ADONIS
Histopathology 1991, 19, 35-46
0309016791001152
Basaloid-squamous carcinoma of the upper aerodigestive tract and so-called adenoid cystic carcinoma of the oesophagus: the same tumour type? W.Y. W.TSANG, J.K.C.CHAN, K.C.LEE*, A.K.F.LEUNG & Y.T.FUT Institutes of Pathology and tRadiology and Oncology, Queen Elizabeth Hospital and *Institute of Pathology, Princess Margaret Hospital, Hong Kong Date of submission 27 December 1990 Accepted for publication 6 February 1991
TSANG W . Y . W . , CHAN J . K . C . ,
LEE K . C . , LEUNG A . K . F . & FU Y . T .
(1991) Histopathology 19, 35-46
Basaloid-squamous carcinoma of the upper aerodigestive tract and so-called adenoid cystic carcinoma of the oesophagus: the same tumour type? Basaloid-squamous carcinoma of the larynx, pharynx and base of tongue and the so-called adenoid cystic carcinoma of the oesophagus are rare but distinctive tumours associated with a grave prognosis. They occur most commonly in elderly males and present at a n advanced stage. Our study of four such laryngeal tumours and five such oesophageal tumours shows that they are histologically and immunohistochemically identical, providing support for the idea that they are the same tumour type. They show a biphasic pattern in which basaloid tumour is intimately associated with a neoplastic squamous component which can be invasive or in situ. The basaloid component is in the form of invasive lobules with frequent comedo-necrosis and hyalinization. The constituent cells possess pale pleomorphic nuclei with frequent mitoses. Immunoreactivity for cytokeratin in the basaloid component is remarkable for its absence or weak and focal nature. Review of the literature shows that only a few cases of ‘adenoid cystic carcinoma’ of the oesophagus are bonafide examples of adenoid cystic carcinoma as it occurs in the salivary glands, while the others are identical to basaloid-squamous carcinoma of the upper aerodigestive tract. Their distinction is important because genuine adenoid cystic carcinoma is much less aggressive than basaloid-squamous carcinoma. Keywords: basaloid-squamous carcinoma, adenoid cystic carcinoma, immunohistochemistry, laryngeal neoplasm, oesophageal neoplasm
Introduction In 1986, Wain et al. proposed the designation ‘basaloidsquamous carcinoma’ for a rare, aggressive neoplasm of the upper aerodigestive tract, characterized by basaloid tumour intimately associated with a neoplastic squamous component, either in the form of an adjacent invasive squamous carcinoma or carcinoma in situ in the overlying epithelium’. We have been impressed by the striking histological similarity between this newly recognized tumour and the oesophageal neoplasm variously reported as ‘adenoid cystic carcinoma’ or ‘carcinoma with adenoid cystic differentiation’2-’8,although such a relationship has not been emphasized previously. So far, only 20 cases of basaloid-squamous carciAddress for correspondence: Dr W.Y.W.Tsang, Institute of Pathology. Queen Elizabeth Hospital, Wylie Road, Kowloon, Hong Kong.
noma of the upper aerodigestive t r a ~ t ’and ~ ’ approxi~ ~ ~ ~ mately 50 cases of ‘adenoid cystic carcinoma’ or ‘carcinoma with adenoid cystic differentiation’ of the oesophagus2-ls. 21 have been reported in the English language literature, and information on the immunohistochemical profile of these uncommon tumours is not available. In this report, we describe the clinical, pathological and immunohistochemical findings of nine such tumours. five located in the oesophagus and four in the larynx/hypopharynx. Our findings support the contention that they represent closely related tumours.
Materials and methods All cases of non-squamous carcinoma of the pharynx, larynx and oesophagus in the surgical pathology files of Queen Elizabeth Hospital, Hong Kong, during the 103s
36
W. Y .W.Tsang et a1
year period 1981-1990 were reviewed. Seven cases fulfillingthe histopathological criteria of basaloid-squamous carcinoma' or carcinoma with adenoid cystic differentiation3.l2were identified. Two additional cases were kindly supplied by other hospitals. Clinical data, therapy and follow-up information were obtained from the medical records. Four cases of adenoid cystic carcinoma of the larynx (including two examples of the solid variant) were also retrieved for comparison of immunohistochemical features. The biopsy and resection materials were fixed in buffered formalin and processed in the usual way for paraffin embedding. Sections, 4 ,um thick, were stained with haematoxylin and eosin, periodic acid-Schiff (PAS) with or without diastase digestion, and alcian blue (pH 2.5). Immunohistochemical studies were performed on paraffin sections of representative portions of the tumours, employing antibodies against cytokeratins (CAM5.2, 34PE12, and AEl/AE3), muscle-specific actin, vimentin, carcino-embryonic antigen (CEA) and S-100 protein (Table 1).The avidin-biotin-peroxidase complex (ABC) technique was used for monoclonal antibodies, and the peroxidase-anti-peroxidase (PAP) technique for polyclonal antisera (CEA and S-100 protein). Briefly, the paraffin sections were dewaxed in xylene and brought to alcohol. Endogenous peroxidase activity was blocked with 0.03% H202 in methanol for 25 min. Trypsinization was carried out for 2 0 min at 3 7"C, except for vimentin staining. The sections were incubated with the primary antibodies for 1 h at room
temperature. For the ABC method, the sections were then incubated with biotinylated anti-mouse immunoglobulin for 1 h, followed by ABC (Dakopatts) for 1 h, with thorough washing between the steps. For the PAP method, the sections were then treated with swine antirabbit immunoglobulin for 3 0 min, followed by PAP complex for 3 0 min. The colour reaction was developed with 0.03% Hz02 and 0.6% diaminobenzidine. Haematoxylin was used for counterstaining. Appropriate positive and negative controls were used for all the antibodies.
Results CLINICAL DATA
The clinical data are summarized in Table 2. All nine patients were Chinese, their ages ranging from 52 to 75 years (mean 66.4 years). Eight were males, and five were chronic smokers. For the laryngeal tumours, the presenting symptoms were hoarseness of voice and throat discomfort. For the oesophageal tumours, the patients presented with dysphagia. The duration of symptoms was short, ranging from 2 weeks to 6 months. In five patients, the cervical or mediastinal lymph nodes were found to be enlarged at presentation or during surgery. In case 9, one cervical lymph node was already palpable at presentation, and another new one reached a size of 3 cm over a 1-month period. Seven cases were treated with surgical resection with or without subsequent radiotherapy, one was treated by radiotherapy alone and one by radiotherapy followed by surgery.
Table 1. Antibodies used in this study Antibody
Source
Dilution
Specificity
CAM5.2
Becton-Dickinson
1: 10
Low molecular weight cytokeratins of 52. 45, 40 kDa (Moll number 8. 18. 19)
AEl/AE3*
Hybritech
1: 500
Low and high molecular weight cytokeratins of 56.5, 50, 48, 40, 65, 67. 64, 59. 58, 56, 54, 52 kDa (Moll number 10. 14, 15, 16, 19, 1-8)
34bE12
Enzo Biochem
Prediluted
High molecular weight cytokeratins of 65, 58. 56.5, 50 kDa (Moll number 1, 5, 10. 14)
HHF35
Enzo Biochem
Prediluted
Muscle-specific actin, present in muscle cells, myofibroblasts and myoepithelial cells
DAKO-Vimentin
Dakopatts
1:20
Vimentin
CEA
Dakopatts
1:100
Carcino-embryonic antigen
s-100
Dakopatts
Prediluted
S-100 protein
*Although AE3 stains high molecular weight cytokeratins well in frozen or alcohol-fixed tissues, it does not always work satisfactorily in formalin-fixed tissues.
Basaloid-squamous carcinoma
37
Table 2. Clinical data
Case Age/sex
64/M 60/M 65/M
68/M 73/F 52/M
69/M 72/M
75/M
Location of tumour
Size
(cm)
3.5 x 3.5 Oesophagus, lower third 3x2 Oesophagus, middlelower third 7x3 Oesophagus, lower third 3x3 Oesophagus, lower third 5 Oesophagus, middlelower third 4.5 x 5 Aryepiglottic fold, supra- and epiglottis
Regional lymph node enlargement
Therapy
Cervical and Palliative oesophagectomy mediastinal Palliative Mediastinal oesophagectomy Palliative oesophagectomy Oesophagectomy
Outcome Died 4 days after operation Died 2 2 days after operation
Lost to follow-up after 3 months
Not available Died 14 months after operation
Mediastinal
Oesophagectomy
Cervical
Laryngectomy followed Developed bilateral pulmonary metastasis at 2; years, by radiotherapy currently on chemotherapy Alive at 1 year, then lost to Radiotherapy follow-up Radiotherapy followed Alive and well 1 year by surgery (no residual tumour) Nil Died from suicide at 2; months
Aryepiglottic fold, supra- and epiglottis Supraglottis,piriform fossa, subglottis
2x1
-
5x4
-
Aryepiglottic fold, epiglottis, base of tongue
5x 5
Cervical
Three of the five oesophageal tumours were located at the lower third of the oesophagus, and two at the junction of the middle and lower third. Their size ranged from 3 to 7 cm in greatest dimension. At operation, extensive infiltration of the surrounding structures, such as pericardium. adventitia of aorta, lung or vertebral body, was noted. All four laryngeal tumours occurred in the supraglottic region with or without epiglottic involvement. The tumour showed such extensive involvement of the upper aerodigestive tract that it was difficult to pinpoint the primary site. In case 8, the laryngeal tumour infiltrated through the thyroid cartilage into the thyroid gland. HISTOPATHOLOGY A N D HISTOCHEMISTRY
The tumours in the oesophagus and in the larynx/ hypopharynx were histologically identical and are therefore described together. The basaloid component of the tumour infiltrated the lamina propria of the mucosa and underlying tissues in the form of smooth-contoured lobules, with or without a surrounding desmoplastic
reaction (Figure 1).The tumour lobules showed connection with the overlying epithelium only in focal areas. The basaloid cells were in the form of solid sheets, anastomosing trabeculae, festoons or microcystic structures (Figure 2). Central (‘comedo’)coagulative necrosis was commonly found within the larger lobules (Figures l a & 3 ) .The microcystic and intertrabecular spaces were often filled with basophilic mucoid matrix which was alcian blue positive but PAS negative. PAS positive diastase-resistant stromal hyaline material was prominent, extending between and replacing the tumour cells (Figure 4).In cases 2, 3 , 4 and 5, small numbers of true glandular spaces were found either within the tumour lobules or as separate units, but the cytological features of the cells lining the lumina were no different from the surrounding basaloid cells (Figures 1b & 5). A two-celltype arrangement was observed focally in two cases, but this was interpreted as probable intraductal spread of tumour22 instead of two-cell-type differentiation, because this phenomenon was confined to the superficial portions of the tumour where mucosal glands were normaliy found (Figure 5b).
3 8 W.Y.W.Tsang et a1
Figure 1 . Oesophageal turnour: a beneath the squamous epithelium are large lobules of basaloid cells with comedo-necrosis (*): b another case with smaller lobules and occasional glandular spaces. H & E.
The basaloid cells possessed round to oval nuclei with dusty chromatin, pale nucleoplasm and small distinct nucleoli (Figure 6). The cytoplasm was scanty and amphophilic, but was sometimes more abundant and clear, due to accumulation of glycogen (Figure 6b). Mitotic figures were characteristically numerous, and it was common to encounter areas with more than five mitoses per high-power field. Tripolar and atypical mitotic figures were frequent. Lymphovascular permeation was demonstrated in four tumours (cases 3 . 5 . 6 , 7). but there was no perineural invasion despite close proximity of the infiltrative tumour to nerve bundles in areas. Except case 9, which was only a biopsy specimen, a variable component of the tumour showed squamous differentiation. In five cases, carcinoma in situ was identified in the overlying epithelium (cases 1 , 2 , 5, 6, 8; Figure 7). In cases 1 and 2, conventional invasive squamous cell carcinoma constituted a recognizable component (3040%) and merged with the basaloid
component (Figure 3 ) . In cases 3 , 4, 6 and 7, the tumour was mostly basaloid, but a few tumour lobules showed squamous differentiation and keratinization (Figure 8). Additional components were noted in two cases. In case 2, part of the tumour exhibited a diffuse permeative infiltrate of closely packed small cells with hyperchromatic nuclei, consistent with small cell ~ a r c i n o m a * ~ . ~ ~ (Figure 9a). In case 4, highly pleomorphic spindle cells infiltrated between the tumour lobules and were associated with a markedly inflamed stroma, consistent with so-called spindle cell carcinoma23(Figure 9b). Lymph nodes were available for histological examination in three cases. In case 6, several small lobules of basaloid tumour were present in the subcapsular sinus of one lymph node, while another node was almost completely replaced by keratinizing squamous cell carcinoma, although the primary tumour was almost exclusively basaloid. In cases 5 and 9 the tumour deposits in lymph node were basaloid.
Basaloid-squamous carcinoma
Figure 2. Laryngeal tumour in which the basaloid cells form a solid sheets and b trabeculae and festoons. Hyalinosis is evident in areas. H & E.
Figure 3. An oesophageal tumour, with basaloid component side-by-side with a keratinizating squamous cell carcinoma. Note prominent comedo-necrosisin the basaloid component. H & E.
39
40 W.Y.W.Tsang et al
Figure 4. a Prominent stromal hyalinization is found in some tumour lobules. H & E. b The hyaline material is highlighted by PAS stain.
Figure 5. a True glandular spaces lined by a slingle layer of neoplastic cells. b In areas, a two-cell-type arrangement (arrows) is occasionally seen. The outer myoepithelial cells are probably derived from residual mucosal glands. H & E.
Basaloid-squamous carcinoma
41
Figure 6. a The basaloid cells possess oval pale nuclei and small nucleoli: note numerous mitotic figures. b Clear cell change is seen in some cases. H & E. IMMUNOHISTOCHEMISTRY
The basaloid component showed poor staining with the anti-cytokeratin antibodies (Figure lo), despite satisfactory positive internal controls (mucosal glands staining strongly with CAM5.2 and AEl/AE3, and the overlying stratified squamous epithelium with 34pE12). In two cases, immunoreactivity for cytokeratin was completely absent (Table 3). In the other seven cases, the staining was weak, usually involving less than 10% of the basaloid cells. Where glandular spaces or tubules were present (four cases), the staining was confined almost exclusively to these structures. Otherwise, the staining was in the form of isolated or small clusters of cells within the tumour lobules (Figure lob). CEA staining also highlighted the glandular spaces in four cases (Figure 1la). Four cases showed focal staining for actin in the basaloid cells, often in a cell membrane pattern. Vimentin immunoreactivity was demonstrated in three cases. Staining for S-100 protein was negative.
The associated squamous cell carcinornaJcarcinoma in situ component stained with AEl/AE3 and 34PE12, but not with CAM5.2. Staining for CEA was also demonstrated, particularly in the keratinizing cells. S100 protein, actin and vimentin immunoreactivity was absent. In case 4, the spindle cell component was negative for all markers except vimentin. In case 2 , the small cell component stained focally with CAM5.2 and AEl/AE3,and diffusely with CEA antibody. In the adenoid cystic carcinomas studied for comparison, CAM5.2 and AEl/AE3 stained all neoplastic cells, but much more strongly in the ductal epithelium interspersed throughout the masses of basaloid cells. 34PE12 stained the ductal cells similarly, but it stained the basaloid cells inconsistently. CEA-immunoreactivity was confined to the ductal component, whereas positivity for S-100 protein, actin and vimentin was confined to the basaloid component. The results were identical to those previously reported for adenoid cystic carcin ~ m a ~ ~ .
42 W. Y .W. Tsang et a2
Discussion
Figure 7. Carcinoma in situ changes in the squamous epithelium overlying the tumour. H & E.
Figure 8. Squamous differentiation (arrow)in this island of basaloid tumour. H & E.
Basaloid-squamous carcinoma, first characterized by Wain et aL1, is a rare but distinctive malignant tumour occurring in the larynx, pharynx and base of tongue‘. It mainly affectsmen in the sixth and seventh decades of life. This aggressive neoplasm usually presents as high stage disease, and widespread metastasis frequently develops during its c o u r ~ e ~ ’ The ~ ~ .salient ~ ” . histological feature is an intimate association between a basaloid component with adenoid cystic carcinoma-like features and squamous carcinoma, although the latter component may be inconspicuous. The four cases in this series are similar to those previously reported, both clinically and histologically, including the typical comedonecrosis and prominent hyalinization. As reported in the literature, ‘adenoid cystic carcinoma’ or ‘carcinoma with adenoid cystic differentiation’ of the oesophagus occurs predominantly in elderly men in their sixties2-18.The patients usually present at an advanced stage, and most die within 1-2 years. Both local and distant metastases are common. Thus, the clinicopathological features, including those of the five cases in this series, are remarkably similar to those of basaloid-squamous carcinoma of the upper aerodigestive tract. However, the situation is in fact much more confusing. In the updated World Health Organization classification of oesophageal tumours, although ‘adenoid cystic carcinoma’ is considered the counterpart of the salivary gland tumours, with cribriform structures and two-cell-type differentiation, neither feature is apparent in the photomicrograph^^^. Furthermore, the vesicular nuclei of the tumour cells and the brisk mitoses, as evident in the illustrations, are more akin to basaloid-squamous than adenoid cystic carcinoma occurring in the major salivary gland^^'!^^. Scrutiny of the published reports shows that only a few cases appear to be bona fide examples of adenoid cystic carcinoma 5.1O.11.13, and at least two of these four cases have survived more than 3 Most cases are histologically identical to basaloid-squamous carcinoma2,3.7,9,12,16.17.28 and have behaved aggressively. However, the exact nature of some cases is difficult to ascertain4~8*14.15.25. Benisch & Toker12 have already proposed labelling tumours in the oesophagus with histological features of basaloid-squamous carcinoma as ‘carcinoma with adenoid cystic differentiation’ instead of ‘adenoid cystic carcinoma’, because of differences in histological features, aggressive clinical course and association with a neoplastic squamous component. This view has been supported by Epstein and coworkers3. Both ‘basaloid-squamous carcinoma’ and ‘carcinoma with adenoid cystic differentiation’ are
Basaloid-squamous carcinoma
Figure 9. a Small cell carcinoma component in case 2. b Spindle cell component in case 4. H & E.
Figure 10. a The basaloid cells are negative for cytokeratin while the mucosal glands are strongly positive. b Focal positivity for cytokeratin (arrows) occasionally observed; some positive cells appear to line abortive glands. Immunoperoxidase.
43
44 W.Y.W.Tsang et a1
Table 3. Immunohistochemical findings Staining* Case no.
1 2
3 4
5
Component Basaloid Squamous Basa1oid Squamous Small cells Basaloid Basaloid Spindle cells Basaloid Squamous Basaloid Squamous Basaloid Squamous Basaloid Squamous Basaloid
Adenoid cystic carcinoma Ductal Basaloid
CAM5.2
+ -
+I-
AEl/AE3
CEA
-
-
-
+++ + +++ ++ + +
+++
++
+ ++ + ++ ++ + ++ + +++ ++/+++
34fiE12
++
-
++ -
++I+++
Actin
Vimentin
+
+ +++ + + -
-
+++
*Percentage of positive cells quantified as: - =OX;
-
S-100
+
++ -
++
+
-
-
++ ++ ++
-
+++
+++
-/+/++
-
+ +
-/+
+++
-
-
+++
+++
+ = 1-10%; + + = 11-50%; + + + = > 50%.
appropriate designations for these uncommon oesophageal tumours, but we prefer the former because it is shorter and more convenient to use. The immunohistochemical profiles of the basaloidsquamous carcinomas of the upper aerodigestive tract and the oesophagus are similar, providing further evidence that they represent the same tumour type. A remarkable feature is the poor or lack of immunoreactivity for cytokeratin in the basaloid component. Since we have employed several antibodies immunoreactive with cytokeratins of a wide range of molecular weights and there are good internal controls, this finding is not artifactual. Furthermore, the few ultrastructural studies have shown that the basaloid cells are poor in organelles and cytoplasmic This is in striking contrast to the strong cytokeratin immunoreactivity in the squamous component of these tumours and in conventional squamous carcinoma of the oesophagus or upper aerodigestive tract29. Therefore, the basaloid cells in basaloid-squamous carcinoma appear to be largely undiffer-
entiated, sometimes exhibiting very focal epithelial (tubular) differentiation and inconsistent myoepithelial differentiation(as supported by actin-positivity). Adenoid cystic carcinoma remains the major differential diagnosis of basaloid-squamous carcinoma. In contrast to the latter, adenoid cystic carcinoma is characterized clinically by female predominance, earlier age of occurrence (40-60 years) and a more protracted clinical course27.Histologically, the focal continuity with the surface epithelium, and the association with squamous carcinoma or other neoplastic components are not features of adenoid cystic carcinoma. Even the solid variant of adenoid cystic carcinoma frequently exhibits identifiable two-cell-type differentiation (paler ductal epithelium and darker basaloid cells) and distinctive cribriform structures in areas", neither of which are found in basaloid-squamous carcinoma. The basaloid cells in adenoid cystic carcinoma possess small hyperchromatic nuclei with only mild pleomorphism and infrequent mitosis, differing from those of basaloid-
Basaloid-squamous carcinoma
45
Figure 11. a CEA immunostaining highlights the glandular spaces. b Membrane staining for actin is seen in some cases. Immunoperoxidase.
squamous carcinoma. Basaloid-squamous carcinoma also lacks the characteristic neurotropism of adenoid cystic carcinoma. Small cell carcinoma of the oesophagus23.24, another highly aggressive tumour, differs from basaloid-squamous carcinoma in showing more diffuse permeative growth, nuclear moulding, indistinct nucleoli, and lack of the stromal hyalinization and mucinous material. Tauchi et aL3” have recently described a superficial oesophageal carcinoma with basaloid features, which is associated with a better prognosis than conventional squamous cell carcinoma. These tumours resemble basal cell carcinoma of the skin, with striking nuclear palisading and without the pale nuclei and hyalinization of basaloid-squamous carcinoma. These authors have also identified a ‘mixed squamous-basaloid’ group which behaves aggressively. Although these ’mixed’ tumours were not illustrated, the authors stated that they correspond well to basaloid-squamous carcinoma. The histogenesis of basaloid-squamous carcinoma remains conjectural. This tumour appears immunohis-
tochemically and ultrastructurally to be mostly undifferentiated despite some superficial resemblance to adenoid cystic carcinoma. The oesophageal tumours have been postulated to arise from embryonal rests of the tracheobronchial tree18,submucosal glands or their intercalated d u ~ t sor~surface .~ epithelium12.However, we agree with Wain et al. * that basaloid-squamous carcinoma probably has its origin from a totipotent primitive cell which is capable of differentiating focally into epithelial structures, myoepithelium or other elements, and the tumour can probably be viewed as a peculiar variant of poorly differentiated squamous call carcinoma. We conclude, therefore, that basaloid-squamous carcinoma is a distinct clinicopathological entity, distinguishable from adenoid cystic carcinoma. It occurs mostly in the upper aerodigestive tract or oesophagus. In the literature, oesophageal tumours reported as ‘adenoid cystic carcinoma’ or ‘carcinoma with adenoid cystic differentiation’ represent a mixture of genuine adenoid cystic carcinoma (rare) and basaloid-squamous carcinoma (more common). It is important to make this
46 W. Y .W. Tsang et a1
distinction, since the former tumour appears to be much less aggressive. The rare pseudo-adenoid cystic squamous cell carcinoma of the anal canal, which is reported to be associated with a poor prognosis, is probably also the same tumour type3l.
References 1. Wain SL. Kier R, Vollmer RT, Bossen EH. Basaloid-squamous carcinoma of the tongue, hypopharynx. and larynx: report of 10 cases. Hum. Pathol. 1986: 17; 1158-1166. 2. Sweeney EC, Cooney T. Adenoid cystic carcinoma of the esophagus. A light and electron microscopic study. Cancer 1980; 45; 1516-1525. 3. Epstein JI, Sears DL, Tucker RS, Eagan JW Jr. Carcinoma of the oesophagus with adenoid cystic differentiation. Cancer 1984; 53; 1131-1136. 4. Petursson SR. Adenoid cystic carcinoma of the oesophagus. Complete response to combination chemotherapy. Cancer 1986; 57; 1464-1467. 5. Bell-Thomson J. Haggitt RC, Ellis FH. Mucoepidermoid and adenoid cystic carcinoma of the oesophagus. 1. Thorac. Cardiovasc. Surg. 1980; 79; 438-446. 6. Jacobsohn WZ. Libson Y. Dollberg L. Adenoid cystic carcinoma of the oesophagus. Gastrointest. Endosc. 1980; 26; 102-105. 7. Pourzand A, Freant L, Levin R. Peabody I. Absolon K. Primary adenoid cystic carcinoma of the oesophagus. Report of a case and review ofthe literature. J Thorac. Cardiovasc. Surg. 1975: 69; 785789. 8. O’SullivanJP. Cockburn JS, Drew CE. Adenoid cystic carcinoma of the oesophagus. Thorax 1975: 3 0 476-480. 9. Allard M. Farkouh E. Atlas H, Paquin JG. Primary adenoid cystic carcinoma of the oesophagus. Can 1. Surg. 1981; 24; 405-406. 10. Kabuto T, Taniguchi K, Iwanaga T, et al. Primary adenoid cystic carcinoma of the oesophagus. Report of a case. Cancer 1979: 43; 24 52-24 56. 1 1 . Nelms DC, Luna MA. Primary adenocystic carcinoma (cylindromatous carcinoma) of the oesophagus. Cancer 1972: 29; 440443. 12. Benisch B. Toker C. Oesophageal carcinomas with adenoid cystic differentiation. Arch. Otolaryngol. 1972: 96; 260-263. 13. Zardawi IM, Talbot IC. Primary adenoid cystic carcinoma of the oesophagus. Diagn. Histoputhol. 1983: 6; 39-46. 14. Rojas RAM, Vallecillo LA. Primary adenoid cystic carcinoma of the oesophagus. Report of one case and review of the literature. Arch. Otolaryngol. 1959; 7 0 197-201. 15. Azzopardi JG, Menzies T. Primary oesophageal adenocarcinoma.
Confirmation of its existence by the finding of mucous gland tumours. Br. 1. Surg. 1962: 49; 497-506. 16 Mukada T, Sat0 E. Adenoid cystic carcinoma of the oesophagus. Tohoku. 1. Exp. Med. 1974; 113; 257-262. 17. Haizuka S. Okuhara T. Homma MS, Kodama T, Kunita T. Tahara E. An autopsy case of adenoid cystic carcinoma of the oesophagus. Stomach Intest. 1976: 11; 1117-1 122 (In Japanese, with English abstract). 18. Bergmann M. Charnas RM. Tracheobronchial rests in the oesophagus, their relation to some benign structures and certain types of cancer of the oesophagus. 1. Thorac. Surg. 1958: 35; 97-104. 19. Luna MA, Naggar AE, Parichatikanond P, Weber RS, Batsakis JG. Basaloid squamous carcinoma of the upper aerodigestive tract. Clinicopathologic and DNA flow cytometric analysis. Cancer 1990; 66; 537-542. 20. McKay MJ, Bilous AM. Basaloid-squamous carcinoma of the hypopharynx. Cancer 1989; 63: 2528-2531. 21. Enterline H, Thompson J. Pathology of the Oesophagus. New York Springer-Verlag, 1984: 134-136. 22. Takubo K, Takai A, Takayama S. Sasajima K, Yamashita K, Fujita K. Intraductal spread of oesophageal squamous cell carcinoma. Cancer 1987: 59; 1751-1757. 23. Watanabe H, Jass JR, Sobin LH et al. Histological Typing of Oesophageal and Gastric Tumours. World Health Organization lnternational Histological Class$cation of Tumours. Berlin: SpringerVerlag, 1990; 13-14; 53-54. 24. Briggs JC, Ibrahim NBN. Oat cell carcinoma of the oesophagus: a clinicopathological study of 23 cases. Histopathology 1983: 7; 2 6 1-2 77. 25. Chen JC, Gnepp DR. Bedrossian CWM. Adenoid cystic carcinoma of the salivary glands: a n immunohistochemical analysis. Oral Surg. Oral Med. Oral Pathol. 1988; 65; 316-326. 26. Szanto PA, Luna MA, Tortoledo ME, White RA. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer 1984; 54; 1062-1069. 27 Thackray AC. Lucas RB. Tumours of the major salivary glands. Atlas of Tumor Pathology. Series 2, Fascicle 10. Washington DC: Armed Forces Institute of Pathology, __ 1974; 91-99. 28. Gregg JB, Stamler FW. Unusual neoplasms of the oesophagus. Review of the literature and report of a case. Arch. Otolaryngol. 1954; 59; 159-169. 29. Yang K, Lipkin M. AE1 cytokeratin reaction patterns in different differentiation states of squarnous cell carcinoma of the oesophagus. Am. 1. Clin. Pathol. 1990: 94; 261-269. 30. Tauchi K. Kakudo K. Machimura T, Makuuchi H, Mitomi T. Superficial oesophageal carcinoma with special reference to basaloid features. Pathol. Res. Pract. 1990; 186; 450-454. 3 1. Dougherty BG. Evans HL. Carcinoma of the anal canal: a study of 79 cases. Am. I. Clin. Pathol. 1985; 83; 159-164.
Histopathology 1991, 19, 35-46
0309016791001152
Basaloid-squamous carcinoma of the upper aerodigestive tract and so-called adenoid cystic carcinoma of the oesophagus: the same tumour type? W.Y. W.TSANG, J.K.C.CHAN, K.C.LEE*, A.K.F.LEUNG & Y.T.FUT Institutes of Pathology and tRadiology and Oncology, Queen Elizabeth Hospital and *Institute of Pathology, Princess Margaret Hospital, Hong Kong Date of submission 27 December 1990 Accepted for publication 6 February 1991
TSANG W . Y . W . , CHAN J . K . C . ,
LEE K . C . , LEUNG A . K . F . & FU Y . T .
(1991) Histopathology 19, 35-46
Basaloid-squamous carcinoma of the upper aerodigestive tract and so-called adenoid cystic carcinoma of the oesophagus: the same tumour type? Basaloid-squamous carcinoma of the larynx, pharynx and base of tongue and the so-called adenoid cystic carcinoma of the oesophagus are rare but distinctive tumours associated with a grave prognosis. They occur most commonly in elderly males and present at a n advanced stage. Our study of four such laryngeal tumours and five such oesophageal tumours shows that they are histologically and immunohistochemically identical, providing support for the idea that they are the same tumour type. They show a biphasic pattern in which basaloid tumour is intimately associated with a neoplastic squamous component which can be invasive or in situ. The basaloid component is in the form of invasive lobules with frequent comedo-necrosis and hyalinization. The constituent cells possess pale pleomorphic nuclei with frequent mitoses. Immunoreactivity for cytokeratin in the basaloid component is remarkable for its absence or weak and focal nature. Review of the literature shows that only a few cases of ‘adenoid cystic carcinoma’ of the oesophagus are bonafide examples of adenoid cystic carcinoma as it occurs in the salivary glands, while the others are identical to basaloid-squamous carcinoma of the upper aerodigestive tract. Their distinction is important because genuine adenoid cystic carcinoma is much less aggressive than basaloid-squamous carcinoma. Keywords: basaloid-squamous carcinoma, adenoid cystic carcinoma, immunohistochemistry, laryngeal neoplasm, oesophageal neoplasm
Introduction In 1986, Wain et al. proposed the designation ‘basaloidsquamous carcinoma’ for a rare, aggressive neoplasm of the upper aerodigestive tract, characterized by basaloid tumour intimately associated with a neoplastic squamous component, either in the form of an adjacent invasive squamous carcinoma or carcinoma in situ in the overlying epithelium’. We have been impressed by the striking histological similarity between this newly recognized tumour and the oesophageal neoplasm variously reported as ‘adenoid cystic carcinoma’ or ‘carcinoma with adenoid cystic differentiation’2-’8,although such a relationship has not been emphasized previously. So far, only 20 cases of basaloid-squamous carciAddress for correspondence: Dr W.Y.W.Tsang, Institute of Pathology. Queen Elizabeth Hospital, Wylie Road, Kowloon, Hong Kong.
noma of the upper aerodigestive t r a ~ t ’and ~ ’ approxi~ ~ ~ ~ mately 50 cases of ‘adenoid cystic carcinoma’ or ‘carcinoma with adenoid cystic differentiation’ of the oesophagus2-ls. 21 have been reported in the English language literature, and information on the immunohistochemical profile of these uncommon tumours is not available. In this report, we describe the clinical, pathological and immunohistochemical findings of nine such tumours. five located in the oesophagus and four in the larynx/hypopharynx. Our findings support the contention that they represent closely related tumours.
Materials and methods All cases of non-squamous carcinoma of the pharynx, larynx and oesophagus in the surgical pathology files of Queen Elizabeth Hospital, Hong Kong, during the 103s
36
W. Y .W.Tsang et a1
year period 1981-1990 were reviewed. Seven cases fulfillingthe histopathological criteria of basaloid-squamous carcinoma' or carcinoma with adenoid cystic differentiation3.l2were identified. Two additional cases were kindly supplied by other hospitals. Clinical data, therapy and follow-up information were obtained from the medical records. Four cases of adenoid cystic carcinoma of the larynx (including two examples of the solid variant) were also retrieved for comparison of immunohistochemical features. The biopsy and resection materials were fixed in buffered formalin and processed in the usual way for paraffin embedding. Sections, 4 ,um thick, were stained with haematoxylin and eosin, periodic acid-Schiff (PAS) with or without diastase digestion, and alcian blue (pH 2.5). Immunohistochemical studies were performed on paraffin sections of representative portions of the tumours, employing antibodies against cytokeratins (CAM5.2, 34PE12, and AEl/AE3), muscle-specific actin, vimentin, carcino-embryonic antigen (CEA) and S-100 protein (Table 1).The avidin-biotin-peroxidase complex (ABC) technique was used for monoclonal antibodies, and the peroxidase-anti-peroxidase (PAP) technique for polyclonal antisera (CEA and S-100 protein). Briefly, the paraffin sections were dewaxed in xylene and brought to alcohol. Endogenous peroxidase activity was blocked with 0.03% H202 in methanol for 25 min. Trypsinization was carried out for 2 0 min at 3 7"C, except for vimentin staining. The sections were incubated with the primary antibodies for 1 h at room
temperature. For the ABC method, the sections were then incubated with biotinylated anti-mouse immunoglobulin for 1 h, followed by ABC (Dakopatts) for 1 h, with thorough washing between the steps. For the PAP method, the sections were then treated with swine antirabbit immunoglobulin for 3 0 min, followed by PAP complex for 3 0 min. The colour reaction was developed with 0.03% Hz02 and 0.6% diaminobenzidine. Haematoxylin was used for counterstaining. Appropriate positive and negative controls were used for all the antibodies.
Results CLINICAL DATA
The clinical data are summarized in Table 2. All nine patients were Chinese, their ages ranging from 52 to 75 years (mean 66.4 years). Eight were males, and five were chronic smokers. For the laryngeal tumours, the presenting symptoms were hoarseness of voice and throat discomfort. For the oesophageal tumours, the patients presented with dysphagia. The duration of symptoms was short, ranging from 2 weeks to 6 months. In five patients, the cervical or mediastinal lymph nodes were found to be enlarged at presentation or during surgery. In case 9, one cervical lymph node was already palpable at presentation, and another new one reached a size of 3 cm over a 1-month period. Seven cases were treated with surgical resection with or without subsequent radiotherapy, one was treated by radiotherapy alone and one by radiotherapy followed by surgery.
Table 1. Antibodies used in this study Antibody
Source
Dilution
Specificity
CAM5.2
Becton-Dickinson
1: 10
Low molecular weight cytokeratins of 52. 45, 40 kDa (Moll number 8. 18. 19)
AEl/AE3*
Hybritech
1: 500
Low and high molecular weight cytokeratins of 56.5, 50, 48, 40, 65, 67. 64, 59. 58, 56, 54, 52 kDa (Moll number 10. 14, 15, 16, 19, 1-8)
34bE12
Enzo Biochem
Prediluted
High molecular weight cytokeratins of 65, 58. 56.5, 50 kDa (Moll number 1, 5, 10. 14)
HHF35
Enzo Biochem
Prediluted
Muscle-specific actin, present in muscle cells, myofibroblasts and myoepithelial cells
DAKO-Vimentin
Dakopatts
1:20
Vimentin
CEA
Dakopatts
1:100
Carcino-embryonic antigen
s-100
Dakopatts
Prediluted
S-100 protein
*Although AE3 stains high molecular weight cytokeratins well in frozen or alcohol-fixed tissues, it does not always work satisfactorily in formalin-fixed tissues.
Basaloid-squamous carcinoma
37
Table 2. Clinical data
Case Age/sex
64/M 60/M 65/M
68/M 73/F 52/M
69/M 72/M
75/M
Location of tumour
Size
(cm)
3.5 x 3.5 Oesophagus, lower third 3x2 Oesophagus, middlelower third 7x3 Oesophagus, lower third 3x3 Oesophagus, lower third 5 Oesophagus, middlelower third 4.5 x 5 Aryepiglottic fold, supra- and epiglottis
Regional lymph node enlargement
Therapy
Cervical and Palliative oesophagectomy mediastinal Palliative Mediastinal oesophagectomy Palliative oesophagectomy Oesophagectomy
Outcome Died 4 days after operation Died 2 2 days after operation
Lost to follow-up after 3 months
Not available Died 14 months after operation
Mediastinal
Oesophagectomy
Cervical
Laryngectomy followed Developed bilateral pulmonary metastasis at 2; years, by radiotherapy currently on chemotherapy Alive at 1 year, then lost to Radiotherapy follow-up Radiotherapy followed Alive and well 1 year by surgery (no residual tumour) Nil Died from suicide at 2; months
Aryepiglottic fold, supra- and epiglottis Supraglottis,piriform fossa, subglottis
2x1
-
5x4
-
Aryepiglottic fold, epiglottis, base of tongue
5x 5
Cervical
Three of the five oesophageal tumours were located at the lower third of the oesophagus, and two at the junction of the middle and lower third. Their size ranged from 3 to 7 cm in greatest dimension. At operation, extensive infiltration of the surrounding structures, such as pericardium. adventitia of aorta, lung or vertebral body, was noted. All four laryngeal tumours occurred in the supraglottic region with or without epiglottic involvement. The tumour showed such extensive involvement of the upper aerodigestive tract that it was difficult to pinpoint the primary site. In case 8, the laryngeal tumour infiltrated through the thyroid cartilage into the thyroid gland. HISTOPATHOLOGY A N D HISTOCHEMISTRY
The tumours in the oesophagus and in the larynx/ hypopharynx were histologically identical and are therefore described together. The basaloid component of the tumour infiltrated the lamina propria of the mucosa and underlying tissues in the form of smooth-contoured lobules, with or without a surrounding desmoplastic
reaction (Figure 1).The tumour lobules showed connection with the overlying epithelium only in focal areas. The basaloid cells were in the form of solid sheets, anastomosing trabeculae, festoons or microcystic structures (Figure 2). Central (‘comedo’)coagulative necrosis was commonly found within the larger lobules (Figures l a & 3 ) .The microcystic and intertrabecular spaces were often filled with basophilic mucoid matrix which was alcian blue positive but PAS negative. PAS positive diastase-resistant stromal hyaline material was prominent, extending between and replacing the tumour cells (Figure 4).In cases 2, 3 , 4 and 5, small numbers of true glandular spaces were found either within the tumour lobules or as separate units, but the cytological features of the cells lining the lumina were no different from the surrounding basaloid cells (Figures 1b & 5). A two-celltype arrangement was observed focally in two cases, but this was interpreted as probable intraductal spread of tumour22 instead of two-cell-type differentiation, because this phenomenon was confined to the superficial portions of the tumour where mucosal glands were normaliy found (Figure 5b).
3 8 W.Y.W.Tsang et a1
Figure 1 . Oesophageal turnour: a beneath the squamous epithelium are large lobules of basaloid cells with comedo-necrosis (*): b another case with smaller lobules and occasional glandular spaces. H & E.
The basaloid cells possessed round to oval nuclei with dusty chromatin, pale nucleoplasm and small distinct nucleoli (Figure 6). The cytoplasm was scanty and amphophilic, but was sometimes more abundant and clear, due to accumulation of glycogen (Figure 6b). Mitotic figures were characteristically numerous, and it was common to encounter areas with more than five mitoses per high-power field. Tripolar and atypical mitotic figures were frequent. Lymphovascular permeation was demonstrated in four tumours (cases 3 . 5 . 6 , 7). but there was no perineural invasion despite close proximity of the infiltrative tumour to nerve bundles in areas. Except case 9, which was only a biopsy specimen, a variable component of the tumour showed squamous differentiation. In five cases, carcinoma in situ was identified in the overlying epithelium (cases 1 , 2 , 5, 6, 8; Figure 7). In cases 1 and 2, conventional invasive squamous cell carcinoma constituted a recognizable component (3040%) and merged with the basaloid
component (Figure 3 ) . In cases 3 , 4, 6 and 7, the tumour was mostly basaloid, but a few tumour lobules showed squamous differentiation and keratinization (Figure 8). Additional components were noted in two cases. In case 2, part of the tumour exhibited a diffuse permeative infiltrate of closely packed small cells with hyperchromatic nuclei, consistent with small cell ~ a r c i n o m a * ~ . ~ ~ (Figure 9a). In case 4, highly pleomorphic spindle cells infiltrated between the tumour lobules and were associated with a markedly inflamed stroma, consistent with so-called spindle cell carcinoma23(Figure 9b). Lymph nodes were available for histological examination in three cases. In case 6, several small lobules of basaloid tumour were present in the subcapsular sinus of one lymph node, while another node was almost completely replaced by keratinizing squamous cell carcinoma, although the primary tumour was almost exclusively basaloid. In cases 5 and 9 the tumour deposits in lymph node were basaloid.
Basaloid-squamous carcinoma
Figure 2. Laryngeal tumour in which the basaloid cells form a solid sheets and b trabeculae and festoons. Hyalinosis is evident in areas. H & E.
Figure 3. An oesophageal tumour, with basaloid component side-by-side with a keratinizating squamous cell carcinoma. Note prominent comedo-necrosisin the basaloid component. H & E.
39
40 W.Y.W.Tsang et al
Figure 4. a Prominent stromal hyalinization is found in some tumour lobules. H & E. b The hyaline material is highlighted by PAS stain.
Figure 5. a True glandular spaces lined by a slingle layer of neoplastic cells. b In areas, a two-cell-type arrangement (arrows) is occasionally seen. The outer myoepithelial cells are probably derived from residual mucosal glands. H & E.
Basaloid-squamous carcinoma
41
Figure 6. a The basaloid cells possess oval pale nuclei and small nucleoli: note numerous mitotic figures. b Clear cell change is seen in some cases. H & E. IMMUNOHISTOCHEMISTRY
The basaloid component showed poor staining with the anti-cytokeratin antibodies (Figure lo), despite satisfactory positive internal controls (mucosal glands staining strongly with CAM5.2 and AEl/AE3, and the overlying stratified squamous epithelium with 34pE12). In two cases, immunoreactivity for cytokeratin was completely absent (Table 3). In the other seven cases, the staining was weak, usually involving less than 10% of the basaloid cells. Where glandular spaces or tubules were present (four cases), the staining was confined almost exclusively to these structures. Otherwise, the staining was in the form of isolated or small clusters of cells within the tumour lobules (Figure lob). CEA staining also highlighted the glandular spaces in four cases (Figure 1la). Four cases showed focal staining for actin in the basaloid cells, often in a cell membrane pattern. Vimentin immunoreactivity was demonstrated in three cases. Staining for S-100 protein was negative.
The associated squamous cell carcinornaJcarcinoma in situ component stained with AEl/AE3 and 34PE12, but not with CAM5.2. Staining for CEA was also demonstrated, particularly in the keratinizing cells. S100 protein, actin and vimentin immunoreactivity was absent. In case 4, the spindle cell component was negative for all markers except vimentin. In case 2 , the small cell component stained focally with CAM5.2 and AEl/AE3,and diffusely with CEA antibody. In the adenoid cystic carcinomas studied for comparison, CAM5.2 and AEl/AE3 stained all neoplastic cells, but much more strongly in the ductal epithelium interspersed throughout the masses of basaloid cells. 34PE12 stained the ductal cells similarly, but it stained the basaloid cells inconsistently. CEA-immunoreactivity was confined to the ductal component, whereas positivity for S-100 protein, actin and vimentin was confined to the basaloid component. The results were identical to those previously reported for adenoid cystic carcin ~ m a ~ ~ .
42 W. Y .W. Tsang et a2
Discussion
Figure 7. Carcinoma in situ changes in the squamous epithelium overlying the tumour. H & E.
Figure 8. Squamous differentiation (arrow)in this island of basaloid tumour. H & E.
Basaloid-squamous carcinoma, first characterized by Wain et aL1, is a rare but distinctive malignant tumour occurring in the larynx, pharynx and base of tongue‘. It mainly affectsmen in the sixth and seventh decades of life. This aggressive neoplasm usually presents as high stage disease, and widespread metastasis frequently develops during its c o u r ~ e ~ ’ The ~ ~ .salient ~ ” . histological feature is an intimate association between a basaloid component with adenoid cystic carcinoma-like features and squamous carcinoma, although the latter component may be inconspicuous. The four cases in this series are similar to those previously reported, both clinically and histologically, including the typical comedonecrosis and prominent hyalinization. As reported in the literature, ‘adenoid cystic carcinoma’ or ‘carcinoma with adenoid cystic differentiation’ of the oesophagus occurs predominantly in elderly men in their sixties2-18.The patients usually present at an advanced stage, and most die within 1-2 years. Both local and distant metastases are common. Thus, the clinicopathological features, including those of the five cases in this series, are remarkably similar to those of basaloid-squamous carcinoma of the upper aerodigestive tract. However, the situation is in fact much more confusing. In the updated World Health Organization classification of oesophageal tumours, although ‘adenoid cystic carcinoma’ is considered the counterpart of the salivary gland tumours, with cribriform structures and two-cell-type differentiation, neither feature is apparent in the photomicrograph^^^. Furthermore, the vesicular nuclei of the tumour cells and the brisk mitoses, as evident in the illustrations, are more akin to basaloid-squamous than adenoid cystic carcinoma occurring in the major salivary gland^^'!^^. Scrutiny of the published reports shows that only a few cases appear to be bona fide examples of adenoid cystic carcinoma 5.1O.11.13, and at least two of these four cases have survived more than 3 Most cases are histologically identical to basaloid-squamous carcinoma2,3.7,9,12,16.17.28 and have behaved aggressively. However, the exact nature of some cases is difficult to ascertain4~8*14.15.25. Benisch & Toker12 have already proposed labelling tumours in the oesophagus with histological features of basaloid-squamous carcinoma as ‘carcinoma with adenoid cystic differentiation’ instead of ‘adenoid cystic carcinoma’, because of differences in histological features, aggressive clinical course and association with a neoplastic squamous component. This view has been supported by Epstein and coworkers3. Both ‘basaloid-squamous carcinoma’ and ‘carcinoma with adenoid cystic differentiation’ are
Basaloid-squamous carcinoma
Figure 9. a Small cell carcinoma component in case 2. b Spindle cell component in case 4. H & E.
Figure 10. a The basaloid cells are negative for cytokeratin while the mucosal glands are strongly positive. b Focal positivity for cytokeratin (arrows) occasionally observed; some positive cells appear to line abortive glands. Immunoperoxidase.
43
44 W.Y.W.Tsang et a1
Table 3. Immunohistochemical findings Staining* Case no.
1 2
3 4
5
Component Basaloid Squamous Basa1oid Squamous Small cells Basaloid Basaloid Spindle cells Basaloid Squamous Basaloid Squamous Basaloid Squamous Basaloid Squamous Basaloid
Adenoid cystic carcinoma Ductal Basaloid
CAM5.2
+ -
+I-
AEl/AE3
CEA
-
-
-
+++ + +++ ++ + +
+++
++
+ ++ + ++ ++ + ++ + +++ ++/+++
34fiE12
++
-
++ -
++I+++
Actin
Vimentin
+
+ +++ + + -
-
+++
*Percentage of positive cells quantified as: - =OX;
-
S-100
+
++ -
++
+
-
-
++ ++ ++
-
+++
+++
-/+/++
-
+ +
-/+
+++
-
-
+++
+++
+ = 1-10%; + + = 11-50%; + + + = > 50%.
appropriate designations for these uncommon oesophageal tumours, but we prefer the former because it is shorter and more convenient to use. The immunohistochemical profiles of the basaloidsquamous carcinomas of the upper aerodigestive tract and the oesophagus are similar, providing further evidence that they represent the same tumour type. A remarkable feature is the poor or lack of immunoreactivity for cytokeratin in the basaloid component. Since we have employed several antibodies immunoreactive with cytokeratins of a wide range of molecular weights and there are good internal controls, this finding is not artifactual. Furthermore, the few ultrastructural studies have shown that the basaloid cells are poor in organelles and cytoplasmic This is in striking contrast to the strong cytokeratin immunoreactivity in the squamous component of these tumours and in conventional squamous carcinoma of the oesophagus or upper aerodigestive tract29. Therefore, the basaloid cells in basaloid-squamous carcinoma appear to be largely undiffer-
entiated, sometimes exhibiting very focal epithelial (tubular) differentiation and inconsistent myoepithelial differentiation(as supported by actin-positivity). Adenoid cystic carcinoma remains the major differential diagnosis of basaloid-squamous carcinoma. In contrast to the latter, adenoid cystic carcinoma is characterized clinically by female predominance, earlier age of occurrence (40-60 years) and a more protracted clinical course27.Histologically, the focal continuity with the surface epithelium, and the association with squamous carcinoma or other neoplastic components are not features of adenoid cystic carcinoma. Even the solid variant of adenoid cystic carcinoma frequently exhibits identifiable two-cell-type differentiation (paler ductal epithelium and darker basaloid cells) and distinctive cribriform structures in areas", neither of which are found in basaloid-squamous carcinoma. The basaloid cells in adenoid cystic carcinoma possess small hyperchromatic nuclei with only mild pleomorphism and infrequent mitosis, differing from those of basaloid-
Basaloid-squamous carcinoma
45
Figure 11. a CEA immunostaining highlights the glandular spaces. b Membrane staining for actin is seen in some cases. Immunoperoxidase.
squamous carcinoma. Basaloid-squamous carcinoma also lacks the characteristic neurotropism of adenoid cystic carcinoma. Small cell carcinoma of the oesophagus23.24, another highly aggressive tumour, differs from basaloid-squamous carcinoma in showing more diffuse permeative growth, nuclear moulding, indistinct nucleoli, and lack of the stromal hyalinization and mucinous material. Tauchi et aL3” have recently described a superficial oesophageal carcinoma with basaloid features, which is associated with a better prognosis than conventional squamous cell carcinoma. These tumours resemble basal cell carcinoma of the skin, with striking nuclear palisading and without the pale nuclei and hyalinization of basaloid-squamous carcinoma. These authors have also identified a ‘mixed squamous-basaloid’ group which behaves aggressively. Although these ’mixed’ tumours were not illustrated, the authors stated that they correspond well to basaloid-squamous carcinoma. The histogenesis of basaloid-squamous carcinoma remains conjectural. This tumour appears immunohis-
tochemically and ultrastructurally to be mostly undifferentiated despite some superficial resemblance to adenoid cystic carcinoma. The oesophageal tumours have been postulated to arise from embryonal rests of the tracheobronchial tree18,submucosal glands or their intercalated d u ~ t sor~surface .~ epithelium12.However, we agree with Wain et al. * that basaloid-squamous carcinoma probably has its origin from a totipotent primitive cell which is capable of differentiating focally into epithelial structures, myoepithelium or other elements, and the tumour can probably be viewed as a peculiar variant of poorly differentiated squamous call carcinoma. We conclude, therefore, that basaloid-squamous carcinoma is a distinct clinicopathological entity, distinguishable from adenoid cystic carcinoma. It occurs mostly in the upper aerodigestive tract or oesophagus. In the literature, oesophageal tumours reported as ‘adenoid cystic carcinoma’ or ‘carcinoma with adenoid cystic differentiation’ represent a mixture of genuine adenoid cystic carcinoma (rare) and basaloid-squamous carcinoma (more common). It is important to make this
46 W. Y .W. Tsang et a1
distinction, since the former tumour appears to be much less aggressive. The rare pseudo-adenoid cystic squamous cell carcinoma of the anal canal, which is reported to be associated with a poor prognosis, is probably also the same tumour type3l.
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