Kaarle Franssila

Occult papillary carcinoma of the thyroid. A “normal” finding in finland. A systematic autopsy study

The thyroids from 101 consecutive autopsies from Finland were subserially sectioned at 2‐ to 3‐mm intervals. From 36 thyroids, 52 foci of occult papillary carcinoma (OPC) were found, giving a prevalence rate of 35.6%, the highest reported rate in the world. The rate was higher, although not significantly, in males (43.3%) than in females (27.1%), but it did not correlate to the age of the patients. Twenty‐six glands contained one tumor focus and ten glands contained two to five tumor foci. Only a minority of the smallest tumors can be detected with the method used. The probable number of OPCs over 0.15 mm in diameter was calculated to be about 300 in this material. The tumor diameter varied from 0.15 mm to 14.0 mm, with 67% of tumors under 1.0 mm. The smallest tumors were usually circumscribed and were composed almost solely of follicles. Larger tumors had more papillary structures and were often invasive. Fibrosis and, in the largest OPCs, lymphocytic reaction were seen around the invasive islands. All tumors were positively stained for thyroglobulin and all but one of the tumors stained positively for epidermal keratin. OPC appears to arise from follicular cells of normal follicles. Apparently the great majority of the tumors remain small and circumscribed and even from those few tumors that grow larger and become invasive OPCs only a minimal proportion will ever become a clinical carcinoma. According to the study, OPC can be regarded as a normal finding which should not be treated when incidentally found. In order to avoid unnecessary operations it is suggested that incidentally found small OPCs (less than 5 mm in diameter) were called occult papillary tumor instead of carcinoma.

Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma

Although papillary thyroid carcinoma (PTC) displays strong heritability, no predisposing germ-line mutations have been found. We show that a common G/C polymorphism (rs2910164) within the pre-miR-146a sequence reduced the amount of pre- and mature miR-146a from the C allele 1.9- and 1.8-fold, respectively, compared with the G allele. This is matched by a similar decrease in the amount of each pre-miR generated from the corresponding pri-miR-146a in an in vitro processing reaction. The C allele also interfered with the binding of a nuclear factor to pre-miR-146a. The reduction in miR-146a led to less efficient inhibition of target genes involved in the Toll-like receptor and cytokine signaling pathway (TRAF6, IRAK1), and PTC1 (also known as CCDC6 or H4), a gene frequently rearranged with RET proto-oncogene in PTC. In an association study of 608 PTC patients and 901 controls, we found marked differences in genotype distribution of rs2910164 (P = 0.000002), the GC heterozygous state being associated with an increased risk of acquiring PTC (odds ratio = 1.62, P = 0.000007), and both homozygous states protective with odds ratio = 0.42 for the CC genotype (P = 0.003) and odds ratio = 0.69 for the GG genotype (P = 0.0006). Moreover, 4.7% of tumors had undergone somatic mutations of the SNP sequence. Thus, our data suggest that a common polymorphism in pre-miR-146a affects the miR expression, contributes to the genetic predisposition to PTC, and plays a role in the tumorigenesis through somatic mutation. Preliminary evidence suggests that these effects are mediated through target genes whose expression is affected by the SNP status.

KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors.

PURPOSE Mutated KIT and platelet-derived growth factor receptor alpha (PDGFRalpha) tyrosine kinases are the principal targets for imatinib mesylate in the treatment of gastrointestinal stromal tumors (GISTs). The frequency of activating KIT and PDGFRA gene mutations in most other histologic types of human cancer is not known. MATERIALS AND METHODS KIT exons 9, 11, 13, and 17 and PDGFRA exons 11 and 17 of 334 human cancers were screened for mutations using sensitive denaturing high-performance liquid chromatography (DHPLC). In addition, all KIT exons from 9 to 21 of 115 tumors were screened. Thirty-two histologic tumor types were examined. Samples with abnormal findings in DHLPC were sequenced. Immunostaining for the KIT protein (CD117) was performed in 322 (96.4%) of the 334 cases. RESULTS Of the 3,039 exons screened, only 17 had mutation. All 17 cases with either mutated KIT (n = 15) or PDGFRA (n = 2) were histologically GIST tumors, whereas none of the other histologic types of cancer (n = 316) harbored KIT or PDGFRA mutation. KIT immunostaining was rarely positive except in GISTs (18 of 18), small-cell lung cancer (10 of 30; 33%), and testicular teratocarcinoma (four of 17; 24%). Wild-type KIT gene amplification or chromosome 4 aneuploidy was common (seven of 12) in non-GIST tumors with strong KIT protein expression when studied with fluorescence in situ hybridization. CONCLUSION Despite frequent KIT protein expression in some tumor types, KIT and PDGFRA gene mutations are uncommon in most human cancers. Cancer KIT expression is frequently associated with multiple copies of the wild-type KIT gene.

Gain of 3q and deletion of 11q22 are frequent aberrations in mantle cell lymphoma

We used comparative genomic hybridization (CGH) to screen for DNA copy number changes in 34 specimens from 27 cases of mantle cell lymphoma (MCL). The most common gains were detected at 3q (52%), 8q (30%), and 15q (26%), whereas the most frequent losses involved 13q (41%), 1p (33%), 6q (30%), 9p (30%), and 11q (30%). The gain of 3q, with a minimal common region at 3q26.1‐27, appeared in more than half of the lymphomas, suggesting the location of an important oncogene here. A common deleted region at 11q22 was found in one‐third of the patients, which suggests that this region may harbor a tumor suppressor gene important in the tumorigenesis of MCL. The mean number of changes was higher in more aggressive blastoid variants of MCL than in lymphomas with typical morphology. Our results show that the chromosomal regions affected in MCL are highly consistent and are different from those seen in other types of non‐Hodgkins lymphoma. Genes Chromosomes Cancer 21:298–307, 1998.

Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: comparison with four other melanoma markers.

The diagnosis of metastatic malignant melanoma (MMM) may be difficult in surgical pathology, often complicated by the unpredictable spread of this tumor and its great variability on histologic evaluation. Traditionally used immunohistochemical markers on melanomas are insufficient because of either a relative lack of specificity (S100 protein) or variably reported sensitivity (HMB45). Information about some newer markers, such as tyrosinase (TYR) and Melan A, is more limited. Recently, based on the study of a small number of tumors, it was suggested that microphthalmia transcription factor (MITF) is 100% sensitive in the identification of metastatic melanoma. In the current study, we compared the diagnostic usefulness of MITF with that of four other markers in 266 cases of conventional metastatic melanomas from different sites, 33 cases of desmoplastic melanomas, and 1 case of melanoma with rhabdoid features. The specificity of MITF was evaluated by using a representative sample of control tumors. Microphthalmia transcription factor with nuclear positivity was seen in 235 of 266 cases of conventional MMM (88%), usually in more than 30% of tumor cells. However, some melanomas had only foci of MITF-and TYR-positive cells, whereas the majority of cells were generally S100 protein-positive. Only 1 of 30 desmoplastic melanomas (3%) had MITF-positive cells, representing epithelioid foci resembling conventional melanoma. Two cases had TYR in a similar pattern; all were HMB45-negative. One metastatic melanoma with rhabdoid features was negative for MITF and other markers except the S100 protein. Half of the S100 protein negative conventional melanomas (6 of 12) were MITF-positive, whereas 4 of 20 (20%) TYR-negative tumors had reactivity for MITF. The percentages of positive cases of MMM (10% or more tumor cells positive) diagnosed with the four other markers in descending order were 90% (S100 protein and TYR), 78% (melan-A), and 66% (HMB45). Microphthalmia transcription factor appeared to be specific, because significant reactivity was not found in 112 carcinomas, 20 lymphomas, 20 angiosarcomas, 20 fibrous histiocytomas, and 20 malignant peripheral nerve sheath tumors. However, positive nuclei were found focally among reactive histiocytes, especially in osteoclasts, epithelioid histiocytes, and sporadic other histiocytes. Microphthalmia transcription factor may be a valuable addition to the marker panel used in diagnosing melanoma, in combination with S100, TYR, and the other markers, but it is not present in cases of desmoplastic melanomas.

Hodgkin's disease, lymphocytic predominance nodular. Increased risk for subsequent non-Hodgkin's lymphomas.

Fifty‐one cases of Hodgkins disease, of lymphocytic predominance type, nodular subtype (HDLPN) were singled out from three sources: lymph nodes originally diagnosed as malignant lymphoma, nodes suspected of lymphoma and nodes suspected of toxoplasmosis. Two thirds of the 51 patients were men, and the median age was 42 years. The disease was characteristically unilocular and cervical and axillary nodes were most often involved. Local recurrences were common (in 13 cases). Oncological treatment (irradiation, cytostatics, or both) was given to 20 patients, whereas 31 patients remained untreated as the original histological diagnosis was not malignant. Despite the lack of treatment, the prognosis was good. Relative actuarial survival for the whole material was 93% at five years and 80% at ten years. During follow‐up, five patients developed a diffuse large–celled non‐Hodgkins lymphoma 4–11 years after the onset of HDLPN. The majority of the subsequent lymphomas cannot be therapy‐induced as only one of these patients had previously been treated (irradiated). Transition to other types of Hodgkins disease was observed only in two cases. It is concluded that HDLPN is a clinicopathological entity with a good prognosis, but that it may sometimes change into a more malignant lymphoma of the Hodgkins or non‐Hodgkins type.

Ki-67 expression level, histological subtype, and the International Prognostic Index as outcome predictors in mantle cell lymphoma

Abstract: Objectives : Mantle cell lymphoma (MCL) is characterised by translocation t(11;14) (q13;q32) leading to rearrangement of bcl1/CCND1 and overexpression of the cell‐cycle regulatory protein cyclin D1. We assessed the significance of the cell proliferation rate as an outcome predictor with the five components of the International Prognostic Index (IPI) and the histological subtypes of MCL. Patients and methods : The hospital case records and histopathological material of 127 patients diagnosed with MCL in a single centre were reviewed. The cell proliferation rate was assessed by Ki‐67 immunostaining and mitosis counting. Coxs multivariate regression model was used in multivariate survival analyses. The median follow‐up time was 87 months. Results : The mantle zone/nodular subtype of the common variant (19%) was associated with median survival of 70 months, the diffuse subtype of the common variant (64%) of 35 months, and the blastoid subtype (17%) of 11 months ( P  < 0.001). Patients with Ki‐67 expression in ≥ 26% (the upper tertile) of the lymphoma cells had median survival of only 13 months as compared with 45 months in the rest of the patients ( P  < 0.001). In a multivariate analysis high Ki‐67 expression, Ann Arbor stage III–IV, and age over 60 yr had independent influence on survival, whereas serum lactate dehydrogenase level, the number of extranodal disease sites, and performance status did not. Conclusions : The IPI may not be an optimal tool for outcome prediction in MCL, and a better prognostic index may be obtained by including Ki‐67 expression and possibly the histological subtype in the index.

Is the differentiation between papillary and follicular thyroid carcinoma valid

All cases of thyroid cancer diagnosed in Finland in 1958‐62 according to the Finnish Cancer Registry were re‐examined and re‐classified histologically. All the carcinomas in which papillary structures were seen regardless of the presence of follicular or solid areas as well, and also the rare purely follicular tumors with so‐called ground‐glass nuclei were classified as papillary carcinoma. The follicular carcinomas comprised the non‐papillary carcinomas in which follicular or trabecular structures were seen and in which the nuclei were not of ground‐glass type. There were 100 papillary and 60 follicular carcinomas. The histologic types differed in age and sex distribution, course of the disease and survival. The female:male ratio of the age‐adjusted incidence rates was 3.3 for papillary but only 1.2 for follicular carcinoma. Papillary carcinoma occurred in all age groups, but the follicular type only in middle and old age. Regional lymph node metastases were common (42%) and distant metastases rare (14%) in papillary carcinoma. The situation was reversed in follicular carcinoma (2% and 72%). The survival rates were significantly higher for papillary than for follicular carcinoma. The relative 5‐year rates were 83% and 54%. Papillary and follicular carcinoma appear to be two biologically different tumors with no intermediate or mixed forms. Therefore, they should be distinguished in clinical and in scientific work.

DNA Copy Number Changes in Thyroid Carcinoma

The genetic changes leading to thyroid cancer are poorly characterized. We studied DNA copy number changes by comparative genomic hybridization (CGH) in 69 primary thyroid carcinomas. In papillary carcinoma, DNA copy number changes were rare (3 of 26, 12%). The changes were all gains, and they were associated with old age (P = 0.01) and the presence of cervical lymph node metastases at presentation (P = 0.08). DNA copy number changes were much more frequent in follicular carcinoma (16 of 20, 80%) than in papillary carcinoma (P < 0.0001), and follicular carcinomas had more often deletions (13/20 versus 0/26, P < 0.0001). Loss of chromosome 22 was common in follicular carcinoma (n = 7, 35%), it was more often seen in widely invasive than in minimally invasive follicular carcinoma (54% versus 0%, P = 0.04), and it was associated with old age at presentation (P = 0.01). In three of the four patients with follicular carcinoma who died of cancer, the tumor had loss of chromosome 22. DNA copy number changes were found in 5 (50%) of the 10 medullary carcinomas studied. Four of these five carcinomas had deletions, and in two of them there was deletion of chromosome 22. Eleven (85%) of the thirteen anaplastic carcinomas investigated had DNA copy number changes, of which five had deletions, and one had deletion of chromosome 22. The most common gains in anaplastic carcinoma were in chromosomes 7p (p22-pter, 31%), 8q (q22-qter, 23%), and 9q (q34-qter, 23%). We conclude that DNA copy number changes are frequent in follicular, medullary, and anaplastic thyroid carcinoma but rare in papillary carcinoma when studied by CGH. Loss of chromosome 22 is particularly common in follicular carcinoma, and it is associated with the widely invasive type.

Occult papillary carcinoma of the thyroid in children and young adults: A systemic autopsy study in Finland

The thyroids from 93 autopsies performed on children and young adults younger than age 40 years, were subserially sectioned at 2‐to 3‐mm intervals. Thirteen thyroids revealed 17 foci of occult papillary carcinoma (OPC), giving a prevalence rate of 14%. The youngest affected patient was a boy aged 18 years. The prevalence rate of individuals between age 18 and 40 years was 27%. The rate appears to be rather constant in adults, although there may be a slight rise in middle age. The prevalence rate was higher for males, but no statistically significant difference was seen. The arise of OPCs after puberty would favor the view that hormonal factors are related to their appearance.Cancer 58:715‐719, 1986.