Double skin tumors with an atypical clinical picture
M. Tichy, D. Ditrichova, S. Brychtova, V. Ticha, and J. Urbanek
- S U M M A R Y
The authors present a rare case of double skin tumors: acral lentiginous melanoma and metatypical carcinoma. The tumors were manifested as gradually enlarging ulcerations on the leg and sole of the foot that did not respond to standard treatment. The skin biopsies showed advanced acral lentiginous melanoma on the sole and metatypical carcinoma of the lower leg. Soon after the diagnosis was made, the melanoma generalized. The article discusses the differential diagnosis of both leg ulcerations, correct diagnostic procedures, and characteristic features of both tumors that are important questions for general practitioners, dermatologists, and surgeons.
Introduction
KEY WORDS
acral lentiginous melanoma, metatypical carcinoma, double skin tumors, leg ulcers
The differential diagnosis of leg ulcerations includes a wide range of conditions of various etiologies . Ulcerating tumors figure as the most serious conditions among leg ulcers (1, 2). An unfavorable prognosis may be due to delayed appropriate therapy because of an initial misdiagnosis as a benign ulceration. Attention must be paid to all atypical lesions that do not respond to standard treatment. We present a patient with such a history.
Case report
A 74-year-old male presented with a long history of relapsing lower leg ulcers resulting from chronic venous insufficiency. The family history was uneventful. The
personal history included cholecystectomy due to lithi-asis performed 25 years earlier and long-term treatment with venotonics and vasodilators. The patient had recently been treated by a general practitioner and then by a surgeon for a progressing lesion of ten months' duration on the sole of the right foot as well as for a minor ulcer on the right shin. The lesion on the sole suggested a neu-rotrophic ulcer; however, detailed examinations did not reveal diabetes or a neuropathological etiology. The shin lesion was considered a relapsing ulcer of venous origin. Local treatment with commonly used enzymatic and antiseptic preparations was not effective. Instead, both lesions were gradually enlarging.
On admission to the hospital, the clinical examination revealed varices of both legs, hyperpigmentation due to hemosiderin deposits, and perimalleolar scarring of the right lower leg resulting from healed ulcers.
Figure 1: Oval lesion with granulating base on the sole of the foot; a proximal brown discoloration is visible.
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Figure 2: Lower leg ulcer with a clear prominent base.
On the right sole at the level of the metatarsophalangeal joint of the 2nd and 3rd toe there was an oval lesion 20 x 27 mm with a clear granulating base; a brown disco-
Figure 4: Malignant melanoma cells express HMB cytoplasmic staining.
loration was visible on the proximal side (Figure 1). On the anterior aspect of the right lower leg there was an ulcer 21 x 15 mm with a clear base and a central prominence (Figure 2). Except for the ulcer, the skin was unchanged; a physical examination of regional lymph nodes also showed nothing. Routine laboratory tests were within normal limits, as was the chest X-ray. Due to the long duration of the ulcerations and lack of response to standard therapy, two biopsies were performed. Histopathology of the ulcer on the sole disclosed an acral lentiginous melanoma in an advanced stage with vertical growth. It was diagnosed as Clark stage IV-V, with a depth of 4 mm according to the Breslaw index, and with invasion into dermal lymphatic vessels (Figures 3 and 4). The histopathology was confirmed immunohistochemically by positive HMB-45 staining. A biopsy from the lesion on the shin disclosed a metatypical carcinoma (Figure 5).
Following the diagnosis, a total excision of the metatypical carcinoma was carried out and radical excision of the melanoma with protective margins of 3 cm and amputation of toes II and III were performed.
Figure 3: Histopathology: superficially ulcerated nodular melanoma spreading into the deep dermis. HE 40x.
Figure 5: Typical picture of metatypical carcinoma with interwoven basaloid and squamous structures and with segments of clear cells. HE 40x.
The excision of the sentinel lymph node verified microscopic metastases. Elective lymph node dissection of the right inguinal area followed; histopathology showed extensive metastases. The surgical intervention was therefore followed by radiotherapy of the inguinal area 7 x 5 Gy (MeV). Two months later metastases to the liver were verified, and palliative radiotherapy and systemic treatment with corticosteroids were indicated.
Discussion
Malignant melanoma (MM) is a highly destructive tumor. Its incidence has increased significantly over the last few years, and today the incidence varies between 12 and 14 cases per 100,000 inhabitants in Europe, and 40 cases per 100,000 inhabitants in the US and Australia (1). Excessive exposure to ultraviolet radiation is considered one of the main factors responsible for the increase in incidence because of the alteration of the ozone layer surrounding the Earth. UV radiation is responsible for irreparable alterations in the DNA of melanocytes. People with pale, less-pigmented skin - phototypes I and II -face the greatest danger, but melanoma often occurs in sites not exposed to UV radiation. Evidently there are also other etiopathogenetic factors. The high incidence (ca. 20%) of acral lentiginous melanomas in the black population (1, 3) serves to illustrate this.
The main clinical-histological subtypes of MM are superficially spreading MM(57%), nodular melanoma (21%), lentigo maligna melanoma (9%), and acral lentiginous melanoma (4%). The other types include amelanotic, mucosal, and unclassifiable MMs (3).
The prognosis of malignant melanoma is based on clinical and histopathological criteria (4). The most significant and independent prognostic factor is the tumor thickness measured with an ocular micrometer from the granular layer of the epidermis to its deepest level according to the Breslow index. The state of the sentinel lymph nodes is the second most important prognostic factor; micrometastases significantly worsen the prognosis even in patients with a Breslow tumor thicknesses of 1 to 4 mm (5, 6). An independent but less significant prognostic factor is the depth of invasion measured according to Clark stages.
Other prognostic criteria are the localization of MM. Lesions on the trunk have a worse prognosis than those on the limbs, and those on the arms have a better prognosis than those on the legs. Hemorrhagic, ulcerating, and amelanotic MMs always have a bad prognosis. Nodular and acral lentiginous MMs are always less favorable. A high number of mitoses and aneuploidy of tumor cells determined by flow cytometry make the prognosis worse. On the other hand, a dense inflammatory infiltrate of the base is prognostically favorable. In general, males have a worse prognosis than females. Traditional serological markers of melanoma activity such as levels of melanin and S-100 protein in the serum are less reliable. The most
accurate serological marker is probably the level of melanoma inhibitory activity (MIA).
The parameters mentioned above are not sufficient to evaluate the prognosis. It is known that even minor lesions may undergo early metastases; on the other hand, even histologically advanced MM may be dormant for many years (7). Therefore, the search for further prognostic factors is recommended. The investigations focus especially on the interactions between the tumor and adjacent stroma. The alteration of the stro-mal microenvironment is significant for tumor growth and invasion (8). The molecular mechanisms of tumor growth remain the subject of active research.
The pTNM staging of the disease is necessary for selecting appropriate therapy: pT = primary tumor, pN = regional lymph nodes, pM = distant metastases. This staging can be done only after the excision and histopathological examination.
Our patient was diagnosed with acral lentiginous melanoma, underwent a radical excision, and was classified as IIIC (pT3b, N3, M0). Elective lymph node dissection in the right inguinal area and actinotherapy followed. Other recommended methods of treatment such as immunotherapy, chemotherapy, or hyperthermic cytostatic perfusion (4, 9, 10, 11) were not applied because of the patient's poor general condition and the rapid progression of the disease.
This variety of MM frequently affects the ungual matrix or ungual bed; the localization may be also palmo-plantar (12). It may be easily misinterpreted as a benign lesion (13). Viral warts, clavus, subungual hematomas, pyoderma, and junctional nevi in particular have to be excluded. In advanced ulcerating tumors it is necessary to consider ulcers of various etiology. Although in our patient there was no preceding history of pigmented lesions, discrete discoloration at the margin of the lesion suggested a malignant melanocytic lesion.
Histologically, acral lentiginous MM shows radial growth characterized by the presence of atypical mel-anocytes in the basal layer of epidermis, sometimes crowded in nests. Usually the epidermis is hyperplastic with possible focal ulcerations. As the tumor advances there is usually invasion of the dermis by nests of epithe-loid or fusiform cells. The presentation of superficially spreading or nodular MM is usually observed (14). The initial stages present difficulties for microscopic interpretations, especially if the biopsy is not large enough. In doubtful cases, immunohistochemical examination is suggested. The expression of S-100 protein, Melan-A, and HMB-45 are characteristic of malignant melanoma (14).
In cases of a suspected MM it is appropriate to perform total excision of the lesion with protective edges, followed by histopathological evaluation.
The second tumor in our patient was a metatypical carcinoma. Its relation to squamous cell carcinoma is widely discussed (1). In the subclass of the so-called transient tumors, whose proportion within basal cell carcinomas varies between 3 and 12%, they may be also clas-
sified as basosquamous carcinomas, which are consid-	entiation were also observed. This distinction between
ered to be the collision of two individual tumors in the	the tumor and the dermis is quite typical, as is a rather
same lesion. Keratotic basal cell carcinoma with pro-	deep invasion into the dermis. Nests and strands of more
nounced keratinization is another type. It is most prob-	mature cells were also present in the case documented
ably of follicular origin (1, 15). As for the clinical mor-	here. Perineural infiltration and invasion into the bones
phology and behavior, it is similar to other types of basal	is rather uncommon (14, 15). None of the common car-
cell carcinomas.	cinogens (excessive exposure to UV or X-rays, chemi-
Metatypical carcinoma is a relatively rare tumor type.	cal carcinogens, or genetic background) were shown
Clinically, it is characterized by locally aggressive be-	to be factors in our patient.
havior and the tendency to pronounced invasion and Although ulcerations of venous etiology prevail
radioresistance (1). The described cases of metastatic	among leg ulcers, one should carefully consider other
basal cell carcinomas mostly represent this type of tu-	etiologies. Attention should be paid to all abnormal-
mor. Histopathology showed basaloid cells of a spiky	looking ulcers, especially those not responding to stan-
shape with a loss of the typical palisade pattern of the	dard therapy. An early and appropriate biopsy is a key
cells at the margins; certain spots of squamous differ-	procedure among diagnostic methods.
R E F E R E N C E S
1.	Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC. Dermatology. 2nd ed. Berlin: Springer; 2000.
2.	Ryan TJ, Burnand K. Diseases of the veins and arteries: leg ulcers. In: Champion RH, Burton JL, Ebling FJG, editors. Textbook of Dermatology. 5th ed. Oxford: Blackwell; 1992. p. 1963-2013.
3.	Brown TJ, Nelson BR. Malignant melanoma: a clinical review. Cutis. 1999;63:275-84.
4.	Krajsova I, Vosmik F, Sukova T. [Principles of correct therapeutic care of patients with primary melanoma.] Cesk Dermatol 1998;73(2):43-8.
5.	Twomey P. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-1, an international multicenter trial. Ann Surg. 2007; 245(1):156-7.
6.	Pearlman NW, McCarter MD, Frank M, Hurtubis C, Merkow RP, Franclin WA, et al. Size of sentinel node metastases predicts other nodal disease and survival in malignant melanoma. Am J Surg. 2006;192 (6):878-81.
7.	Heenen M, Laporte M. Molecular markers associated to prognosis of melanoma. Ann Dermatol Venereol. 2003;130(11):1025-31.
8.	Hendrix MJ, Seftor EA, Kirschmann DA, Quaranta V, Seftor RE. Remodeling of the microenvironment by aggressive melanoma tumor cells. Ann NY Acad Sci. 2003;995(1):151-61.
9.	Balch CM. Efficacy of an elective regional lymph node dissection of 1-4 mm thick melanomas. ASCO Educational Book; 1997 May 17-20; Denver, CO, USA. p. 325.
10.	Jacobsen KD, Fossa SD, Aamdal S. Malignant melanoma - diagnosis and treatment. Tidsskr Nor Laegeforen. 2006;126(23):3094-7.
11.	Anonymous. Guidelines for the management of cutaneous melanoma. Sydney: The Australian Cancer Network. 1997;31-3.
12.	Dwyer PK, Mackie RM, Watt DC. Plantar malignant melanoma in a white Caucasian population. Br J Dermatol 1993;128:115-20.
13.	Grant-Kels JM, Bason ET, Grin CM. The misdiagnosis of malignant melanoma. J Am Acad Dermatol. 1999;40:539-48.
14.	Weedon D. Skin pathology. Melbourne: Churchill Livingstone 1997.
15.	Kirkham N. Tumors and cysts of the epidermis. In: Elder D, et al., editors. Lever's histopathology of the skin. 8th ed. Philadelphia: Lippincott-Raven; 1997. p. 728-9.
AUTHORS' Martin Tichy, MD, Department of Dermatovenereology, Medical Faculty ADDRESSES of Palacky University, I.P. Pavlova 6, Olomouc 77520, Czech Republic,
E-mail: tichy.martin.jun@fnol.cz
Dagmar Ditrichovä MD, PhD, Head of Department, same address Jaroslav Urbänek MD, same address
Svitlana Brychtovä MD, PhD, Institute of Pathology, Medical Faculty of Palacky University, Hnivotinskä 3, Olomouc 77520, Czech Republic Vlastislava Tichä MD, PhD, same address