The diffuse sclerosing variant of PTC is more frequent in female, young patients [1]. It is a PTC variant that diffusely involves one or both thyroid lobes, clinically mimicking Hashimoto thyroiditis [1, 2]. This variant is characterized by dense sclerotic stroma involving nests of solid, squamoid, spindled and papillary arranged cells (Fig. 2.7). The cells express focally thyroglobulin, TTF-1, PAX8 and p63 (Fig. 2.7). Abundant psammoma bodies , lymphocytic infiltration and extensive lymph vessel invasion are also present. Lymph node and lung metastases are frequent and may be difficult to diagnose since they may be thyroglobulin (often) and TTF-1 (more rarely) negative. The disease-free survival rate is lower than that of patients with conventional PTC.

Spindle cell transformation or metaplasia has been so far demonstrated in the context of epithelial benign and malignant conditions [1, 2, 17]. Rare cases of PTC show areas of spindle cell differentiation that may represent more than 80% of the tumour [1, 17]. Microscopically, spindle tumour cells are arranged in bundles, frequently showing nuclear grooves and occasional, less frequent, pseudoinclusions (Fig. 2.10). Follicular structures are usually seen in the periphery of the tumour. The spindle cells are actually epithelial in nature and follicular cell originated, as evidenced by their positivity, sometimes focal, for pan-keratins and thyroglobulin, TTF-1 and PAX8 (Fig. 2.10). The differential diagnosis of this tumour includes reactive processes and a variety of primary thyroid tumours and metastatic neoplasms (see spindle cell tumours in Chap. 6). In contrast to reactive changes occurring post FNAB, true spindle cell foci of PTC are not associated with haemorrhage, new capillary blood vessels or hemosiderin-laden macrophages. Distinguishing features from anaplastic carcinoma include the fact that the PTC spindle cells are bland without mitotic activity, pleomorphism and necrosis. Because spindle cell variant of PTC behaves similarly to PTC lacking such features, it is important to separate this variant of PTC from aggressive spindle cell malignant neoplasms (see Chap. 6).

In rare cases , the stroma of PTC is so abundant and cellular as to resemble nodular fasciitis, fibromatosis and other proliferative myofibroblastic processes [1, 2]. PTC with fasciitis-like stroma, also designated as PTC with fibromatosis-like stroma, is a biphasic tumour composed by a stromal benign component and PTC neoplastic foci [1]. The stromal component may predominate obscuring the presence of PTC foci. The stromal cells are spindled, bland looking and arranged in fascicles in a more or less collagen-rich background. This component, thought to be representative of a myofibroblastic population, expresses nuclear beta-catenin and cytoplasmic smooth muscle actin and does not express cytokeratins nor TTF-1 [18]. The PTC foci disclose the typical nuclear features and the respective immunohistochemical profile. The recognition of this malignant component, with the eventual aid of cytokeratins staining to highlight the epithelial cells, will allow the differential diagnosis with other stromal-rich lesions of the thyroid, namely, end-stage/fibrous variant of Hashimoto thyroiditis , IgG4-associated/Riedel thyroiditis , multifocal fibrosing thyroiditis and solitary fibrous tumour (see Chap. 6). The distinction between PTC with fasciitis-like stroma and paucicellular variant of anaplastic carcinoma is not difficult since the latter presents as (very) large tumour with atypical, often bizarre, cells throughout its extension (see Chap. 6). The overall and recurrence-free survival for patients with PTC with fasciitis-like stroma/fibromatosis may be lower than for other PTC variants.

The case illustrated in Fig. 2.11 is a PTC with fasciitis-like stroma diagnosed in a 68-year-old female patient submitted to total thyroidectomy due to nodular adenomatous goitre. The macroscopic examination disclosed a poorly circumscribed nodule in the isthmus with microscopic predominance of a cellular bland stroma component with occasional lymphoid aggregates and scarce PTC foci.

The angiomatoid variant of PTC that develops in the context of Hashimoto thyroiditis can be confused with a vascular tumour if the characteristic nuclear features of PTC in the cells lining the vascular-like spaces are not searched at high magnification [19]. Such vascular-like spaces can display a prominent anastomosing pattern; are lined by TTF-1, PAX-8 and thyroglobulin positive; are cuboidal to flat cells; and are surrounded by a collagenous to myxoid stroma.