Subtyping in Poorly Differentiated Tumors

High-grade penile tumors include basaloid, sarcomatoid, and high-grade usual SCC, each of them presenting distinctive morphological features. Clinically, these tumors are characterized by an aggressive course, with high recurrence and metastatic rates and dismal prognosis.9,10,53 Grossly, basaloid carcinomas tend to present a vertical pattern of growth with an ulcerated surface and have a glans predilection.10,13 Invasion of deep erectile tissues is the rule although some rare superficial cases have been reported.56 Histologically, basaloid carcinoma is characterized by the presence of deeply infiltrative tumor nests composed of a monotonous population of small-to-intermediate-sized cells with basophilic cytoplasm, high nuclear/cytoplasmic ratio, inconspicuous nucleoli, indistinctive boundaries, lack of intercellular bridges, high mitotic rate, and abundant apoptosis, all hallmarks of basaloid differentiation (Fig. 3.13). Nests are usually regular and a surrounding clear space artifact is frequently seen. The presence of abrupt parakeratosis and necrotic debris located in the center of tumor nests is a constant feature. In some occasions a more variegated

Fig. 3.13 Basaloid carcinoma. Deeply infiltrative tumor nests composed of neoplastic cells with scant and basophilic cytoplasm, indistinctive cellular borders, and high mitotic rate. Areas of central necrosis (leftfield) and abrupt parakeratosis (right field) in tumor nests are characteristic

Fig. 3.14 Sarcomatoid carcinoma. (a) Malignant proliferation of spindle cells, with morphological features resembling leiomyosarcoma or fibrosarcoma. (b) Prominent pseudovascular pattern of growth simulating an angiosarcoma

morphology is observed with pleomorphic and fusiform cells, hyperchromatic nuclei, coarser chromatin, and evident nucleoli within more irregular tumor nests. These pleomorphic variants can be confused with high-grade usual SCC (see below). In other occasions an adenoid-like aspect is noted with tumor nests showing a cribriform pattern or the presence of pseudolumina. Differentiating this variant from pseudoglandular SCC can be difficult and it is discussed in the following sections.

Grossly, most sarcomatoid carcinomas may be polypoid and exhibit a vertical pattern of growth with extensive areas of necrosis and hemorrhage. Histologically, the predominant neoplastic population depicts a spindle cell morphology resembling fibrosarcoma, leiomyosarcoma, or even malignant fibrous histiocytoma (Fig. 3.14a).9,10,14,15 Myxosarcoma- and angiosarcoma-like areas may occasionally predominate (Fig. 3.14b).57 Nuclear atypia is overt and mitoses are abundant and often atypical. Evidence of squamous differentiation, with neoplastic nests of an otherwise usual SCC, is found in the majority of cases although it can be very inconspicuous. Conversely, caution should be taken to identify sarcomatoid areas in an otherwise usual SCC. The presence of sarcomatoid differentiation, even if focal, suggests an aggressive biological behavior and should be enough to classify a tumor

Fig. 3.15 High-grade usual SCC. Marked nuclear pleomorphism is evident and tumor presents a predominant solid pattern of growth. Signs of squamous differentiation are usually found (lower left field), although may be focal. Neoplastic cells retain their squamous features with eosinophilic cytoplasm and distinctive cellular borders

as a sarcomatoid carcinoma. The main differential diagnosis is with true penile sarcomas. However, penile sarcomas usually originate in the penile shaft, manifesting as a tumor mass or with priapism or Peyronie's-like signs and symptoms, while sarcomatoid carcinomas preferentially affects the glans. Immunohistochemical stains are helpful in problematic cases and are usually indicated to confirm the diag-nosis.14,15,27,57 Neoplastic cells are positive for p53 and 34PE12 and negative for muscle-specific actin, smooth muscle actin, desmin, and S-100.

High-grade usual SCC can grossly simulate a basaloid or a sarcomatoid carcinoma. Histologically, it is composed of anaplastic cells with nuclear pleomorphism, irregular nuclear membrane, coarse chromatin, prominent nucleolus, and abundant and atypical mitoses (Fig. 3.15). Cytoplasm ranges from scant to ample but usually retains squamous features with an eosinophilic hue, distinctive boundaries, and intercellular bridges. These anaplastic squamous cells can predominate or be very inconspicuous. However, their mere presence is associated with an increased risk for nodal metastasis regardless of the proportion found.58 The vast majority of highgrade usual SCC also harbors areas of low-grade, mainly grade 2 but also grade 1 in some occasions. This heterogeneity is a typical feature of usual SCC in general. Distinction from basaloid and sarcomatoid carcinoma should be straightforward. Nevertheless, as previously stated, the pleomorphic variant of basaloid carcinoma can be confused with a high-grade usual SCC. Clues for differential diagnosis are found in the morphological features of the cytoplasm of neoplastic cells.

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