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Pathological factors, behavior, and histological prognostic risk groups in subtypes of penile squamous cell carcinomas (SCC)
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Available online at www.sciencedirect.com
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Pathological factors, behavior, and histological prognostic risk groups in subtypes of penile squamous cell carcinomas (SCC) Diego F. Sanchez, MDa,b, Fernando Soares, MDc, Isabel Alvarado-Cabrero, MDd, Sofía Cañete, MDa, María José Fernández-Nestosa, PhDe, Ingrid M. Rodríguez, MDa,b, José Barreto, MDa,b, Antonio L. Cubilla, MDa,b,n a
Instituto de Patología e Investigación, Asunción, Paraguay Facultad de Ciencias Médicas, UNA, Asunción, Paraguay c Department of Anatomic Pathology, AC Camargo Cancer Center, São Paulo, Brazil d Hospital de Oncología, Centro Médico Nacional, Mexico City, México e Facultad Politécnica, UNA, Asunción, Paraguay b
article info
abstract
Keywords:
Pathologists’ contribution in the determination of prognosis in invasive penile squamous cell
Penile neoplasm
carcinoma is crucial. The TNM staging system is based on the identification of pathological
Penile carcinoma
data. There are multiple pathologically based factors believed to be important in relation to
Squamous cell carcinoma
the rates of regional inguinal lymph node and specific cancer death. Among them are tumor
Prognostic risk groups
site, size, histological subtypes, thickness or anatomical level of invasion, tumor front, and
Penile carcinoma subtypes
vascular or perineural invasion. The identification of these factors determines the prognostic profile of patients with penile cancer. These factors are used for the construction of pathological risk groups, prognostic index, or nomograms and are helpful in the prediction of nodal metastasis or patients’ outcome. This review will describe in detail the influential pathological prognostic factors present in each tumor category emphasizing the impact of especial histological subtypes in tumor spread and final outcome. There are few studies comprehensibly addressing the relation of tumor morphology and prognosis according to histological types. We are summarizing findings of prognostic factors in 3 different series for the most common types and individual series in more recently described tumor entities. We had found a broad correlation of special subtypes of penile squamous cell carcinomas that made regional nodal status and final outcome predictable according to histological features of the tumor. These findings permitted grouping special subtypes of squamous cell carcinomas into prognosis risk groups of low, intermediate, and high. In the first category of excellent prognoses are the usual grade I, verrucous, papillary NOS, pseudohyperplastic and cuniculatum carcinomas. In the second group, there are the grade II usual, mixed and warty carcinomas. The third category of tumors, with the worst prognosis is composed of high grade usual, basaloid, warty–basaloid, papillary basaloid, and sarcomatoid carcinomas. We found that subtyping of penile squamous cell carcinoma is important to determine risk for nodal metastasis and patients’ survival. & 2015 Elsevier Inc. All rights reserved.
n
Corresponding autor at: Facultad Politécnica, UNA, Brizuela 325, Asuncion, Paraguay. E-mail address: [email protected] (A.L. Cubilla).
http://dx.doi.org/10.1053/j.semdp.2014.12.017 0740-2570/& 2015 Elsevier Inc. All rights reserved.
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General features More than half of penile invasive carcinomas have features of the usual or conventional squamous cell carcinomas (SCC) similar to other sites, especially vulva and head and neck.1–5 However, a diversity of clinicopathological entities were reported, some quite unusual. The distribution of the various subtypes of SCC in 3 series is shown in Table 1. Pathologists’ contribution in the determination of prognosis in treated invasive penile squamous cell carcinoma is crucial. The TNM staging system, of worldwide use, is based on the identification of pathological data. There are multiple pathologically based factors that are believed to be important in relation to the rates of regional inguinal lymph node and specific cancer death. Among them are tumor site, size, anatomical level of invasion (LP ¼ lamina propria, CS ¼ corpus spongiosum, and CC ¼ corpora cavernosa) (Figs. 1 and 2), histological subtypes, histological grade (I ¼ well differentiated, II ¼ moderately differentiated, and III ¼ poorly differentiated or anaplastic) (Figs. 3 and 4), thickness, tumor front, vascular (VI) (Fig. 5), or perineural invasion (PNI) (Fig. 6).6–13 The distribution of the factors and their relation to nodal regional metastasis and outcome is presented in Table 2. These factors are also used for the construction of pathological risk groups, prognostic index, or nomograms, which are helpful in the prediction of nodal metastasis or patient outcomes.8,14 This review will describe in detail the influential prognostic factors present in each tumor category, emphasizing the impact of especial histological subtypes in tumor spread and final outcome. There are few studies addressing comprehensibly the relation of tumor morphology and prognosis. The data presented are from 3 such studies, one of them is unpublished.12,15 Data from other series related to especial subtypes are also reviewed (warty–basaloid, warty, papillary basaloid, clear cell, and lymphoepithelioma-like). The increased variation in tumor types is related to the inclusion of newly described entities.
Fig. 1 – Anatomical levels of glans. From surface to deep tissues, there are the epithelium (E), lamina propria (LP), corpus spongiosum (CS), and corpus cavernosum (CC), which includes the tunica albuginea (TA).
Subtypes of squamous cell carcinoma, prognostic factors, and clinical behavior Usual Biologic behavior of usual squamous cell carcinoma is related to pathological factors like size, histological grade, depth of infiltration, and vascular and perineural invasion. The average tumor size is about 4.5 cm in high-risk areas, while in low-incidence regions, the average is 2.0 cm, reflecting the variability in clinical stage in the 2 populations.16 The tumors usually compromise the lamina propria, dartos, corpus spongiosum (45%), or corpora cavernosa (35%).17 The typical case is a grade II carcinoma invading up to the corpus spongiosum. Tumors limited to the lamina propria are uncommon. Vascular and perineural invasion are observed in a third of the cases.12 Recurrences in the surgical stump or groin are
Table 1 – Subtypes of penile squamous cell carcinoma.
Verrucous Papillary NOS Pseudohyperplastic Cuniculatum Usual Warty Basaloid Warty–Basaloid Papillary Basaloid Sarcomatoid Pseudoglandular Adenosquamous Mixed
MSKCC series 61 cases (%)15
Brazilian series 333 cases (%)12
Mexican series 154 cases (%) (unpublished)
2 (3) 9 (15) – – 36 (59) 6 (10) 6 (10) – – 2 (3) – – –
24 (7) 17 (5) – – 215 (65) 23 (7) 14 (4) – – 4 (1) – 4 (1) 32 (10)
4 (3) 3 (2) 4 (3) 1 (1) 69 (45) 13 (8) 8 (5) 6 (4) 5 (3) 10 (6) 1 (1) – 30 (19)
Fig. 2 – Level of invasion. Usual squamous cell carcinoma infiltrating the corpus spongiosum.
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Fig. 3 – Histological grade. Well-differentiated grade I squamous cell carcinoma.
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Fig. 6 – Perineural invasion. Moderately differentiated squamous cell carcinoma invading the perineural space. observed in about a third of the cases. Inguinal lymph node metastases develop in 25–40% of patients. The mortality rate of patients with usual squamous cell carcinoma ranges from 20% to 38% with a 10-year survival rate of 75–80%12,15 (Table 3).
Verrucous
Fig. 4 – Histological grade. Poorly differentiated grade III squamous cell carcinoma.
Verrucous carcinomas, especially in endemic areas for penile cancer, have a long-standing history of several years before a diagnosis is made. The larger the tumor and the evolution, the higher chances of “malignant transformation,” defined as the presence of overt invasive squamous cell carcinoma within an otherwise typical or pure verrucous carcinoma. Once a verrucous carcinoma is properly diagnosed, there is no metastatic potential and the cure rate is 100%. Several studies were reported with negative inguinal nodes.12,15,18–20 In patients with insufficient surgical excision, recurrent rates are high, about 40%. Recurrent tumors may be of the classical verrucous histology and re-excision may suffice, but in cases where a higher grade histology or even sarcomatoid changes are found, aggressive treatment is required.12,21 For these reasons, despite their low malignant features, verrucous carcinomas need adequate initial surgery with negative resection margins. Pathologists should be careful when interpreting verrucoid “hyperplastic” thickening of tissues adjacent to verrucous carcinomas, because when present at surgical margins, they may be related to tumor recurrence (Table 4).
Papillary NOS
Fig. 5 – Vascular invasion. Multiple superficial lymphatics vessels with tumor emboli from a case with basaloid carcinoma of the glans. (Courtesy of Dr. Alberto Ayala, Methodist Hospital Houston, TX.)
Papillary carcinomas are infrequent low-grade penile verruciform tumors with a good prognosis despite their large size, moderate–to-deep invasion, and wide extension into penile anatomical compartments (Table 5). They are typically well to moderately differentiated, grades I or II, with definite invasion of corpora, most commonly, the corpus spongiosum. Vascular and perineural invasion are unusual and observed in up to 12% of the cases.12,22 Recurrence is seen in about
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Table 2 – Pathological factors, nodal metastasis, and outcome. MSKCC series 61 cases
Brazilian series 333 cases
Mexican series 154 cases
Age
58.4
55
61.7
Site Glans (%) Other (%)
27 (44) 34 (56)
– –
47 (31) 107 (69)
Size (cm)
–
4.8
4.4
Thickness (mm)
10.3
7.4
14.5
Level LP (%) CS (%) CC (%)
4 (7) 38 (62) 19 (31)
11 (3) 149 (45) 173 (52)
21 (14) 65 (42) 68 (44)
Grade I (%) II (%) III (%)
13 (21) 25 (41) 23 (38)
90 (27) 109 (33) 134 (40)
19 (12) 53 (34) 82 (53)
PNI (%)
–
95 (29)
58 (38)
VI (%)
–
83 (26)
91 (59)
Nodal metastasis (%), n
20 (49), 41
81 (53), 153
52 (41), 126
Mortality rate (%)
18 (30)
52 (16)
53 (34)
Table 3 – Usual squamous cell carcinoma.
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Table 4 – Verrucous carcinoma. MSKCC series 2 cases
Brazilian series 24 cases
Mexican series 4 cases
Age
42
58
67.5
Site Glans (%) Other (%)
1 (50) 1 (50)
– –
3 (75) 1 (25)
Size (cm)
2.9
4.8
2.9
Thickness (mm)
4.5
5.5
5.3
Level LP (%) CS (%) CC (%)
0 2 (100) 0
4 (17) 14 (58) 6 (25)
3 (75) 1 (25) 0
Grade I (%) II (%) III (%)
2 (100) 0 0
24 (100) 0 0
4 (100) 0 0
PNI (%)
0
1 (4)
0
VI (%)
0
0
0
Nodal metastasis (%)
No dissection
0
0
Mortality rate (%)
0
0
0
Table 5 – Papillary carcinoma, not otherwise specified.
MSKCC series 36 cases
Brazilian series 215 cases
Mexican series 69 cases
MSKCC series 9 cases
Brazilian series 17 cases
Mexican series 3 cases
Age
60
54
62
Age
63
53
62
Site Glans (%) Other (%)
14 (39) 22 (61)
– –
26 (38) 43 (62)
Site Glans (%) Other (%)
4 (44) 5 (56)
– –
1 (33) 2 (67)
Size (cm)
4.1
4.7
4.4
Size (cm)
4.5
6.3
4.6
Thickness (mm)
10.6
7.3
14.8
Thickness (mm)
7.4
6.5
7.7
Level LP (%) CS (%) CC (%)
1 (3) 26 (72) 9 (25)
6 (3) 96 (45) 113 (52)
8 (12) 28 (40) 33 (48)
Level LP (%) CS (%) CC (%)
2 (22) 5 (56) 2 (22)
1 (4) 10 (44) 12 (52)
2 (67) 1 (33) 0
Grade I (%) II (%) III (%)
4 (11) 17 (47) 15 (42)
34 (16) 80 (37) 101 (47)
8 (12) 22 (32) 39 (56)
Grade I (%) II (%) III (%)
6 (67) 3 (33) 0
6 (26) 12 (52) 5 (22)
0 2 (100) 0
PNI (%)
–
74 (35)
26 (38)
PNI (%)
–
2 (12)
1 (33)
VI (%)
–
59 (28)
44 (64)
VI (%)
–
2 (12)
1 (33)
Nodal metastasis (%)
14 (54), n ¼ 26
60 (28)
28 (47), n ¼ 60
Nodal metastasis (%)
0
2 (12)
0
Mortality rate (%)
13 (36)
42 (20)
27 (41)
Mortality rate (%)
0
1 (6)
0
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10–12% of the cases. Inguinal metastasis rate is low, from 0% to 25% according to different series.15,22 Mortality is low, ranging from 0% to 6%.12,15
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Table 7 – Carcinoma cuniculatum. Paraguayan series 7 cases25
Mexican series 1 case
Canadian case report 1 case26
Age
77
98
55
Site Glans (%) Other (%)
0 7 (100)
1 –
– 1
Size (cm)
6.3
4.5
4
Thickness (mm)
32
11
Level LP (%) CS (%) CC (%)
0 1 (14) 6 (86)
– 1 –
Grade I (%) II (%) III (%)
1 (14) 6 (86) 0
– 1 –
1 – –
PNI (%)
0
1
–
VI (%)
0
1
–
Cuniculatum
Nodal metastasis (%)
0, n ¼ 4
0
0
They are unusual large tumors of low-grade histology and a paradoxical deep labyrinthine penetration into erectile tissues especially corpora cavernosa (Table 7). Tumor front is, however, broad-based like verrucous carcinoma, and this pattern of growth likewise appears not to affect outcome adversely. None of the few reported cases disclosed nodal metastasis and all patients are alive.23,25,26
Mortality rate (%)
0
0
0
Pseudohyperplastic These unusual highly differentiated tumors are confused with hyperplasia especially on small biopsies. However, they are bona fide invasive carcinomas with low-grade histology. Invasion is usually superficial, rarely beyond lamina propria or dartos. No perineural or vascular invasion is present. Their multicentricity in a background of coexisting lichen sclerosus and differentiated Penile Intraepithelial Neoplasia (PeIN), with a usual subclinical component of the lesion, makes the complete excision of the tumor important so as to prevent recurrences. The prognosis is excellent, with no inguinal nodal metastases. Recurrence in the glans after a circumcision has been described in one of 10 cases.23,24 There is no reported patient death due to this tumor (Table 6).
Table 6 – Pseudohyperplastic carcinoma. Paraguayan series 10 cases 20 tumors 24
Mexican series 4 cases
Age
69
65.5
Site Glans (%) Other (%)
– 10 (100)
1 (25) 3 (75)
Size (cm)
2
2.2
Thickness (mm)
2.9
7.5
Level LP (%) CS (%) CC (%)
15 (75) 5 (25) 0
1 (25) 2 (50) 1 (25)
Grade I (%) II (%) III (%)
20 (100) – –
3 (75) 1 (25) 0
PNI (%)
–
0
VI (%)
–
0
Nodal metastasis (%)
0 of 5
0
Mortality rate (%)
0 of 6
0
– 1 –
Warty Warty carcinomas are bulky slow-growing condylomatous tumors that are histologically and cytologically malignant, unlike their benign counterparts, the common and the giant condylomas (Table 8). A moderate differentiation (grade II) and invasion of the corpus spongiosum is the typical presentation, with a low but definite risk for nodal metastasis. Invasion of the corpora cavernosa is not unusual. Superficial invasion restricted to the lamina propria (2–3 mm) is infrequent. Non-invasive cases with a broad separation between tumor and stroma (pushing borders) are occasionally encountered. High-grade differentiated areas in the tumor may be observed. Vascular and perineural invasion are uncommon (9% and 4%, respectively).12 Local recurrence after penectomy occurs in 10% of warty carcinomas and inguinal lymph node metastasis in about 17–25% cases.27 This is one of the HPVrelated tumors with a relatively good prognosis that despite deep tumor invasion rarely disseminates, and the mortality rate is low (0–10%).12,15,28,29
Basaloid More than half of basaloid carcinoma patients present with inguinal adenopathy due to metastatic cancer. The primary tumor measures 2–5 cm and is usually deeply invasive into both erectiles tissues. These tumors are, by definition, of high grade; perineural and especially vascular invasion is particularly frequent in lamina propria around invasive tumor. Regional metastasis has been reported from 50% to 100% of the cases.12,15,18,30 If partial penectomy is the surgical
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Table 8 – Warty (condylomatous) carcinoma. MSKCC series 6 cases
Brazilian series 23 cases
Mexican series 13 cases
Age
48
59
57
Site Glans (%) Other (%)
1 (17) 5 (83)
– –
4 (31) 9 (69)
Size (cm)
3.6
6.3
3.3
Thickness (mm)
6.3
6.5
11.2
Level LP (%) CS (%) CC (%)
1 (17) 4 (66) 1 (17)
1 (4) 10 (44) 12 (52)
5 (39) 6 (46) 2 (15)
Grade I (%) II (%) III (%)
1 (17) 4 (66) 1 (17)
6 (26) 12 (52) 5 (22)
0 11 (85) 2 (15)
PNI (%)
–
1 (4)
1 (8)
VI (%)
–
2 (9)
5 (38)
Nodal metastasis (%)
1 (25), n ¼ 4
4 (17)
3 (23)
Mortality rate (%)
0
2 (9)
1 (10), n ¼ 10
operation, local recurrence is high (36%).12,21 Basaloid carcinomas disseminate widely, and mortality ranges from 21% to 88% according to different series (Table 9). The difference may
Table 9 – Basaloid carcinoma.
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be due to the stage of the tumor at presentation or more likely by the completeness and adequacy of the initial surgical treatment.12,15,30 The disparity in the high rate of regional metastasis and the much lower rate of mortality is related to the response of the tumor to various treatment modalities as well as the probable biologically better outcome in proven HPV-positive tumors.31,32
Warty–basaloid Warty–basaloid carcinomas are large high-grade tumors with frequent invasion of erectile tissues. Vascular and perineural invasion is frequent. Inguinal lymph node metastatic rate is midway between warty and basaloid subtypes in about half of cases and is related to the proportions of the basaloid component. Systemic dissemination as well as cancer-related death is seen in about a third to half of cases (Table 10).23,33,34
Papillary-basaloid Unusual exophytic or exo-endophytic tumor in older males considered to be a variant of classical basaloid carcinoma. If exophytic or superficially exo-endophytic, the prognosis is excellent. However, if the endophytic, or invasive component of the tumor predominates, the prognosis is dismal. The difference in pathological stage at presentation explains this difference. In 2 such series, we found a variation in nodal metastasis from 17% to 60% and in mortality of 0% to 80% (Table 11).35
Table 10 – Warty–Basaloid carcinoma.
MSKCC series 6 cases
Brazilian series 14 cases
Mexican series 8 cases
Age
54
57
66
Site Glans (%) Other (%)
5 (83) 1 (17)
– –
Size (cm)
4.5
Thickness (mm)
Multiinstitutional series 45 cases33
Mexican series 6 cases
Age
62
53.3
0 8 (100)
Site Glans (%) Other (%)
9 (21) 36 (79)
2 (33) 4 (67)
3
5.8
Size (cm)
5.5
4.8
18
10.9
21.1
Thickness (mm)
12.5
18.3
Level LP (%) CS (%) CC (%)
0 1 (17) 5 (83)
0 3 (21) 11(79)
0 0 8 (100)
Level LP (%) CS (%) CC (%)
3 (6) 21 (47) 21 (47)
0 3 (50) 3 (50)
Grade I (%) II (%) III (%)
– 1 (17) 5 (83)
– – 14 (100)
– – 8 (100)
Grade I (%) II (%) III (%)
– 5 (11) 40 (89)
0 2 (33) 4 (67)
PNI (%)
–
6 (43)
7 (88)
PNI (%)
10 (25)
3 (50)
VI (%)
–
9 (64)
8 (100)
VI (%)
17 (43)
4 (67)
Nodal metastasis (%)
3 (60), n ¼ 5
7 (50)
5 (100), n ¼ 5
Nodal metastasis (%)
11 (52), n ¼ 21
2 (40), n ¼ 5
Mortality rate (%)
4 (67)
3 (21)
7 (88)
Mortality rate (%)
7 (33), n ¼ 21
3 (50)
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Table 11 – Papillary basaloid carcinoma.
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Table 12 – Sarcomatoid carcinoma.
International group 12 cases35
Mexican series 5 cases (%)
79
64
Site Glans (%) Other (%)
7 (58) 5 (42)
2 (40) 3 (60)
Size (cm)
3
6.4
Thickness (mm)
7
19.2
Level LP (%) CS (%) CC (%)
7 (58) 5 (42) 0
0 1 (20) 4 (80)
Grade I (%) II (%) III (%)
– – 12 (100)
– – 5 (100)
PNI (%)
0
3 (60)
VI (%)
2
5 (100)
Nodal metastasis (%)
2 (17)
3 (60)
Mortality rate (%)
0
4 (80%)
Sarcomatoid It is the most aggressive of all penile carcinomas.34 They are rapidly growing polypoid necrotic and hemorrhagic masses compromising all epithelial compartments (Table 12). There is deep invasion into the corpora cavernosa of a high-grade neoplasm, with frequent positivity of surgical margins in patients with partial penectomies. Vascular and perineural invasion are common. Most patients have inguinal metastasis at the time of diagnosis and many have distant dissemination by that time.12,36,37 Mortality is high (50–90%).21
Pseudoglandular It is a rare albeit aggressive penile tumor (Table 13). Typical presentation is that of a high-grade carcinoma with deep invasion of erectile tissues, especially the corpora cavernosa. These features are present in two-thirds of the few reported cases. Vascular and perineural invasion are frequent. Inguinal metastases are noted in at least 75% of the cases and mortality is about 29%.23,39–41
Adenosquamous Due to the rarity of this tumor, there is limited experience with its biological behavior (Table 14). Recurrences and nodal metastasis have been reported.12,42,43
Clear cell carcinoma These are locally aggressive carcinomas involving the glans and foreskin. Adverse factors common in these rare neoplasms are deep invasion of the corpora cavernosa, high
MSKCC series 2 cases
Brazilian series 4 cases
Mexican series 10 cases
Paraguayan series 15 cases38
Age
42
54
65
59
Site Glans (%) Other (%)
2 (100) 0
– –
0 10 (100)
– –
Size (cm)
3.3
5
6.2
5
Thickness (mm)
12.5
10.3
21.1
–
Level LP (%) CS (%) CC (%)
0 2 (100) 0
0 0 4 (100)
0 0 10 (100)
0 3 (20) 12 (80)
Grade I (%) II (%) III (%)
– 2 (100)
– – 4 (100)
– – 10 (100)
– – 15 (100)
PNI (%)
–
2 (50)
9 (90)
VI (%)
–
1 (25)
10 (100)
8 (53)
Nodal metastasis (%)
2 (100)
3 (75)
4 (67), n¼6
8 (89) of 9
Mortality rate (%)
1 (50)
3 (75)
9 (90)
2 (40) of 5
Table 13 – Pseudoglandular SCC. Brazilian series 7 cases40
Mexican series 1 cases
Age
54
45
Site Glans (%) Other (%)
2 (29) 5 (71)
– 1 (100)
Size (cm)
4.6
6.5
Thickness (mm)
–
18
Level LP (%) CS (%) CC (%)
0 3 (43) 4 (57)
– – 1 (100)
Grade I (%) II (%) III (%)
0 1 (14) 6 (86)
– – 1 (100)
PNI (%)
2 (29)
0
VI (%) Nodal metastasis (%)
4 (57) 3 (75), n ¼ 4
1 (100) 1 (100)
Mortality rate (%)
2 (29)
0
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Table 14 – Pathological factors, nodal metastasis and outcome in adenosquamous SCC.
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Table 15 – Clear cell SCC. Austrian series 5 cases44
Paraguayan series 3 cases (unpublished)
Age
49.6
80
– –
Site Glans (%) Other (%)
5 (100)
3 (100) 0
7.6
7.5
Size (cm)
3.5
6.1
Thickness (mm)
10.3
13
Thickness (mm)
–
Level LP (%) CS (%) CC (%)
0 2 (67) 1 (33)
0 1 (25) 3 (75)
Level LP (%) CS (%) CC (%)
– – –
0 0 3 (100)
Grade I (%) II (%) III (%)
0 2 (67) 1 (33)
1 (25) 0 3 (75)
Grade I (%) II (%) III (%)
– – 5 (100)
0 0 3 (100)
PNI (%)
3 (100)
2 (50)
PNI (%)
–
3 (100)
VI (%)
–
3 (75)
Nodal metastasis (%)
0 of 1
2 (50)
LVI (%) Nodal metastasis (%)
5 (100) 5 (100)
3 (100) 1 of 1
Mortality rate (%)
1 (20)
1 (33)
Mortality rate (%)
0
Paraguayan series 3 cases43
Brazilian series 4 cases
Age
61
63
Site Glans (%) Other (%)
3 (100)
Size (cm)
0
histological grade, extensive geographical necrosis, and frequent vascular and perineural invasion. Regional metastases are present in the majority of the cases. Systemic extension was seen in 40% and mortality was found in 20% of the cases (Table 15).44
Lymphoepithelioma-like In the 2 cases reported,45 these unusual tumors invaded the corpora cavernosa, had a high-grade histology with syncytial appearance, perineural and vascular invasion, and frequent nodal metastasis. Cancer-related mortality was not seen in these cases.
However, a pathologist is confronted in clinical practice with individual tumors. Their immediate recognition, categorization, and the knowledge of its biological behavior are important issues for patients’ management and communication with treating physicians and nowadays with patients themselves.
Table 16 – Mixed carcinoma. Brazilian series 32 cases
Mexican series 30 cases
Age
56
60
Site Glans (%) Other (%)
– –
9 (30) 21 (70)
Size (cm)
4.1
4.1
Thickness (mm)
8.6
12.6
Level LP (%) CS (%) CC (%)
0 14 (44) 18 (56)
2 (7) 22 (73) 6 (20)
Grade I (%) II (%) III (%)
13 (41) 12 (37) 7 (22)
4 (14) 13 (43) 13 (43)
PNI (%)
7 (22)
7 (23)
VI (%)
7 (22)
12 (40)
Nodal metastasis (%)
3 (9)
11 (39), n ¼ 28
Mortality rate (%)
1 (3)
2 (7)
Mixed The typical presentation is similar to that of the usual SCC, with a well to moderately differentiated carcinoma invading up to the corpus spongiosum, with a low rate of nodal metastasis (about 9%). Perineural invasion is present in about 20% of the cases (Table 16). Vascular invasion is more common (22–40%). Recurrences have been reported in 19% of the cases. Mortality rate is low (about 3–7%).8,21
Prognostic risk groups There is a correlation between histological subtypes of squamous cell carcinomas and rates of regional or systemic dissemination and patients’ outcome, although on multivariate analysis, histological type appears to be less important than other pathologic factors such as level of invasion, perineural invasion, histological grade, and vascular invasion.9,11,14,18,46
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Table 17 – Histological risk groups. Low risk group
Intermediate risk group
High risk group
Usual, grade I Verrucous
Usual, grade II Warty (condylomatous)
Usual, grade III Basaloid
Papillary NOS Pseudohyperplastic
Warty–basaloid Papillary basaloid Sarcomatoid
Mixed
Cuniculatum
Evaluating data from several studies, we found a striking predictable correlation of tumor types and incidence of nodal metastasis and survival. In a recent study, we classified these special neoplasms according to their behavior into 3 groups with different risks for regional tumor spread and patients’ mortality: low, intermediate and high (Table 17). In the low-risk group were the following variants of penile squamous cell carcinoma: usual grade I, verrucous, papillary, pseudohyperplastic, and cuniculatum carcinomas. These tumors were grossly large, replaced more than one anatomical compartment but histologically were of low grade, noninvasive, or superficially invasive (verrucous, cuniculatum, and pseudohyperplastic carcinomas) or deeply invasive like the papillary carcinomas. Despite these features, the outcome of these patients was excellent, with very low mortality.
Table 18 – Pathological features according to histological risk groups. Histological risk group
Low, n ¼ 31
Intermediate, n ¼ 48
High, n ¼ 47
p Value
Age Site Glans (%) Multiple compartments (%)
62.8 16 (52) 15 (48)
60.3 20 (42) 28 (48)
64.5 8 (17) 39 (83)
o0.2477 o0.004
Size (cm)
3.16
3.35
5.25
o0.0001
Thickness (mm)
8.4
12
18
o0.0001
Level LP; n ¼ 19 (%) CS; n ¼ 59 (%) CC; n ¼ 48 (%)
12 (63) 15 (26) 4 (8)
6 (32) 35 (59) 7 (15)
1 (5) 9 (15) 37 (77)
o0.0005
Grade I; n ¼ 18 (%) II; n ¼ 49 (%) III; n ¼ 59 (%)
17 (94) 12 (25) 2 (4)
1 (6) 35 (71) 12 (20)
0 2 (4) 45 (76)
o0.0005
PNI (%)
4 (13)
6 (13)
33 (70)
o0.0005
VI (%)
5 (16)
18 (38)
43 (91)
o0.0005
Metastasis density
2%
4%
18%
o0.0001
Systemic metastasis (%)
3 (10)
10 (22)
36 (80)
o0.0005
TNM stage Z2 (%)
19 (61)
42 (88)
47 (100)
o0.0005
Fig. 7 – Kaplan–Meier survival curve (p o 0.00005).
Tumors in the high-risk category were the usual poorly differentiated grade III, basaloid, warty–basaloid, papillary basaloid, and sarcomatoid carcinomas. The majority of these neoplasms were large and locally destructive with high-grade histology, perineural and vascular invasion, and deep invasion of corpora cavernosa, resulting in frequent nodal metastasis and a poor survival (Table 18). There was a category of intermediate-risk tumors, comprising about one-half of penile carcinomas. To this group belonged the usual moderately differentiated grade II, the warty and the mixed carcinomas. Typically these neoplasms were grade II and invaded up to penile corpus spongiosum, with low incidence of perineural or vascular invasion. Regional metastasis and outcome were intermediate or low, more like the low-risk tumors and quite different from highrisk tumors, as can be noted in the Kaplan–Meier survival curve (Fig. 7).
re fe r en ces
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26. Lau P, Li Chang HH, Gomez JA, et al. A rare case of carcinoma cuniculatum of the penis in a 55-year-old. Can Urol Assoc J. 2010;4(5):E129–E132. 27. Bezerra AL, Lopes A, Landman G, et al. Clinicopathologic features and human papillomavirus dna prevalence of warty and squamous cell carcinoma of the penis. Am J Surg Pathol. 2001;25(5):673–678. 28. Cubilla AL, Velazques EF, Reuter VE, et al. Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classification of ’verruciform’ penile tumors. Am J Surg Pathol. 2000;24(4):505–512. 29. Manipadam MT, Bhagat SK, Gopalakrishnan G, et al. Warty carcinoma of the penis: a clinicopathological study from South India. Indian J Urol. 2013;29(4):282–287. 30. Cubilla AL, Reuter VE, Gregoire L, et al. Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases. Am J Surg Pathol. 1998;22 (6):755–761. 31. Djajadiningrat RS, Jordanova ES, Kroon BK, et al. Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol. 2015;193(2):526–531. 32. Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer. 2006;119(5): 1078–1081. 33. Chaux A, Tamboli P, Ayala A, et al. Warty-basaloid carcinoma: clinicopathological features of a distinctive penile neoplasm. Report of 45 cases. Mod Pathol. 2010;23(6):896–904. 34. Chaux A, Cubilla AL. Advances in the pathology of penile carcinomas. Hum Pathol. 2012;43(6):771–789. 35. Cubilla AL, Lloveras B, Alemany L, et al. Basaloid squamous cell carcinoma of the penis with papillary features: a clinicopathologic study of 12 cases. Am J Surg Pathol. 2012;36(6): 869–875. 36. Cubilla AL, Reuter V, Velazquez E, et al. Histologic classification of penile carcinoma and its relation to outcome in 61 patients with primary resection. Int J Surg Pathol. 2001;9(2): 111–120. 37. Challa VR, Swamyvelu K, Amirtham U, et al. Sarcomatoid carcinoma of penis with bilateral inguinal metastases-a case report and review of literature. Indian J Surg. 2014;76(4): 316–318. 38. Velazquez EF, Melamed J, Barreto JE, et al. Sarcomatoid carcinoma of the penis: a clinicopathologic study of 15 cases. Am J Surg Pathol. 2005;29(9):1152–1158. 39. Colecchia M, Insabato L. Pseudoglandular (adenoid, acantholytic) penile squamous cell carcinoma. Am J Surg Pathol. 2009;33(9):1421–1422. 40. Cunha IW, Guimaraes GC, Soares F, et al. Pseudoglandular (adenoid, acantholytic) penile squamous cell carcinoma: a clinicopathologic and outcome study of 7 patients. Am J Surg Pathol. 2009;33(4):551–555. 41. Zamecnik M, Mukensnabl P, Chlumska A. Pseudoglandular (adenoid, acantholytic) squamous cell carcinoma of the penis. A case report. Cesk Patol. 2011;47(1):15–18. 42. Romero FR, de Castro MG, Garcia CR, et al. Adenosquamous carcinoma of the penis. Clinics. 2006;61(4):363–364. 43. Cubilla AL, Ayala MT, Barreto JE, et al. Surface adenosquamous carcinoma of the penis. A report of three cases. Am J Surg Pathol. 1996;20(2):156–160. 44. Liegl B, Regauer S. Penile clear cell carcinoma: a report of 5 cases of a distinct entity. Am J Surg Pathol. 2004;28(11):1513–1517. 45. Mentrikoski MJ, Frierson HF Jr., Stelow EB, et al. Lymphoepithelioma-like carcinoma of the penis: association with human papilloma virus infection. Histopathology. 2014; 64(2):312–315. 46. Ficarra V, Akduman B, Bouchot O, et al. Prognostic factors in penile cancer. Urology. 2010;76(2 Suppl 1):S66–S73.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semdp
Pathological factors, behavior, and histological prognostic risk groups in subtypes of penile squamous cell carcinomas (SCC) Diego F. Sanchez, MDa,b, Fernando Soares, MDc, Isabel Alvarado-Cabrero, MDd, Sofía Cañete, MDa, María José Fernández-Nestosa, PhDe, Ingrid M. Rodríguez, MDa,b, José Barreto, MDa,b, Antonio L. Cubilla, MDa,b,n a
Instituto de Patología e Investigación, Asunción, Paraguay Facultad de Ciencias Médicas, UNA, Asunción, Paraguay c Department of Anatomic Pathology, AC Camargo Cancer Center, São Paulo, Brazil d Hospital de Oncología, Centro Médico Nacional, Mexico City, México e Facultad Politécnica, UNA, Asunción, Paraguay b
article info
abstract
Keywords:
Pathologists’ contribution in the determination of prognosis in invasive penile squamous cell
Penile neoplasm
carcinoma is crucial. The TNM staging system is based on the identification of pathological
Penile carcinoma
data. There are multiple pathologically based factors believed to be important in relation to
Squamous cell carcinoma
the rates of regional inguinal lymph node and specific cancer death. Among them are tumor
Prognostic risk groups
site, size, histological subtypes, thickness or anatomical level of invasion, tumor front, and
Penile carcinoma subtypes
vascular or perineural invasion. The identification of these factors determines the prognostic profile of patients with penile cancer. These factors are used for the construction of pathological risk groups, prognostic index, or nomograms and are helpful in the prediction of nodal metastasis or patients’ outcome. This review will describe in detail the influential pathological prognostic factors present in each tumor category emphasizing the impact of especial histological subtypes in tumor spread and final outcome. There are few studies comprehensibly addressing the relation of tumor morphology and prognosis according to histological types. We are summarizing findings of prognostic factors in 3 different series for the most common types and individual series in more recently described tumor entities. We had found a broad correlation of special subtypes of penile squamous cell carcinomas that made regional nodal status and final outcome predictable according to histological features of the tumor. These findings permitted grouping special subtypes of squamous cell carcinomas into prognosis risk groups of low, intermediate, and high. In the first category of excellent prognoses are the usual grade I, verrucous, papillary NOS, pseudohyperplastic and cuniculatum carcinomas. In the second group, there are the grade II usual, mixed and warty carcinomas. The third category of tumors, with the worst prognosis is composed of high grade usual, basaloid, warty–basaloid, papillary basaloid, and sarcomatoid carcinomas. We found that subtyping of penile squamous cell carcinoma is important to determine risk for nodal metastasis and patients’ survival. & 2015 Elsevier Inc. All rights reserved.
n
Corresponding autor at: Facultad Politécnica, UNA, Brizuela 325, Asuncion, Paraguay. E-mail address: [email protected] (A.L. Cubilla).
http://dx.doi.org/10.1053/j.semdp.2014.12.017 0740-2570/& 2015 Elsevier Inc. All rights reserved.
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General features More than half of penile invasive carcinomas have features of the usual or conventional squamous cell carcinomas (SCC) similar to other sites, especially vulva and head and neck.1–5 However, a diversity of clinicopathological entities were reported, some quite unusual. The distribution of the various subtypes of SCC in 3 series is shown in Table 1. Pathologists’ contribution in the determination of prognosis in treated invasive penile squamous cell carcinoma is crucial. The TNM staging system, of worldwide use, is based on the identification of pathological data. There are multiple pathologically based factors that are believed to be important in relation to the rates of regional inguinal lymph node and specific cancer death. Among them are tumor site, size, anatomical level of invasion (LP ¼ lamina propria, CS ¼ corpus spongiosum, and CC ¼ corpora cavernosa) (Figs. 1 and 2), histological subtypes, histological grade (I ¼ well differentiated, II ¼ moderately differentiated, and III ¼ poorly differentiated or anaplastic) (Figs. 3 and 4), thickness, tumor front, vascular (VI) (Fig. 5), or perineural invasion (PNI) (Fig. 6).6–13 The distribution of the factors and their relation to nodal regional metastasis and outcome is presented in Table 2. These factors are also used for the construction of pathological risk groups, prognostic index, or nomograms, which are helpful in the prediction of nodal metastasis or patient outcomes.8,14 This review will describe in detail the influential prognostic factors present in each tumor category, emphasizing the impact of especial histological subtypes in tumor spread and final outcome. There are few studies addressing comprehensibly the relation of tumor morphology and prognosis. The data presented are from 3 such studies, one of them is unpublished.12,15 Data from other series related to especial subtypes are also reviewed (warty–basaloid, warty, papillary basaloid, clear cell, and lymphoepithelioma-like). The increased variation in tumor types is related to the inclusion of newly described entities.
Fig. 1 – Anatomical levels of glans. From surface to deep tissues, there are the epithelium (E), lamina propria (LP), corpus spongiosum (CS), and corpus cavernosum (CC), which includes the tunica albuginea (TA).
Subtypes of squamous cell carcinoma, prognostic factors, and clinical behavior Usual Biologic behavior of usual squamous cell carcinoma is related to pathological factors like size, histological grade, depth of infiltration, and vascular and perineural invasion. The average tumor size is about 4.5 cm in high-risk areas, while in low-incidence regions, the average is 2.0 cm, reflecting the variability in clinical stage in the 2 populations.16 The tumors usually compromise the lamina propria, dartos, corpus spongiosum (45%), or corpora cavernosa (35%).17 The typical case is a grade II carcinoma invading up to the corpus spongiosum. Tumors limited to the lamina propria are uncommon. Vascular and perineural invasion are observed in a third of the cases.12 Recurrences in the surgical stump or groin are
Table 1 – Subtypes of penile squamous cell carcinoma.
Verrucous Papillary NOS Pseudohyperplastic Cuniculatum Usual Warty Basaloid Warty–Basaloid Papillary Basaloid Sarcomatoid Pseudoglandular Adenosquamous Mixed
MSKCC series 61 cases (%)15
Brazilian series 333 cases (%)12
Mexican series 154 cases (%) (unpublished)
2 (3) 9 (15) – – 36 (59) 6 (10) 6 (10) – – 2 (3) – – –
24 (7) 17 (5) – – 215 (65) 23 (7) 14 (4) – – 4 (1) – 4 (1) 32 (10)
4 (3) 3 (2) 4 (3) 1 (1) 69 (45) 13 (8) 8 (5) 6 (4) 5 (3) 10 (6) 1 (1) – 30 (19)
Fig. 2 – Level of invasion. Usual squamous cell carcinoma infiltrating the corpus spongiosum.
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Fig. 3 – Histological grade. Well-differentiated grade I squamous cell carcinoma.
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Fig. 6 – Perineural invasion. Moderately differentiated squamous cell carcinoma invading the perineural space. observed in about a third of the cases. Inguinal lymph node metastases develop in 25–40% of patients. The mortality rate of patients with usual squamous cell carcinoma ranges from 20% to 38% with a 10-year survival rate of 75–80%12,15 (Table 3).
Verrucous
Fig. 4 – Histological grade. Poorly differentiated grade III squamous cell carcinoma.
Verrucous carcinomas, especially in endemic areas for penile cancer, have a long-standing history of several years before a diagnosis is made. The larger the tumor and the evolution, the higher chances of “malignant transformation,” defined as the presence of overt invasive squamous cell carcinoma within an otherwise typical or pure verrucous carcinoma. Once a verrucous carcinoma is properly diagnosed, there is no metastatic potential and the cure rate is 100%. Several studies were reported with negative inguinal nodes.12,15,18–20 In patients with insufficient surgical excision, recurrent rates are high, about 40%. Recurrent tumors may be of the classical verrucous histology and re-excision may suffice, but in cases where a higher grade histology or even sarcomatoid changes are found, aggressive treatment is required.12,21 For these reasons, despite their low malignant features, verrucous carcinomas need adequate initial surgery with negative resection margins. Pathologists should be careful when interpreting verrucoid “hyperplastic” thickening of tissues adjacent to verrucous carcinomas, because when present at surgical margins, they may be related to tumor recurrence (Table 4).
Papillary NOS
Fig. 5 – Vascular invasion. Multiple superficial lymphatics vessels with tumor emboli from a case with basaloid carcinoma of the glans. (Courtesy of Dr. Alberto Ayala, Methodist Hospital Houston, TX.)
Papillary carcinomas are infrequent low-grade penile verruciform tumors with a good prognosis despite their large size, moderate–to-deep invasion, and wide extension into penile anatomical compartments (Table 5). They are typically well to moderately differentiated, grades I or II, with definite invasion of corpora, most commonly, the corpus spongiosum. Vascular and perineural invasion are unusual and observed in up to 12% of the cases.12,22 Recurrence is seen in about
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Table 2 – Pathological factors, nodal metastasis, and outcome. MSKCC series 61 cases
Brazilian series 333 cases
Mexican series 154 cases
Age
58.4
55
61.7
Site Glans (%) Other (%)
27 (44) 34 (56)
– –
47 (31) 107 (69)
Size (cm)
–
4.8
4.4
Thickness (mm)
10.3
7.4
14.5
Level LP (%) CS (%) CC (%)
4 (7) 38 (62) 19 (31)
11 (3) 149 (45) 173 (52)
21 (14) 65 (42) 68 (44)
Grade I (%) II (%) III (%)
13 (21) 25 (41) 23 (38)
90 (27) 109 (33) 134 (40)
19 (12) 53 (34) 82 (53)
PNI (%)
–
95 (29)
58 (38)
VI (%)
–
83 (26)
91 (59)
Nodal metastasis (%), n
20 (49), 41
81 (53), 153
52 (41), 126
Mortality rate (%)
18 (30)
52 (16)
53 (34)
Table 3 – Usual squamous cell carcinoma.
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Table 4 – Verrucous carcinoma. MSKCC series 2 cases
Brazilian series 24 cases
Mexican series 4 cases
Age
42
58
67.5
Site Glans (%) Other (%)
1 (50) 1 (50)
– –
3 (75) 1 (25)
Size (cm)
2.9
4.8
2.9
Thickness (mm)
4.5
5.5
5.3
Level LP (%) CS (%) CC (%)
0 2 (100) 0
4 (17) 14 (58) 6 (25)
3 (75) 1 (25) 0
Grade I (%) II (%) III (%)
2 (100) 0 0
24 (100) 0 0
4 (100) 0 0
PNI (%)
0
1 (4)
0
VI (%)
0
0
0
Nodal metastasis (%)
No dissection
0
0
Mortality rate (%)
0
0
0
Table 5 – Papillary carcinoma, not otherwise specified.
MSKCC series 36 cases
Brazilian series 215 cases
Mexican series 69 cases
MSKCC series 9 cases
Brazilian series 17 cases
Mexican series 3 cases
Age
60
54
62
Age
63
53
62
Site Glans (%) Other (%)
14 (39) 22 (61)
– –
26 (38) 43 (62)
Site Glans (%) Other (%)
4 (44) 5 (56)
– –
1 (33) 2 (67)
Size (cm)
4.1
4.7
4.4
Size (cm)
4.5
6.3
4.6
Thickness (mm)
10.6
7.3
14.8
Thickness (mm)
7.4
6.5
7.7
Level LP (%) CS (%) CC (%)
1 (3) 26 (72) 9 (25)
6 (3) 96 (45) 113 (52)
8 (12) 28 (40) 33 (48)
Level LP (%) CS (%) CC (%)
2 (22) 5 (56) 2 (22)
1 (4) 10 (44) 12 (52)
2 (67) 1 (33) 0
Grade I (%) II (%) III (%)
4 (11) 17 (47) 15 (42)
34 (16) 80 (37) 101 (47)
8 (12) 22 (32) 39 (56)
Grade I (%) II (%) III (%)
6 (67) 3 (33) 0
6 (26) 12 (52) 5 (22)
0 2 (100) 0
PNI (%)
–
74 (35)
26 (38)
PNI (%)
–
2 (12)
1 (33)
VI (%)
–
59 (28)
44 (64)
VI (%)
–
2 (12)
1 (33)
Nodal metastasis (%)
14 (54), n ¼ 26
60 (28)
28 (47), n ¼ 60
Nodal metastasis (%)
0
2 (12)
0
Mortality rate (%)
13 (36)
42 (20)
27 (41)
Mortality rate (%)
0
1 (6)
0
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10–12% of the cases. Inguinal metastasis rate is low, from 0% to 25% according to different series.15,22 Mortality is low, ranging from 0% to 6%.12,15
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Table 7 – Carcinoma cuniculatum. Paraguayan series 7 cases25
Mexican series 1 case
Canadian case report 1 case26
Age
77
98
55
Site Glans (%) Other (%)
0 7 (100)
1 –
– 1
Size (cm)
6.3
4.5
4
Thickness (mm)
32
11
Level LP (%) CS (%) CC (%)
0 1 (14) 6 (86)
– 1 –
Grade I (%) II (%) III (%)
1 (14) 6 (86) 0
– 1 –
1 – –
PNI (%)
0
1
–
VI (%)
0
1
–
Cuniculatum
Nodal metastasis (%)
0, n ¼ 4
0
0
They are unusual large tumors of low-grade histology and a paradoxical deep labyrinthine penetration into erectile tissues especially corpora cavernosa (Table 7). Tumor front is, however, broad-based like verrucous carcinoma, and this pattern of growth likewise appears not to affect outcome adversely. None of the few reported cases disclosed nodal metastasis and all patients are alive.23,25,26
Mortality rate (%)
0
0
0
Pseudohyperplastic These unusual highly differentiated tumors are confused with hyperplasia especially on small biopsies. However, they are bona fide invasive carcinomas with low-grade histology. Invasion is usually superficial, rarely beyond lamina propria or dartos. No perineural or vascular invasion is present. Their multicentricity in a background of coexisting lichen sclerosus and differentiated Penile Intraepithelial Neoplasia (PeIN), with a usual subclinical component of the lesion, makes the complete excision of the tumor important so as to prevent recurrences. The prognosis is excellent, with no inguinal nodal metastases. Recurrence in the glans after a circumcision has been described in one of 10 cases.23,24 There is no reported patient death due to this tumor (Table 6).
Table 6 – Pseudohyperplastic carcinoma. Paraguayan series 10 cases 20 tumors 24
Mexican series 4 cases
Age
69
65.5
Site Glans (%) Other (%)
– 10 (100)
1 (25) 3 (75)
Size (cm)
2
2.2
Thickness (mm)
2.9
7.5
Level LP (%) CS (%) CC (%)
15 (75) 5 (25) 0
1 (25) 2 (50) 1 (25)
Grade I (%) II (%) III (%)
20 (100) – –
3 (75) 1 (25) 0
PNI (%)
–
0
VI (%)
–
0
Nodal metastasis (%)
0 of 5
0
Mortality rate (%)
0 of 6
0
– 1 –
Warty Warty carcinomas are bulky slow-growing condylomatous tumors that are histologically and cytologically malignant, unlike their benign counterparts, the common and the giant condylomas (Table 8). A moderate differentiation (grade II) and invasion of the corpus spongiosum is the typical presentation, with a low but definite risk for nodal metastasis. Invasion of the corpora cavernosa is not unusual. Superficial invasion restricted to the lamina propria (2–3 mm) is infrequent. Non-invasive cases with a broad separation between tumor and stroma (pushing borders) are occasionally encountered. High-grade differentiated areas in the tumor may be observed. Vascular and perineural invasion are uncommon (9% and 4%, respectively).12 Local recurrence after penectomy occurs in 10% of warty carcinomas and inguinal lymph node metastasis in about 17–25% cases.27 This is one of the HPVrelated tumors with a relatively good prognosis that despite deep tumor invasion rarely disseminates, and the mortality rate is low (0–10%).12,15,28,29
Basaloid More than half of basaloid carcinoma patients present with inguinal adenopathy due to metastatic cancer. The primary tumor measures 2–5 cm and is usually deeply invasive into both erectiles tissues. These tumors are, by definition, of high grade; perineural and especially vascular invasion is particularly frequent in lamina propria around invasive tumor. Regional metastasis has been reported from 50% to 100% of the cases.12,15,18,30 If partial penectomy is the surgical
S
E M I N A R S I N
D
I A G N O S T I C
P
Table 8 – Warty (condylomatous) carcinoma. MSKCC series 6 cases
Brazilian series 23 cases
Mexican series 13 cases
Age
48
59
57
Site Glans (%) Other (%)
1 (17) 5 (83)
– –
4 (31) 9 (69)
Size (cm)
3.6
6.3
3.3
Thickness (mm)
6.3
6.5
11.2
Level LP (%) CS (%) CC (%)
1 (17) 4 (66) 1 (17)
1 (4) 10 (44) 12 (52)
5 (39) 6 (46) 2 (15)
Grade I (%) II (%) III (%)
1 (17) 4 (66) 1 (17)
6 (26) 12 (52) 5 (22)
0 11 (85) 2 (15)
PNI (%)
–
1 (4)
1 (8)
VI (%)
–
2 (9)
5 (38)
Nodal metastasis (%)
1 (25), n ¼ 4
4 (17)
3 (23)
Mortality rate (%)
0
2 (9)
1 (10), n ¼ 10
operation, local recurrence is high (36%).12,21 Basaloid carcinomas disseminate widely, and mortality ranges from 21% to 88% according to different series (Table 9). The difference may
Table 9 – Basaloid carcinoma.
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32 (2015) 222–231
be due to the stage of the tumor at presentation or more likely by the completeness and adequacy of the initial surgical treatment.12,15,30 The disparity in the high rate of regional metastasis and the much lower rate of mortality is related to the response of the tumor to various treatment modalities as well as the probable biologically better outcome in proven HPV-positive tumors.31,32
Warty–basaloid Warty–basaloid carcinomas are large high-grade tumors with frequent invasion of erectile tissues. Vascular and perineural invasion is frequent. Inguinal lymph node metastatic rate is midway between warty and basaloid subtypes in about half of cases and is related to the proportions of the basaloid component. Systemic dissemination as well as cancer-related death is seen in about a third to half of cases (Table 10).23,33,34
Papillary-basaloid Unusual exophytic or exo-endophytic tumor in older males considered to be a variant of classical basaloid carcinoma. If exophytic or superficially exo-endophytic, the prognosis is excellent. However, if the endophytic, or invasive component of the tumor predominates, the prognosis is dismal. The difference in pathological stage at presentation explains this difference. In 2 such series, we found a variation in nodal metastasis from 17% to 60% and in mortality of 0% to 80% (Table 11).35
Table 10 – Warty–Basaloid carcinoma.
MSKCC series 6 cases
Brazilian series 14 cases
Mexican series 8 cases
Age
54
57
66
Site Glans (%) Other (%)
5 (83) 1 (17)
– –
Size (cm)
4.5
Thickness (mm)
Multiinstitutional series 45 cases33
Mexican series 6 cases
Age
62
53.3
0 8 (100)
Site Glans (%) Other (%)
9 (21) 36 (79)
2 (33) 4 (67)
3
5.8
Size (cm)
5.5
4.8
18
10.9
21.1
Thickness (mm)
12.5
18.3
Level LP (%) CS (%) CC (%)
0 1 (17) 5 (83)
0 3 (21) 11(79)
0 0 8 (100)
Level LP (%) CS (%) CC (%)
3 (6) 21 (47) 21 (47)
0 3 (50) 3 (50)
Grade I (%) II (%) III (%)
– 1 (17) 5 (83)
– – 14 (100)
– – 8 (100)
Grade I (%) II (%) III (%)
– 5 (11) 40 (89)
0 2 (33) 4 (67)
PNI (%)
–
6 (43)
7 (88)
PNI (%)
10 (25)
3 (50)
VI (%)
–
9 (64)
8 (100)
VI (%)
17 (43)
4 (67)
Nodal metastasis (%)
3 (60), n ¼ 5
7 (50)
5 (100), n ¼ 5
Nodal metastasis (%)
11 (52), n ¼ 21
2 (40), n ¼ 5
Mortality rate (%)
4 (67)
3 (21)
7 (88)
Mortality rate (%)
7 (33), n ¼ 21
3 (50)
228
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E M I N A R S I N
D
I A G N O S T I C
P
Table 11 – Papillary basaloid carcinoma.
Age
A T H O L O G Y
32 (2015) 222–231
Table 12 – Sarcomatoid carcinoma.
International group 12 cases35
Mexican series 5 cases (%)
79
64
Site Glans (%) Other (%)
7 (58) 5 (42)
2 (40) 3 (60)
Size (cm)
3
6.4
Thickness (mm)
7
19.2
Level LP (%) CS (%) CC (%)
7 (58) 5 (42) 0
0 1 (20) 4 (80)
Grade I (%) II (%) III (%)
– – 12 (100)
– – 5 (100)
PNI (%)
0
3 (60)
VI (%)
2
5 (100)
Nodal metastasis (%)
2 (17)
3 (60)
Mortality rate (%)
0
4 (80%)
Sarcomatoid It is the most aggressive of all penile carcinomas.34 They are rapidly growing polypoid necrotic and hemorrhagic masses compromising all epithelial compartments (Table 12). There is deep invasion into the corpora cavernosa of a high-grade neoplasm, with frequent positivity of surgical margins in patients with partial penectomies. Vascular and perineural invasion are common. Most patients have inguinal metastasis at the time of diagnosis and many have distant dissemination by that time.12,36,37 Mortality is high (50–90%).21
Pseudoglandular It is a rare albeit aggressive penile tumor (Table 13). Typical presentation is that of a high-grade carcinoma with deep invasion of erectile tissues, especially the corpora cavernosa. These features are present in two-thirds of the few reported cases. Vascular and perineural invasion are frequent. Inguinal metastases are noted in at least 75% of the cases and mortality is about 29%.23,39–41
Adenosquamous Due to the rarity of this tumor, there is limited experience with its biological behavior (Table 14). Recurrences and nodal metastasis have been reported.12,42,43
Clear cell carcinoma These are locally aggressive carcinomas involving the glans and foreskin. Adverse factors common in these rare neoplasms are deep invasion of the corpora cavernosa, high
MSKCC series 2 cases
Brazilian series 4 cases
Mexican series 10 cases
Paraguayan series 15 cases38
Age
42
54
65
59
Site Glans (%) Other (%)
2 (100) 0
– –
0 10 (100)
– –
Size (cm)
3.3
5
6.2
5
Thickness (mm)
12.5
10.3
21.1
–
Level LP (%) CS (%) CC (%)
0 2 (100) 0
0 0 4 (100)
0 0 10 (100)
0 3 (20) 12 (80)
Grade I (%) II (%) III (%)
– 2 (100)
– – 4 (100)
– – 10 (100)
– – 15 (100)
PNI (%)
–
2 (50)
9 (90)
VI (%)
–
1 (25)
10 (100)
8 (53)
Nodal metastasis (%)
2 (100)
3 (75)
4 (67), n¼6
8 (89) of 9
Mortality rate (%)
1 (50)
3 (75)
9 (90)
2 (40) of 5
Table 13 – Pseudoglandular SCC. Brazilian series 7 cases40
Mexican series 1 cases
Age
54
45
Site Glans (%) Other (%)
2 (29) 5 (71)
– 1 (100)
Size (cm)
4.6
6.5
Thickness (mm)
–
18
Level LP (%) CS (%) CC (%)
0 3 (43) 4 (57)
– – 1 (100)
Grade I (%) II (%) III (%)
0 1 (14) 6 (86)
– – 1 (100)
PNI (%)
2 (29)
0
VI (%) Nodal metastasis (%)
4 (57) 3 (75), n ¼ 4
1 (100) 1 (100)
Mortality rate (%)
2 (29)
0
S
E M I N A R S I N
D
I A G N O S T I C
P
Table 14 – Pathological factors, nodal metastasis and outcome in adenosquamous SCC.
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32 (2015) 222–231
Table 15 – Clear cell SCC. Austrian series 5 cases44
Paraguayan series 3 cases (unpublished)
Age
49.6
80
– –
Site Glans (%) Other (%)
5 (100)
3 (100) 0
7.6
7.5
Size (cm)
3.5
6.1
Thickness (mm)
10.3
13
Thickness (mm)
–
Level LP (%) CS (%) CC (%)
0 2 (67) 1 (33)
0 1 (25) 3 (75)
Level LP (%) CS (%) CC (%)
– – –
0 0 3 (100)
Grade I (%) II (%) III (%)
0 2 (67) 1 (33)
1 (25) 0 3 (75)
Grade I (%) II (%) III (%)
– – 5 (100)
0 0 3 (100)
PNI (%)
3 (100)
2 (50)
PNI (%)
–
3 (100)
VI (%)
–
3 (75)
Nodal metastasis (%)
0 of 1
2 (50)
LVI (%) Nodal metastasis (%)
5 (100) 5 (100)
3 (100) 1 of 1
Mortality rate (%)
1 (20)
1 (33)
Mortality rate (%)
0
Paraguayan series 3 cases43
Brazilian series 4 cases
Age
61
63
Site Glans (%) Other (%)
3 (100)
Size (cm)
0
histological grade, extensive geographical necrosis, and frequent vascular and perineural invasion. Regional metastases are present in the majority of the cases. Systemic extension was seen in 40% and mortality was found in 20% of the cases (Table 15).44
Lymphoepithelioma-like In the 2 cases reported,45 these unusual tumors invaded the corpora cavernosa, had a high-grade histology with syncytial appearance, perineural and vascular invasion, and frequent nodal metastasis. Cancer-related mortality was not seen in these cases.
However, a pathologist is confronted in clinical practice with individual tumors. Their immediate recognition, categorization, and the knowledge of its biological behavior are important issues for patients’ management and communication with treating physicians and nowadays with patients themselves.
Table 16 – Mixed carcinoma. Brazilian series 32 cases
Mexican series 30 cases
Age
56
60
Site Glans (%) Other (%)
– –
9 (30) 21 (70)
Size (cm)
4.1
4.1
Thickness (mm)
8.6
12.6
Level LP (%) CS (%) CC (%)
0 14 (44) 18 (56)
2 (7) 22 (73) 6 (20)
Grade I (%) II (%) III (%)
13 (41) 12 (37) 7 (22)
4 (14) 13 (43) 13 (43)
PNI (%)
7 (22)
7 (23)
VI (%)
7 (22)
12 (40)
Nodal metastasis (%)
3 (9)
11 (39), n ¼ 28
Mortality rate (%)
1 (3)
2 (7)
Mixed The typical presentation is similar to that of the usual SCC, with a well to moderately differentiated carcinoma invading up to the corpus spongiosum, with a low rate of nodal metastasis (about 9%). Perineural invasion is present in about 20% of the cases (Table 16). Vascular invasion is more common (22–40%). Recurrences have been reported in 19% of the cases. Mortality rate is low (about 3–7%).8,21
Prognostic risk groups There is a correlation between histological subtypes of squamous cell carcinomas and rates of regional or systemic dissemination and patients’ outcome, although on multivariate analysis, histological type appears to be less important than other pathologic factors such as level of invasion, perineural invasion, histological grade, and vascular invasion.9,11,14,18,46
230
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32 (2015) 222–231
Table 17 – Histological risk groups. Low risk group
Intermediate risk group
High risk group
Usual, grade I Verrucous
Usual, grade II Warty (condylomatous)
Usual, grade III Basaloid
Papillary NOS Pseudohyperplastic
Warty–basaloid Papillary basaloid Sarcomatoid
Mixed
Cuniculatum
Evaluating data from several studies, we found a striking predictable correlation of tumor types and incidence of nodal metastasis and survival. In a recent study, we classified these special neoplasms according to their behavior into 3 groups with different risks for regional tumor spread and patients’ mortality: low, intermediate and high (Table 17). In the low-risk group were the following variants of penile squamous cell carcinoma: usual grade I, verrucous, papillary, pseudohyperplastic, and cuniculatum carcinomas. These tumors were grossly large, replaced more than one anatomical compartment but histologically were of low grade, noninvasive, or superficially invasive (verrucous, cuniculatum, and pseudohyperplastic carcinomas) or deeply invasive like the papillary carcinomas. Despite these features, the outcome of these patients was excellent, with very low mortality.
Table 18 – Pathological features according to histological risk groups. Histological risk group
Low, n ¼ 31
Intermediate, n ¼ 48
High, n ¼ 47
p Value
Age Site Glans (%) Multiple compartments (%)
62.8 16 (52) 15 (48)
60.3 20 (42) 28 (48)
64.5 8 (17) 39 (83)
o0.2477 o0.004
Size (cm)
3.16
3.35
5.25
o0.0001
Thickness (mm)
8.4
12
18
o0.0001
Level LP; n ¼ 19 (%) CS; n ¼ 59 (%) CC; n ¼ 48 (%)
12 (63) 15 (26) 4 (8)
6 (32) 35 (59) 7 (15)
1 (5) 9 (15) 37 (77)
o0.0005
Grade I; n ¼ 18 (%) II; n ¼ 49 (%) III; n ¼ 59 (%)
17 (94) 12 (25) 2 (4)
1 (6) 35 (71) 12 (20)
0 2 (4) 45 (76)
o0.0005
PNI (%)
4 (13)
6 (13)
33 (70)
o0.0005
VI (%)
5 (16)
18 (38)
43 (91)
o0.0005
Metastasis density
2%
4%
18%
o0.0001
Systemic metastasis (%)
3 (10)
10 (22)
36 (80)
o0.0005
TNM stage Z2 (%)
19 (61)
42 (88)
47 (100)
o0.0005
Fig. 7 – Kaplan–Meier survival curve (p o 0.00005).
Tumors in the high-risk category were the usual poorly differentiated grade III, basaloid, warty–basaloid, papillary basaloid, and sarcomatoid carcinomas. The majority of these neoplasms were large and locally destructive with high-grade histology, perineural and vascular invasion, and deep invasion of corpora cavernosa, resulting in frequent nodal metastasis and a poor survival (Table 18). There was a category of intermediate-risk tumors, comprising about one-half of penile carcinomas. To this group belonged the usual moderately differentiated grade II, the warty and the mixed carcinomas. Typically these neoplasms were grade II and invaded up to penile corpus spongiosum, with low incidence of perineural or vascular invasion. Regional metastasis and outcome were intermediate or low, more like the low-risk tumors and quite different from highrisk tumors, as can be noted in the Kaplan–Meier survival curve (Fig. 7).
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