Cutaneous myxoid spindle cell squamous cell carcinoma

Myxoid spindle cell squamous cell carcinoma (SCC) is a rare variant of squamous cell carcinoma (SCC) or a distinct carcinoma that may occur at varied anatomical sites. It was first characterized in a series of six cases by Yang et al.1 in 2010. Their proposed diagnostic criteria included poorly differentiated spindle cells with more than 50% of the lesion showing myxoid stromal change and a concordant epithelial immunophenotype (usually high molecular weight cytokeratins). These lesions may be mistaken for various mesenchymal malignancies such as myxoid atypical fibroxanthoma/pleomorphic dermal sarcoma, myxofibrosarcoma, or malignant peripheral nerve sheath tumor (MPNST). Consensus has not yet been attained on whether this represents a distinct SCC subtype or an entity in itself. We report a case of cutaneous myxoid spindle cell SCC with complete myxoid stromal change and aberrant immunohistochemical expression of mesenchymal markers. An 84-year-old man, with a history of multiple cutaneous SCCs, presented with a thick, erythematous, indurated, and ulcerated plaque on the right forehead. The lesion rapidly enlarged over a period of 3 months. A deep shave biopsy of the plaque was performed, as well as complementary curettage and electrodesiccation of the base, demonstrating an exophytic nodular dermal growth expanding an atrophic and ulcerated epidermis (Figure 1A). Pleomorphic spindled cells with long delicate cytoplasmic extensions and epithelioid cells were arrayed in sheets and single cells, floating in pools of amorphous blue mucin (Figure 1B). Glandular structures were not seen. Hemorrhage and hemosiderin were present throughout the tumor (Figure 1C). Nucleoli were prominent and chromatin was vesicular. SCC in situ was present at the tumor edge (Figure 1D). Perineural invasion and lymphatic invasion were not identified. Necrosis was not seen. There was no component of conventional SCC and the tumor extended to the deep resection margin. The initial differential diagnosis included spindle cell melanoma with myxoid stroma, spindle cell angiosarcoma given the hemorrhagic zones and hemosiderin deposition, myxoid MPNST, atypical fibroxanthoma/pleomorphic dermal sarcoma, or myxofibrosarcoma. However, the presence of adjacent SCC in situ did allow us to initially orient toward a poorly differentiated SCC. An immunohistochemical panel was performed and showed immunolabeling for epithelial markers such as CK AE1/AE3 (Figure 2A), p63 (Figure 2A), CK 5/6 (focal), CK18, and EMA. The tumor cells expressed SMA (75% of tumor cells with strong staining, accentuated near the zone of ulceration, Figure 2D). The same SMA-positive areas are also labeled for CD10. In addition, the tumor was negative for S100, MITF, CD31, CD34, FVIII, ERG, p40, INI1 (preserved expression) and desmin. The pools of mucin stained for mucicarmine and alcian blue (Figure 2C). Altogether, the findings were consistent with an invasive primary myxoid spindle cell SCC. Given the patient's multiple comorbidities and ambulatory difficulties, after discussion with the patient, a surgical re-excision of the biopsy site was not performed. At 6-month follow-up, the patient did not show any sign of local or distance metastasis or recurrence but is being closely monitored. Spindle cell SCC is a sarcomatoid morphologic variant of SCC composed predominantly of spindle cells. Prominent myxoid stroma is not a usual finding and may pose a challenge with regard to its differential diagnosis. The presence of a marked myxoid stroma in a poorly differentiated spindle cell SCC has been thought to represent either a distinct, rare entity, titled “primary cutaneous myxoid squamous cell carcinoma” by Yang et al.,1 or alternatively an underreported morphologic variant of SCC.2 Certain authors have proposed the term “spindle cell squamous cell carcinoma with myxoid stroma” to highlight the stromal features of these tumors.2 Similar to most cutaneous SCCs, myxoid spindle cell SCC usually presents on skin with high exposure to ultraviolet light (such as the head and neck region).2 Cutaneous origin of the myxoid SCC may portend a better prognosis compared to mucosal areas, based on limited case reports and case series.1-4 Previous reports of such neoplasms indicate local recurrences of lesions. While there are no established guidelines or consensus on the management of primary cutaneous myxoid SCC, the diffuse myxoid change along with high-grade cytological atypia likely represents poor differentiation of SCC, which constitutes a high-risk prognostic factor as per the Brigham and Women's Tumor Classification System for head and neck SCC.5 In addition, the National Comprehensive Cancer Network (NCCN) 2024 squamous cell skin cancer guidelines recommend risk stratification of localized SCC with poor differentiation as “very high risk” (SCC-4 and SCC-5). Alternatively, carcinosarcomas as categorized as “high risk” (SCC-4) by the NCCN. The incidence of primary cutaneous myxoid SCC is quite low. We performed a review of the published literature and identified 15 cases (including the current case) published from 1990 to 2024 (Table 1). We did not include tumors with only focal myxoid change as this does not fulfill the Yang et al. diagnostic criteria. Most patients were male (10/15, or 67%) ranging in age from 59 to 95 years. Moreover, this tumor or tumor variant is not described in the latest World Health Organization Classification of Skin Tumors fifth edition, highlighting either or both its rarity and underreporting.6 The differential diagnosis of myxoid spindle cell SCC includes spindle cell melanoma, angiosarcoma, MPNST, AFX/PDS, myxofibrosarcoma, myxoid epithelioid sarcoma, or cutaneous carcinosarcoma. Other myxoid cutaneous or superficial soft tissue tumor diagnoses to be considered include myxoid DFSP, myxoid cellular neurothekeoma, cutaneous myoepithelial carcinoma, and low-grade fibromyxoid sarcoma. The presence of extensive hemorrhage and hemosiderin in this instance could have misled one to angiosarcoma. Angiosarcomas are among the few sarcomas that may notoriously express cytokeratins, but vascular immunohistochemical markers were negative, helping exclude this possibility. MPNST and myxofibrosarcoma tend to be deeper soft tissue lesions but may also be superficially sampled. Adjacent in situ SCC, as seen in this case, is helpful for making the diagnosis of myxoid spindle cell SCC but actinic keratosis or SCCis is most often lacking in this entity.1, 2 SCCis can also be seen adjacent to AFX, but only in infrequent instances (~5% of AFX).7, 8 In addition, positive SMA expression could be misinterpreted as the tumor having a mesenchymal origin, but aberrant IHC expression of mesenchymal markers in spindle cell SCC such as SMA and vimentin has been reported.9, 10 Therefore, immunohistochemistry is key to confirming an epithelial origin with diffuse positive staining for both low and high molecular weight cytokeratins (CK5/6, CK AE1/AE3, CK8/18, etc.) and epithelial markers (p40, p63, EMA). This positive cytokeratin staining makes the diagnosis of myxoid DFSP, myxoid cellular neurothekeom, and low-grade fibromyxoid sarcoma unlikely.11, 12 In addition, other superficial cutaneous sarcomas such as low-grade fibromyxoid sarcoma classically show prominent myxoid change, yet do not display marked atypia. The combined expression of SMA and cytokeratins raises the possibility of a cutaneous carcinosarcoma or myxoid epithelioid sarcoma.13, 14 Cutaneous carcinosarcoma is biphasic with a distinct sarcomatous component, which differs from the diffuse myxoid change seen throughout the whole lesion in this case along with the homogenous immunophenotype seen. In addition, there is no loss of INI1, helping to preclude a diagnosis of myxoid epithelioid sarcoma and rendering cutaneous myoepithelial carcinoma less likely.11-13 Negative IHC staining for S100 and p40 also emphasize that the lesion is not of myoepithelial origin. Finally, CD10 staining expression has, to our knowledge, not been reported in myxoid SCC, but both the unique immunolabeling (strong and diffuse) of the same tumor cells in this instance and the clinical presentation (presenting on sun-damaged skin from the head and neck area of an elderly man) could mimic AFX/PDS. The expression of several cytokeratins and epithelial markers argue against this possibility. In conclusion, we describe a case of a rare variant of spindle cell SCC with myxoid stroma that may mimic myxoid sarcomas such as myxofibrosarcoma, myxoid atypical fibroxanthoma, and angiosarcoma. The prominent hemorrhagic changes with focal hemosiderin accentuated its resemblance to angiosarcoma in this instance, and the expression of SMA and CD10 could have misled one to an AFX/PDS diagnosis. This case met five of six criteria of Yang et al.'s1 original diagnostic criteria. As in previously reported cases, the lesion was composed mainly of poorly differentiated squamous spindle cells, was composed of prominent myxoid stroma in more than 50% of the lesion, expressed multiple epithelial markers, and was negative for mesenchymal (albeit for SMA) and melanocytic markers. Further characterization of additional myxoid spindle cell SCC cases is needed to better characterize the biological behavior of this neoplasm and determine if it shares underlying genetics common to spindle SCC or alternatively constitutes a distinct, rare cutaneous carcinoma with prominent myxoid stroma. The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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