It was considered that the extremely high Langerhans cell infiltration in the tumours was caused by HPV infection. The extremely large number of Langerhans cells in the tumours contributes to the favourable prognosis for HPV-infected lung cancer.

Aims-The incidence of lung cancer in Okinawa has been the highest in Japan since 1975, and squamous cell carcinoma (SCC), especially the well diVerentiated form, is the most prevalent form in Okinawa, although well diVerentiated SCC is relatively rare in mainland Japan. Furthermore, a high proportion of SCC of the lung in Okinawa was positive for human papillomavirus (HPV). In this study, we report recent striking changes in histological features and in the incidence of HPV infection. Methods-In Okinawa between 1986 and 1998, 1109 surgically resected lung tumours were examined histopathologically. In addition, human papillomavirus infection was detected by the polymerase chain reaction and Southern blot analysis in SCC cases reported in 1993 and 1995-8. Non-isotopic in situ hybridisation of HPV DNA was also carried out. Results-Up until 1994 SCC, especially the well diVerentiated form, was the most prevalent type of tumour. However, since 1995 the number of such cases has diminished steadily, accompanied by a slight rise in the incidence of adenocarcinoma. Although most present and past patients are heavy smokers, the incidence of SCC, especially the well diVerentiated form, continues to decrease steadily. Furthermore, in 1993, HPV was detected in 79% of all cases, and was particularly prevalent in the well diVerentiated form, but the rate fell to 68% in 1995, 35% in 1996, 23% in 1997, and 24% in 1998. The age distribution of patients, the male to female ratio, and the number of tumours overexpressing p53 protein did not change significantly over the study period, and thus did not correlate with changes in the diVerentiation of SCC. Conclusions-The decreasing incidence of viral infection correlates strongly with the falling numbers of SCC cases, especially well diVerentiated cases. These findings suggest that HPV might be involved in the development of SCC of the lung, aVecting the histological diVerentiation of SCC in particular, at least in Okinawa, a subtropical island in southern Japan. (J Clin Pathol 2000;53:676-684) Keywords: squamous cell carcinoma of the lung; histological diVerentiation; human papillomavirus Lung cancer increased 40-fold and 36-fold in Japanese men and women, respectively, between 1950 and 1997.

The rhabdoid cells in these three cases were considered to represent the dedifferentiated components of the accompanying adenocarcinoma. Dedifferentiated characteristics (neuroendocrine markers, GM-CSF, vimentin, and the aggressive behaviour) were evident.

In Okinawa, a subtropical island in Southern Japan, the incidence of oral squamous cell carcinoma is 1.5 times higher than that in mainland Japan. Sixty cases of oral squamous cell carcinoma from 1993 to 1996 in Okinawa and 42 cases over the same period in Sapporo were examined histologically. Human papillomavirus (HPV) and Epstein-Barr virus (EBV) were detected by polymerase chain reaction (PCR) amplification with primers specific for HPV and EBV. In situ hybridisations of the viruses were also carried out. In the case of Epstein-Barr virus, in situ PCR was also performed. Thirty-five (58.3%) Okinawan tumours were well-differentiated in type, but in Sapporo, 18 (42%) were of such type. In Okinawa, tumours of the mouth floor (10 cases, 16.7%) and oropharynx (12 cases, 20%) were frequently observed, whereas in Sapporo only five cases (12%) of each were found. HPV was demonstrated in 78% of Okinawan cases and 26.2% of Sapporon cases by PCR or non-isotopic in situ hybridisation (NISH). There were 76.6% (46 cases) of Okinawan and 38.1% (16 cases) of Sapporo cases positive for EBV by PCR. In only 12 Okinawan cases and 4 Sapporon cases, were positive signals demonstrated by in situ PCR on the cancer cells themselves. EBV was demonstrated in the large number of infiltrating lymphocytes, most of which were CD3+, and a few were CD19+. In Okinawa, HPV might be an important causative factor of oral squamous cell carcinoma and EBV a less important factor, whereas in Sapporo HPV and EBV might play only a small part in the aetiology of the tumour.

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