Anal carcinoma - exploring the epidemiology, risk factors, pathophysiology, diagnosis, and treatment

Table 1 Immunohistochemistry markers for anal cancers

Tumor markers	Squamous cell carcinoma	Anal adenocarcinoma	Melanoma	Basal cell carcinoma	Neuroendocrine	Paget primary	Paget secondary
AE1/AE2	+	+	-	+	+	+	+
Ber-EP4	-	+	-	+	-	+	+
CAM5.2	+	+	-	Nonspecific	+	+	+
CDX-2	-	Mostly-	-	-	-	-	+
CEA	-	-	-	-	-	+	+
Chromogranin	-	-	-	-	+	-	-
CK5/6	+	-		+	-	-	-
CK7/20	-/-	+/Mostly-	-	-/-	-/-	+/-	Mostly-/+
GCDFP-15	-	-	-	-	-	+	-
HMB45	-	-	+	-	-	-	-
MELAN-A	-	-	+	-	-	-	-
Mucin	-	+	-	-	-	+	+
p63	+	-	-	+	-	-	-
S100	-	-	+	-	-	-	-
Synaptophysin	-	-	-	-	+	-	-
Vimentin	-	-	+	-	-	-	-

AE1: Anti-pan cytokeratin AE1; Ber-EP4: Anti-epithelial cell adhesion antibody; CAM5.2: Anticytokeratin CAM5.2; CDX-2: Caudal-related homeobox transcription factor 2; CEA: Carcinoembryonic antigen; CK5/6: Cytokeratin 5/6; GCDFP-15: Gross cystic disease fluid protein 15; MELAN-A: Melanoma antigen recognized by T cells.

Table 2 World Health Organization histological classification of anal tumors

Tumor type	Characteristics
Epithelial tumors
Premalignant lesions	Intraepithelial neoplasia (dysplasia), low-grade
	Intraepithelial neoplasia (dysplasia), high-grade
	Bowden disease
	Perianal squamous intraepithelial neoplasia
	Paget disease
Carcinoma	Squamous cell carcinoma
	Adenocarcinoma
	Mucinous adenocarcinoma
	Small cell carcinoma
	Undifferentiated carcinoma
	Others
Nonepithelial tumors	Leiomyoma
	Gastrointestinal stromal tumor
	Myofibroma
Carcinoid tumors	NA
Melanoma	NA
Secondary tumors	Direct extension from adjacent organs: Rectal, cervical, and prostate carcinoma

NA: Not applicable.

Table 3 Tumor, node, and metastasis classification system for anal cancer

Primary tumor	Characteristics
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	HSIL (previously termed carcinoma in situ, Bowden disease, anal intraepithelial neoplasia II-III, high-grade anal intraepithelial neoplasia)
T1	Tumor ≤ 2 cm in greatest dimension
T2	Tumor > 2 cm but ≤ 5 cm in greatest dimension
T3	Tumor > 5 cm in greatest dimension
T4	Tumor of any size invades adjacent organ(s) (e.g., vagina, urethra, bladder)
Lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes
	N1a: Metastasis in inguinal, mesorectal, or internal iliac lymph nodes
	N1b: Metastasis in external iliac lymph nodes
	N1c: Metastasis in external iliac with any N1a nodes
Metastasis
M0	No distant metastasis
M1	Distant metastasis

HSIL: High-grade squamous intraepithelial lesion.

Table 4 Anatomic stage of anal cancer

Stage	T	N	M
0	Tis	N0	M0
I	T1	N0	M0
IIA	T2	N0	M0
IIB	T3	N0	M0
IIIA	T1-T2	N1	M0
IIIB	T4	N0	M0
IIIC	T3-T4	N1	M0
IV	Any T	Any N	M1

M: Metastasis; N: Node; T: Tumor.

Table 5 Ongoing clinical trials investigating the use of anti-programmed cell death-1 agents in anal squamous cell carcinoma

NCT number	Official title	Interventions	Study type	Phase	Status	Location
NCT04719988	Ezabenlimab (BI 754091) and mDCF (Docetaxel, Cisplatin, and 5-fluorouracil) Followed by Chemoradiotherapy in Patients With Stage III Squamous Cell Anal Carcinoma. A Phase II Study	Biological: Blood sample collection	Interventional	Phase 2	Active	France
		Procedure: Biopsy
NCT04894370	Spartalizumab, mDCF (Docetaxel, Cisplatin, and 5-fluorouracil) and Radiotherapy in Patients With Metastatic Squamous Cell Anal Carcinoma. A Phase IIA Study	Biological: Sample collection	Interventional	Phase 2	Recruiting	France
NCT04708470	A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers	Drug: Bintrafusp Alfa	Interventional	Phases 1 and 2	Recruiting	United States
		Drug: NHS-IL12
		Drug: Entinostat
NCT04432597	Phase I/II Trial of HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PD-L1/TGF-Beta Trap (M7824) in Subjects With HPV-Positive Cancers	Biological: PRGN-2009 (Phase I)	Interventional	Phases 1 and 2	Active	United States
		Biological: PRGN-2009 (Phase II)
		Biological: M7824
		Diagnostic test: MRI
		Diagnostic test: Bone scan
		Diagnostic test: CT scan
		Diagnostic test: Brain CT
		Diagnostic test: Brain MRI
		Procedure: Biopsy (Phase I)
		Procedure: Biopsy (Phase II)
NCT05544929	A Phase I, Open-label, Multicenter Study of KFA115 as a Single Agent and in Combination With Pembrolizumab in Patients With Select Advanced Cancers	Drug: KFA115	Interventional	Phase 1	Recruiting	United States
		Drug: Pembrolizumab
NCT04357873	Phase II Basket Trial Evaluating the Efficacy of a Combination of Pembrolizumab and Vorinostat in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma	Drug: Pembrolizumab; vorinostat	Interventional	Phase 2	Active	France
NCT04802876	Efficacy of Tislelizumab and Spartalizumab Across Multiple Cancer-types in Patients With PD1-high mRNA Expressing Tumors Defined by a Single and Pre-specified Cutoff	Drug: Spartalizumab	Interventional	Phase 2	Recruiting	Spain
		Drug: Tislelizumab

CT: Computed tomography; HPV: Human papillomavirus; mDCF: Modified DCF regimen; MRI: Magnetic resonance imaging; PD1: Programmed cell death 1; PD-L1: Programmed cell death ligand 1; TGF: Transforming growth factor.