Portal de Periódicos da CAPES

Diffuse and Strong TTF-1 Positivity in a Combined Merkel Cell Carcinoma

2019; Lippincott Williams & Wilkins; Volume: 42; Issue: 3 Linguagem: Inglês

10.1097/dad.0000000000001432

1533-0311

Aaron Hughes, Matthew French, A. Ah-Weng, Manuraj Singh,

Tumors and Oncological Cases

To the Editor: We describe a case of a combined Merkel cell carcinoma (MCC) associated with Bowen disease and squamous cell carcinoma that demonstrated strong and significant positivity for TTF-1 by immunohistochemistry. In addition, the tumor was CK7 and CK20 negative while demonstrating positivity for the keratin markers AE1/3, MNF116, and CK5 with areas of dot-like positivity. A 100-year-old lady presented with a fast growing hemorrhagic nodule measuring 20 × 20 mm at the site of a venous leg ulcer on the left inner calf. The ulcer had been longstanding for 30 years. She had a history of congestive cardiac failure, atrial fibrillation, hypertension, subclavian artery embolism, and osteoarthritis. The patient had no history of lung cancer or symptoms to suggest this. Examination revealed an ulcerated and pedunculated nodule over the left inner calf. There was no local or regional lymphadenopathy. An incisional biopsy showed an extensively ulcerated small-blue-round-cell tumor focally arising from the clear cell and follicular Bowen disease (squamous cell carcinoma in situ). Despite significant transverse sectioning, there were also features suggestive of squamous cell carcinoma. There was clear transition of the atypical squamous epithelium to a small-blue-round-cell tumor that constituted the majority of the tumor. These tumor cells demonstrated nuclear molding with finely dispersed chromatin, indistinct nucleoli, and scant cytoplasm. There were also spindle cell areas within the MCC component giving rise to a focally sarcomatoid appearance. Frequent mitoses and apoptotic cells were identified. The atypical squamous component of the tumor also demonstrated focal areas of clear cell change, keratinization, and acantholysis (Figs. 1A–D).FIGURE 1.: A, Lower power image showing a focally polypoid and intradermal small-blue-round-cell tumor. B, The overlying epidermis demonstrated Bowen disease in close association with the MCC component. Note small areas of squamous differentiation within the central island of the MCC component. C and D, Images showing clear transition of the MCC from follicular Bowen disease demonstrating areas of clear cell change [(D) represents high-power image of the area in black box in (C)]. E, Tumor cells were diffusely positive for CK5. Inset highlights areas of perinuclear dot-like positivity. F, Tumor cells were negative for CK20. G, Very focal positivity for neurofilament was observed in the MCC component of the tumor and also less strongly within the squamous component (left half of the image). H, TTF-1 was strongly positive within the tumor. Inset shows that staining was also positive in the squamous part of the tumor (right half of the image) but was weaker than the MCC component [magnifications: A, E, F, and H ×40; C and H (inset) ×100; B, D, E (inset), and G ×200].Immunohistochemistry showed that most tumor cells were diffusely and strongly positive for MNF116 and CK5, with a focal perinuclear dot-like pattern. CK7 and CK20 were both negative. Most cells were positive for TTF-1 (clone SP141 from Ventana) including the atypical squamous component. However, the staining was weaker and more focal in the squamoid component. EMA and p63 both showed strong positivity in the squamoid component with weaker positivity in the MCC component including the spindle cell areas. Ber-EP4 showed the reverse pattern to EMA and p63. Neurofilament was very focally positive in both the squamous and MCC components, although the staining was more noticeable in the latter component (Figs. 1E–F). Synaptophysin and CD56 were weakly but diffusely positive in the MCC component only, whereas chromogranin, TdT, and PAX-5 were all negative. Most tumor cells were strongly positive for p16 and p53. A PAS and DPAS stain confirmed the presence of glycogen within the clear cell/follicular Bowen disease areas. The patient declined further investigations and therefore did not have a computed tomography of the chest to exclude a primary lung malignancy. As there were no clinical features to suggest underlying metastatic lung cancer and this was a solitary lesion, a diagnosis of combined MCC with an aberrant phenotype was made. The patient declined further intervention, and complete excision was not performed. MCC with mixed morphology is commonly referred to as combined MCC or occasionally MCC with divergent differentiation.1 It is now recognized as a distinct subset within MCC. It represents the association of pure MCC with either Bowen disease or nonmelanoma skin cancers such as squamous cell carcinoma and porocarcinoma. This subset tends to occur in a slightly older population than pure MCC. In addition, the underlying pathogenesis appears to be different, with these lesions typically being Merkel cell polyomavirus negative and harboring UV signature mutations in p53 and/or the retinoblastoma gene.2–4 Unusual phenotypes have been described in MCC including CK20 negative and CK7 positive tumors.5 There have also been occasional cases of double, CK20 and CK7, negative tumors.6 However, the combination of a double negative tumor with significant and strong positivity for TTF-1 has not been previously described in the literature. Two cases have been reported of combined MCC with associated squamous cell carcinoma and Bowen disease, which were TTF-1 positive and CK20 negative.7,8 CK7 status was not reported. Other cases of combined MCC have been reported with TTF-1 positivity, but these were CK20 positive.9 Our case showed clear histological transition from the squamous to the MCC component. This has been demonstrated previously in a case series by Martin et al,10 which showed transition in all their 15 cases. Before this, it was felt not to be typical of combined MCC, with other reported cases showing 2 distinct histological lesions.7,8 Our case also showed TTF-1 positivity within the atypical squamous component and the MCC component. There was stronger and more diffuse staining in the MCC component with a clear gradient and transition of staining between the 2 components. Martin et al showed focal positivity of TTF-1 in 4 of their 15 cases, but the staining was reported as being restricted to the MCC component. Czapiewski et al showed positive TTF-1 staining in 4 of their 5 cases, 2 of which showed positive staining in the atypical squamous component. One of these cases showed positive staining in the MCC component and intermediate/transition area, and the other case showed negative staining in the MCC component and positive staining restricted to the squamous cell carcinoma area.9 The pattern of TTF-1 staining in our case suggests that the MCC is arising from the area of Bowen disease and is not a collision tumor. This case highlights that MCC, especially combined variants, may have unusual phenotypes by immunohistochemistry and that strong and diffuse positivity for TTF-1 does not exclude a primary skin tumor.