Introduction
Cutaneous squamous cell carcinoma being the second most common non melanoma skin cancer, has a lifetime incidence between 7 and 11%.1, 2, 3 The appearance of cutaneous SCCs varies greatly, presenting as firm, hyperkeratotic, ulcerated, skin-colored papules or plaques found on sun-exposed skin and may be itchy or painful. Nodular squamous cell carcinomas are characterized by nodules with keratin crust or scale, a central keratin mass, prominent vascularity or haemorrhage, and multiple colors. 4 Currently, it is stated that these SCCs are rather metastatic: either from a visceral malignancy or as an in-transit metastasis from a prior SCC, similar to melanoma.5, 6 The percentage of local and distant metastasis increases up to 15 to 38% in cases of high-risk squamous cell carcinoma. In immunosuppressed patients, the metastatic rate of Cutaneous SCC is reported as 12.9%, twice the rate of non-immunosuppressed patients. 7 In-transit metastases are rare and present as dermal and subcutaneous metastatic foci located between the tumor and the closest regional lymph node. 8 This case has been presented hoping that such atypical presentations of a common tumor of skin should not be missed out and be properly managed.
Case History
A 72 year old male, with no known co morbidities, presented with multiple swellings over left shoulder and left side of chest since 2 months. He had a history of blackish lesion just lateral to left nipple, noticed 6 months back. All the nodular lesions were of varying sizes, ranging from, 1cm to 8cm in the greatest dimension, largest lesion being ulcerated with bleeding. (Figure 1) On examination, left axillary lymphnodes were enlarged. FNAC was done on the nipple lesion and the prominent cutaneous nodules, which was reported as Moderately differentiated Squamous cell carcinoma (Figure 2).
USG of left breast showed, heteroechoic lesion with in 2-3 O clock position in the peri areolar region. There was no obvious infiltration into muscular plane or abnormal internal vascularity in the left breast. Metastatic work up with CT Chest showed lung metastasis with hilar lymphadenopthy. Considering the bleeding from the lesion palliative surgery - Wide local excision with left axillary lymphnode dissection and coverage of the defect with LD flap and the specimen sent to the Histopathology department of our institution. (Figure 3)
Specimen received in the department showed multiple nodules, on cut section shows, homogenous subcutaneous whitish growth with pushing borders. (Figure 4)
Formalin fixed paraffin embedded sections stained with Hematoxylin & eosin, from the multiple nodules showed features of invasive squamous cell carcinoma, but none showed the malignancy originating from the overlying epidermis. There were nodules and islands and sheets of moderately differentiated malignant squamous cells, with scattered mitotic figures and a few keratin pearls. More sections were studied and areas were re sampled, which showed tumor emboli in the dermal lymphatics, in different foci (Figure 5a-d). The sections taken from nipple lesion showed invasive squamous cell carcinoma, evidently arising from the lining epithelium, which, along with the chronicity of lesion, established that the primary site of origin was the nipple lesion.
Sections from the axillary lymphnode dissection specimen showed metastasis from squamous cell carcinoma. The patient was worked up extensively for finding out a primary elsewhere, and was not seen. The case was reported as Primary cutaneous Squamous cell carcinoma, arising from the left peri areolar skin, with multiple nodules on the ipsilateral chest wall skin, showing in transit metastasis. 2/2 axillary nodes show metastasis from the same neoplasm.
Discussion
The American Joint Committee on Cancer, 8th edition, have described In-transitmetastases for malignant melanoma and such cases are classified as stage 3 disease. They are defined as intralymphatic metastases occurring more than 2 cm from the primary tumor, whereas intralymphatic metastases occurring within 2 cm of the primary tumor are termed satellites.8
Any microscopic focus of metastatic tumor cells in the skin or subcutis adjacent or deep to but discontinuous from the primary tumor are called as microsatellites.
In transit metastasis usually present as 0.1 to 1.2 cm exophytic dermal and sub-cutaneous papules or nodules that locate approximately more than 2 cm away from the primary tumor. The mean number of lesions was reported as 3-5.9
The lesion in our case started in the left peri areolar skin 6 months before, and within a duration of 2 months, a second nodule appeared at a distance of 7cm from it. This was followed by appearance of other multiple nodules and later axillary node involvement.
The mean age of patients with in-transit metastasis is 61. Men are more commonly affected than women. In transit metastasis development is more in high risk squamous cell carcinomas. Squamous cell carcinomas with poor prognosis are associated with features such as the lip, ear, forehead, scalp, and temple locations; size greater than 2 cm in diameter; thickness greater than 2 mm; perineural, lymphatic, or vascular invasion; poorly differentiated or undifferentiated; certain histologic types; occurrence in an immunosuppressed patient; human papillomavirus infection; recurrence; inadequate tumor resection; and expressions of certain tumor genes.10 In transit metastasis phenomenon can be seen in the umbilical region, which are defined as skin nodules developing from the dermal and subdermal lymphatics in the abdominal region prior to reaching the regional inguinal lymph nodes. 11
It is noted that, histologic differentiation of primary tumor and in-transit metastasis has been reported to be mostly well differentiated in the literature. In our case, the neoplasm was moderately differentiated. Diagnosing in-transit metastasis can be challenging, and requires clinicopathological correlation to distinguish it from local recurrence and perineural spread of tumor. New diagnostic criteria, incorporating clinical and histological features, are proposed. (Table 1) 12
Table 1
Diagnostic criteria for in transit squamous cell carcinoma
Being a rare pattern of lymphatic metastasis, the pathophysiological mechanism of in transit metastasis can be explained by the clonal evolution model of metastasis mechanisms, where the tumor cells invades the skin through dermal lymphatics. As a risk factor, lymphedema is been described, which ends with a delay in lymphnode involvement and results in increased extravasation of tumor cells within the lymphedematous limb. 10
Treatment choices for in-transit metastasis are Mohs surgery or excision surgery, radiotherapy, excision followed by radiotherapy, amputation, intralesional or systemic chemotherapy (cis-platinum, 5-fluorouracil [5- FU], bleomycin, and methotrexate), oral retinoids (13-cisretinoic acid) immunotherapy (interferon-2a), reduction of immunosuppressive medication, and anti–epidermal growth factor receptor (EGFR) agents. 13
Conclusion
As only a few case series and reports have been described such rare pattern of lymphatic metastasis, there are limited data on features and prognosis of the same. Diagnosis of in-transit SCC relies on clinicopathologic correlation. Prognosis was poor with 5-year overall survival of 13%. 12 Important to have a low index of suspicion when evaluating new skin lesions in elderly / immunocompromised patients. Subcutaneous SCCs may be a sign of cutaneous or extra-cutaneous metastasis and are particularly aggressive and recurrent, it is important to treat such cancers aggressively to optimize patient outcomes.
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