Immunohistochemistry of lung carcinomas for cytokeratins and neuroendocrine markers
Cytokeratins:
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AE1
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AE3
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BG-8
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Cam5.2
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35BH11 (LMW CK)
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34bE1234b2(HMW CK)
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B72.3
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small cell carcinoma
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5
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6/65
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11/115
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4/65
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5/65, 13/1330
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19/3515
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12% (,
3/43(variously bronchial biopsies, FNAs or bronchial washings)14,
9/35(some cases counted as positive showed reactivity of 1-10% of cells)15,
7/56(the positive foci were composed of larger cells and suggested minimal squamous or glandular differentiation.)13, 0/1016
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2/375
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carcinoid
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0/50(27 typical and 23 atypical. Entrapped bronchial epithelium is intensely positive)13,
0/10(5 typical and 5 atypical)14
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large cell carcinoma (non-endocrine)
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9/95
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9/930
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8/95
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4/95
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large cell neuroendocrine
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6/65
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1/6(One case showed positivity but in less than 10% of cells.),
1/44(One case showed scattered weakly positive cells.),
11/64(in all cases, <10% of cells stained)13, 0/214, 0/332
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3/65
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adenocarcinoma
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33/335
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8/85
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8/85
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7/85
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8/85, 11/1130
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14/335,
8/2610,
10/10(variously bronchial biopsies, FNAs or bronchial washings: poorly differentiated)14, 0/1432
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29/335
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bronchioloalveolar
see also mucinous bronchioloalveolar
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13/135
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3/35
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3/35
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2/35
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3/35
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12/135
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adenosquamous carcinoma
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1/132
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basaloid carcinoma
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5/514
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squamous cell carcinoma
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37/375
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12/125
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12/125
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10/125
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12/125, 12/1230
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98%(41/425,
28/28(basaloid variant of squamous cell carcinoma)10,
15/16(variously bronchial biopsies, FNAs or bronchial washings: poorly differentiated. Staining was focal - less than 5% of tumour cells)14,
22/23(basaloid squamous cell carcinomas)16, 5/532 )
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31/375
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CK5/6
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CK7
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CK14
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CK17
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CK19
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CK20
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small cell carcinoma
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0%21,
1/30(positivity only in a squamous component)22, 2/2831
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2/385, 2/117, 11%21,
11/30(dot-like)22, 11/1330
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2/375, 1/76, 5%21
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2/385
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80%21,
23/30(dot-like)22
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0/115, 0/117, 1%21,0/3022, 2/1330
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carcinoid
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10%21, 0/2322
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2/912, 10/1611, 21%21,1/2322
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0/96
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20%21,16/2322
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0/912, 0/1611, 0%21,0/2322
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large cell carcinoma (non-endocrine)
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0/2522
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5/95,10/2522, 8/930
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6/95
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6/95
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9/2522
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0/617,0/2522, 0/930
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large cell neuroendocrine
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17%21, 3/1022
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2/65, 33%21,7/1022, 2/332
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1/65, 17%21
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0/65
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0%21,
8/10(dot-line in some cases)22
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1/1022
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adenocarcinoma
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0/3022 , 2/1031
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31/335, 45/547, 70/748, 80/8020, 30/3022, 11/1130, 15/1532
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7/335, 2/106
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5/335
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30/3022,8/1022, 30/3022
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0/85, 6/547, 6/748, 6/699,
13/212(5 cases with <25% of cells positive, 3 cases with 26-50% of cells positive, 2 cases with 51-75% of cells positive, 3 cases with >75% of cells positive. Positive cases were 6 mixed, 4 acinar and 3 papillary.)17,
10/80( positivity focal in six cases, 10-25% of cells in one case, 26-75% in one case and >75% in two cases)20,1/3022, 1/1130
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bronchioloalveolar
see also mucinous bronchioloalveolar
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0/1422
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13/135, 3/37 ,
26/26(positivity in 51-75% of tumour in one case, >75% in 25 cases)18, 14/1420,13/1422
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5/135
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1/135
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14/1422
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0/35, 0/37,
1/26(positivity in 26-50% of tumour in one case)18,
4/14( positivity 10-25% of cells in one case, 26-75% in one case and >75% in two cases20,0/1422
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adenosquamous carcinoma
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squamous component 3/3, glandular component 1/322
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squamous component 0/3, glandular component 2/322
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3/3(both components positive)
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0/322
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squamous cell carcinoma
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30/30(predominantly intense diffuse and membrane staining: less strong in poorly differentiated tumours.)22, 31/3931
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8/375, 0/127,
7/30(positivity often seen in areas without either squamous or glandular differentiation)22, 4/1230, 0/532
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35/375, 13/156
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34/375
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30/3022
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0/125, 1/127, 0/4117,
1/30(positivity of 5% of cells in one case)22, 1/1230
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In combined large cell neuroendocrine carcinomas, only the squamous component (6/613) or adenocarcinomatous component (5/613) shows positivity for 34betaE12: combined small cell / squamous cell carcinomas show positivity of the squamous cell component (3/313), but combined small cell / large cell neuroendocrine carcinomas show no positivity (0/513).
Neuroendocrine markers:
Neuroendocrine differentiation occurs in non small cell carcinomas. Reports have been conflicting as to clinical or prognostic significance26.
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CD 56
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chromogranin
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synaptophysin
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small cell carcinoma
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64/662, 8/1014
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37% (7/662, 32/385, 8/181,
19/43(with microwave treatment: 4/43 without microwave treatment)14, 8/3515)
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54% (27/662, 21/365, 9/1014, 23/3515)
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carcinoid
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9/11(nine cases showed tumour cell membrane staining: the remaining two showed staining of sustentacular cells)3, 7/1014
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15/17(foregut carcinoids: 11 lung, 4 gastric and 2 duodenal)3,
10/10(5 typical and 5 atypical)14
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11/113,
8/10(4/5 typical and 4/5 atypical)14
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large cell carcinoma (non-neuroendocrine)
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2/32, 2/3526
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0/32, 1/95, 0/3526
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0/32, 1/95, 3/3526
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large cell neuroendocrine
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2/22, 40/4410, 2/214, 4/432
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0/22, 30/4410, 5/65,
2/2(with microwave treatment)14
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2/22, 37/4410, 6/65,
2/2(focal - less than 5% of tumour cells)14
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adenocarcinoma
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1/382, 0/254,
1/10(poorly differentiated)14,
11/209(2 of the positive cases were also positive for synaptophysin, none for chromogranin)26, 0/1432
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0/382, 3/671, 2/335,
0/10(poorly differentiated)14,
1/209(the one positive case was also positive for synaptophysin)26
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1/382, 2/335,
0/10(poorly differentiated)14, 23/20926
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bronchioloalveolar
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0/135
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0/135
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basaloid carcinoma
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3/2810,
1/5(focal - less than 5% of cells)14
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0/2810, 1/514
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1/2810, 1/514
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squamous cell carcinoma
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4/522, 0/254,
2/16(poorly differentiated)14,
29/242(2 cases were positive for both CD56 and synaptophysin, one for CD56 and chromogranin, none for all three)26, 0/532
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1/522, 2/375,
0/16(poorly differentiated)14,
1/242(the one positive case was also positive for CD56, not for synaptophysin)26
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1/522, 0/355,
0/16(poorly differentiated)14, 10/24226
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Other neuroendocrine markers in small cell carcinoma: bombesin; 28/3515, neurofilament; 24/3515, NSE; 21/3515, ACTH; 0/3515
There is preliminary evidence the desmocollin-3 may be useful in the identification of squamous cell differentiation33.
Diagnostic utility
Various panels of antibodies have been recommended29.
Differentiation of non-small cell carcinoma from small cell carcinoma5. 34bE123, CK5/6, CK14 and CK17 all preferentially stain squamous cell carcinomas. If the threshold is set at 10% of cells showing Immunoreactivity, 34bE12 excludes all neuroendocrine tumours. CK7 and B72.3 stain adenocarcinomas, where they have a complementary role; those adenocarcinomas staining weakly with one tend to stain strongly with the other. Conversely, small cell carcinomas are usually positive for CD 56, chromogranin and synaptophysin.
Differentiating the intermediate type of small cell carcinoma from poorly differentiated squamous cell carcinoma ("small cell variant") may be particularly difficult. Small cell carcinoma is more likely to be positive for CD56 and to show punctate positivity for Cam5.2. Non-small cell carcinoma is more likely to be positive for 34bE12 and CK5/6. Cytokeratin 14 should be positive in squamous cell carcinoma, but my personal experience is that in poorly differentiated squamous cell carcinoma it is often negative. p63 and TTF-1 both have the advantage of being nuclear stains, avoiding the problem of scant cytoplasm in small cell carcinoma and in the small cell variant of squamous cell carcinoma: they have been applied in a panel to previously 24.
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p16
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p63
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TTF-1
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34bE12
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small cell carcinoma
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28/28(high level of staining in 27 cases, low level in one case)23
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0/23(17 tissue and 6 cytology)19, 0/2823,
0/13(this study was performed using a panel of p63 and TTF-1 on previously Papanicolaou - stained cytological smears and cytospin preparations)24,
negative(using destained cytological material)27,
0/16(using cell block cytological material)28 , 0/2831
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20/23(17 tissue and 6 cytology)19, 26/2823,
12/13(this study was performed using a panel of p63 and TTF-1 on previously Papanicolaou - stained cytological smears and cytospin preparations)24, 28/2831
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0/2823
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squamous cell carcinoma
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15/28(includes seven cases with a component of small call variant of squamous carcinoma, which had the same profile as the conventional poorly differentiated squamous cell carcinoma)23
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13/13(12 tissue and 1 cytology)19,
28/28(includes seven cases with a component of small call variant of squamous carcinoma, which had the same profile as the conventional poorly differentiated squamous cell carcinoma)23,
13/13(this study was performed using a panel of p63 and TTF-1 on previously Papanicolaou - stained cytological smears and cytospin preparations)24,
positive(using destained cytological material)27,
4/4(using cell block cytological material)28 , 32/3931
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0/13(12 tissue and 1 cytology)19,
1/28(includes seven cases with a component of small call variant of squamous carcinoma, which had the same profile as the conventional poorly differentiated squamous cell carcinoma)23,
0/13(this study was performed using a panel of p63 and TTF-1 on previously Papanicolaou - stained cytological smears and cytospin preparations)24
7%; see TTF-1, lung, squamous cell carcinoma
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28/28(includes seven cases with a component of small call variant of squamous carcinoma, which had the same profile as the conventional poorly differentiated squamous cell carcinoma)23
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primary adenocarcinoma
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0/12(using destained cytological material)27,
0/4(using cell block cytological material)28 , 0/1031
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78%; see TTF-1, lung, adenocarcinoma
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adenocarcinoma metastatic to lung
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0/5(using destained cytological material)27,
0/6(using cell block cytological material)28
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large cell carcinoma
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0/4(using destained cytological material)27
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While immunoreactivity for 34bE12 increases with the degree of keratinisation, staining for p63 shows an inverse relation to keratinisation and is therefore particularly useful in poorly differentiated squamous cell carcinomas23. p16 may be positive in TTF-1-negative small cell carcinomas23.
Large cell neuroendocrine carcinomas are often positive for CK7, while carcinoid tumours are almost invariably negative.
Small cell carcinomas tend to show greater staining with CD56 than with synaptophysin or chromogranin, whereas the converse holds for carcinoid tumours25.
References
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33 Monica V, Ceppi P, Righi L, et al. Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung. Mod Pathol 2009; 22:709-17
This page last revised 23.5.2009.