaseWestern Reserve University, University Hospitals of Cleve-land, St. Luke's Hospital of Cleveland, and The Mount SinaiHospital of Cleveland, Cleveland, Ohio. Requests for re-prints should be addressed to Dr. Hillard M. Lazarus, Di-vision of Hematology/Oncology, University Hospitals ofCleveland, University Circle, Cleveland, OH 44106.

produces a low incidence of metastasis.4 Insquamous cell carcinomas that appear in non-exposed areas (non-actinic carcinoma), it has beenpossible to identify predisposing factors such ascontact with toxins, eg, arsenic,5 nitrates,6 tar andpitch,' oils and paraffin,7 or radiation.89 Venousstasis ulcers,10 burn scars,1'12 or burn-relatedchronic ulcers, the sinus tracts of chronicosteomyelitis, 13-16 and skin disease (acrodermatitischronica atrophicans Herxheimer)'7 may give riseto this lesion. Squamous cell carcinoma arising inassociation with these factors raises major con-cern about the possibility of metastases. A case ofwell differentiated keratinizing squamous cellcarcinoma of the skin (Broders classification'8Grade I) arising de novo on the fifth toe (unrelatedto the nailbed) of a black man is reported here.This tumor had metastasized to groin nodes at thetime of presentation, and later more widely. It isthe purpose of this communication to underscorethe metastatic potential of non-actinic squamouscell carcinoma of the skin and the therapeutic im-plications.

CASE REPORTA 50-year-old black man presented in March

1978 with an asymptomatic enlarging mass of the

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W' W4A

Figure 1. Section from the amputated right toewhich illustrates the filiform pattern of the tumor.The surface is keratinized and contains many de-generated epithelial cells. Horn cysts are alsopresent at a deeper level (H & E, x 40)

right fifth toe, which was 2.5 x 3.0 cm in size.Enlarged ipsilateral groin lymph nodes were pres-ent. X-rays of the involved toe revealed bone ero-sion. A resection of the toe and a lymph node dis-section were performed. The skin of the toe andtwo of 11 lymph nodes were positive for keratiniz-ing squamous cell carcinoma (Figure 1). The pa-tient did well for six months, when he developedshortness of breath and was found to have numer-ous small lesions throughout the lung fields onchest x-ray. Multiple, fixed, nontender lymphnodes were palpable in the left supraclavicular andleft groin areas. A biopsy of the left supraclavicu-lar nodes revealed keratinizing squamous cellcarcinoma. He developed ascites; the fluid ob-tained by paracentesis was positive for malignantsquamous cells. An initial course of systemicchemotherapy was administered consisting of cy-clophosphamide (1,000 mg IV) and methotrexate(50 mg IV). The patient died 30 days later after astormy course complicated by E coli septicemiaand peritonitis.

410~~~~~~~~~~~4

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Figure 2. Tumor within alveolar spaces demonstrat-ing keratin pearl formation (H & E, x 200)

Postmortem examination revealed widespreadmetastases. The lungs contained numerousnodules in both pleura and cut surfaces through-out. Microscopically, these nodules showedkeratinizing squamous cell carcinoma. Randomsections from grossly uninvolved areas of the lungalso showed extensive foci of tumor (Figure 2). Allmajor bronchi were free from lesions. The liver,heart, stomach and gallbladder serosa, bone mar-row, and hilar nodes were involved with histologi-cally identical tumor.

COMMENTAlthough extremely rare, unsuspected lung

carcinoma can present with widespread skinmetastases.'9 However, a more likely explanationin a patient with extensive squamous cell car-cinoma involving skin and other organs is originfrom a non-actinic skin carcinoma. Squamous cellcarcinoma of the skin is quite common and manyinternists regard it as non-metastasizing. Actinicor solar carcinomas, largely in white people, areextremely common and have low metastaticpotential.20~22 This case exemplifies the fact thatnon-actinic lesions are a separate considerationand can metastasize early and widely, even whenwell differentiated. Epstein et a123 reported a seriesof approximately 6,900 patients with squamouscell carcinoma in which 142 patients had metas-tasis, 2.5 percent of these within one month ofdiagnosis and 68.1 percent at less than one year.Most large series have reported that the depth ofinvasion, the site of origin, duration of lesion, size

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TABLE 1. METASTATIC SITES OF SQUAMOUS CELL CARCINOMA OF THESKIN

Site of Metastases Percent Metastases*

Lymph node12'17'23,27,28'30'34'38-40 4.3 (410/9,623)Lu ng17'23'26 0.2 (12/7,444)Liver'1726 1.1 (6/544)Bone23 0.2 (14/6,900)Subcutaneous tissue23 0.2 (17/6,900)Brain26'40 0.2 (2/1,208)MediastinuM26 0.2(1/401)Generalized23 0.1 (9/9,600)Site unspecified5 16'17'20'23-2636 1.6 (200/12, 371)

*Numbers in parenthesis represent number of cases with site involved/numberof cases reported

of lesion, degree of differentiation, and sex allhave a bearing on biologic behavior.2426 Glass eta127 observed 35 patients with squamous cell car-cinoma arising in the lower extremity and notedthat carcinomas arising in association with pre-existing benign lesions metastasized less com-monly than de novo malignancies of the lower ex-tremity. These de novo carcinomas, most likely toarise on the skin of the feet, were felt to have anincreased tendency to metastasize because of alonger duration of symptoms before patientssought medical care (median delay of 18 monthsuntil diagnosis was established) and the larger sizeobtained before biopsy and definitive treatment.

Mortality has been shown to be greater in le-sions arising in the lower extremity compared tothe upper extremity, which may indirectly relateto a non-actinic origin. Taylor and coworkers28 re-ported a 15.5 percent mortality in 265 patients withupper extremity lesions and 38.5 percent mortalityin 70 patients with lower extremity lesions. Abraoand Bastor29 noted 7.6 percent of patients withupper extremity lesions had positive regionalnodes, whereas those with lower extremity lesionshad 11.5 percent positive inguinal nodes. Schrek30did not confirm this finding, reporting a 16 percentincidence of regional node involvement independ-ent of the site of origin. Lavedan et a131 providedguidelines as to which lesions were most likely tometastasize, including those which were of largersize, present for longer periods of time, poorly dif-ferentiated histologically, deeply invasive, or in-adequately resected initially.

Several writers2.34 have stated that the size ofthe primary lesion was an important factor in pre-dicting metastatic disease. Smaller lesions (lessthan 2 cm) metastasized uncommonly, while

metastases were observed frequently with largerlesions. To quantify this relationship further,Taylor et a128 correlated the size of the primarylesion with regional node involvement: lesions upto 1 cm had 14 percent positive nodes; 1-2 cm had60 percent; and larger than 2 cm had 94 percentregional node involvement.

Male individuals tend to develop squamous cellcarcinoma of the skin about twice as often asfemales23'30'35 and to have more aggressive disease;two thirds of foot lesions in male patients metas-tasize.23'28 Anaplastic lesions carry a much poorerprognosis, as do lesions arising in normal skin (denovo as in the patient reported here) compared tothose of definable etiologies.4'21'2227'3"

Metastatic sites most commonly involved areregional nodes, lung, and bone. Table 1 sum-marizes the incidence from the literature, 1939 tothe present. Lymph node and liver involvementwere most commonly observed. Clearly, thestudies were notable for lack of specificity of sitesinvolved, making it difficult to draw conclusions.

This patient's tumor was widely metastatic andunresponsive to a single course of chemotherapy.The treatment is difficult to evaluate, since onlyone course was given late in the patient's illness.Squamous cell carcinoma does metastasize asdocumented in the older literature (almost fivepercent of cases as noted in Table 1), but re-emphasis of this observation is warranted. Thescope of the problem is further delineated by Dunnet a137 who reported 6,000 new cases of squamouscell carcinoma diagnosed in California each year,accounting for 40-50 annual deaths. Therefore, ad-juvant chemotherapy may sometimes be appro-priate for patients with non-actinic lesions, evenwhen well differentiated. This case underscores

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this point since earlier treatment may have alteredhis course, although there is no literature to sup-port this concept. Certainly the cases of squamouscell carcinoma of the skin which would fall into apoor prognosis category (inflammatory, chemical,or radiation-induced lesions, poorly differentiatedlesions, males, long-standing and large tumors,lower extremity lesions) might benefit from earlytreatment. Thus, it is important to recognize themalignant potential of non-actinic squamous cellskin carcinoma in order to plan early and adequatetreatment.

Literature Cited1. Andrade R, Gumport SL, Popkin GL, et al: Cancer of

the Skin: Biology, Diagnosis, Management. Philadelphia,WB Saunders, 1976, pp 413-419, 925

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8. Martin H, Strong E, Spiro R: Radiation-induced skincancer of the head and neck. Cancer 25:61-71, 1970

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tors of squamous cell skin cancer of different locations:Part 1: The lower limbs. Acta Derm Venereol (Stockh)49:427-435, 1969

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21. Graham JH, Helwig EB: Premalignant cutaneousand mucocutaneous diseases. In Graham JH, Johnson WC,Helwig EB (eds): Dermal Pathology. Hagerstown, Md,Harper and Row, 1972, pp 561-581

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25. Mohs FE: Chemosurgery in Cancer, Gangrene, andInfection. Springfield, Ill, Charles C Thomas, 1956, pp 113-116

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27. Glass RL, Spratt JS, Perez-Meso C: Epidermoidcarcinomas of the lower extremities: An analysis of 35cases. Arch Surg 89:955-960, 1964

28. Taylor GW, Nathanson IT, Shaw DT: Epidermoidcarcinoma of the extremities with reference to lymph nodeinvolvement. Ann Surg 113:268-275, 1941

29. Abrao A, Bastor JAV: Carcinoma da pele das ex-tremidades. Rev Brasil Chir 54:124-131, 1967

30. Schrek R: Cutaneous carcinoma: Part 3: A statisti-cal analysis with respect to site, sex, pre-existing scars.Arch Path 31:434-448, 1941

31. Lavedan J, Ennuyes A, Soenen A: Frequence deadenopathie secondaires aux cancer cutanes de la tete etdu cou, enfonction de la localization, de 1'extension en sur-face et du degre d'infiltration. Rev Med Liege 5:415-418,1950

32. Editorial. Epidermoid carcinoma of the lower ex-tremity. JAMA 191 :44,1965

33. Glass RL, Spratt JS, Perez-Mesa C: The fate of in-adequately excised epidermoid carcinoma of the skin. SurgGynecol Obstet 122:245-248, 1966

34. Modlin JJ: Cancer of the skin: Surgical treatment.Missouri Med 51 :364-367, 1954

35. Katz AD, Urbach F, Lilienfeld AM: The frequencyand risk of metastases in squamous cell carcinoma of theskin. Cancer 10:1162-1166, 1957

36. Kopf AW, Andrade R: Yearbook of Dermatology,1966-1967. Chicago, Year Book Medical Publishers, 1967, p229

37. Dunn JE, Levin EA, Linden G, et al: Skin cancer as acause of death. Calif Med 102:361-363, 1965

38. Jensen TS, Vetner MO: Treatment of 443 cases ofskin carcinoma with curettage and soft roentgen rays bythe Ebbehoj method. Acta Radiol 12:369-377, 1973

39. Browne HJ, Coventry MB, McDonald JR: Squamouscarcinoma of the extremities. Proc Staff Meet Mayo Clin28:590-598, 1953

40. Mohs FE, Lathrop TG: Modes of spread of cancer ofskin. AMA Arch Dermatol 66:427-439, 1952

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