A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma.

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

The advantage of using a synoptic pathology report format for cutaneous melanoma.

AIMS: Although the synoptic format is being increasingly used for primary cutaneous melanoma pathology reporting, no study assessing its value has yet been reported in the literature. The aim was to determine whether the use of synoptic reports increases the frequency with which pathological features that may influence prognosis and guide management are documented. METHODS AND RESULTS: Melanoma pathology reports (n = 1692) were evaluated; 904 were in a synoptic format [671 Sydney Melanoma Unit (SMU) reports and 233 non-SMU reports] and 788 were non-synoptic (184 SMU reports and 604 non-SMU reports). Reports (n = 1354) from 677 patients who had both a SMU report and a non-SMU report were compared. Almost all features were reported more frequently in synoptic than in non-synoptic reports (P < 0.001). No significant differences were found in the frequency of reporting the main pathological features between SMU and non-SMU synoptic reports. Synoptic reports were more frequently used by SMU (78%) than by non-SMU pathologists (28%). CONCLUSIONS: This is the first study to provide objective evidence that synoptic pathology reports for melanoma are more complete than non-synoptic reports (regardless of whether the reports are generated within or outside a specialist melanoma centre). All synoptic reports should include the facility for free text, be tailored to individual institutional requirements and be updated regularly to be of maximal value.

Myopericytoma: a unifying term for a spectrum of tumours that show overlapping features with myofibroma. A review of 14 cases.

BACKGROUND: Myopericytoma (MPC) is a recently proposed term to describe a group of tumours that originate from perivascular myoid cells and show a range of histological growth patterns. Only a small number of series describing MPC have been reported. MPC is frequently misdiagnosed as a sarcoma. AIMS: To document the clinical and histopathological findings of a series of MPCs, to describe the range of growth patterns and morphological spectrum, and to compare MPC with myofibroma (MF). PATIENTS/METHODS: Fourteen patients with features of MPC and/or MF were identified from the archival files of the department of anatomical pathology, Royal Prince Alfred Hospital, Sydney, Australia. RESULTS: There were six female and eight male patients. The mean and median patient ages were 37 and 35.5 years, respectively. The tumours were located in the skin, subcutis, or superficial soft tissues of the distal extremities (13 patients) or the head and neck region (one patient), and showed a spectrum of morphological appearances. They were divided into two groups based upon the predominant growth pattern corresponding to MPC (seven cases) and MF (seven cases). The feature most suggestive of MPC was the presence of a concentric perivascular arrangement of plump spindle shaped cells. The presence of a zonation/biphasic appearance was most characteristic of MF. CONCLUSIONS: MPC exhibits a spectrum of growth patterns that overlap with MF. Tumours can be designated as MPC or MF depending on the predominant growth pattern.

Surgical biopsy with intra-operative frozen section. An accurate and cost-effective method for diagnosis of musculoskeletal sarcomas.

The most appropriate protocol for the biopsy of musculoskeletal tumours is controversial, with some authors advocating CT-guided core biopsy. At our hospital the initial biopsies of most musculoskeletal tumours has been by operative core biopsy with evaluation by frozen section which determines whether diagnostic tissue has been obtained and, if possible, gives the definitive diagnosis. In order to determine the accuracy and cost-effectiveness of this protocol we have undertaken a retrospective audit of biopsies of musculoskeletal tumours performed over a period of two years. A total of 104 patients had biopsies according to this regime. All gave the diagnosis apart from one minor error which did not alter the management of the patient. There was no requirement for re-biopsy. This protocol was more labour-intensive and 38% more costly than CT-guided core biopsy (AU$1804 vs AU$1308). However, the accuracy and avoidance of the anxiety associated with repeat biopsy outweighed these disadvantages.

Activation of the extracellular signal regulated kinase (ERK) pathway in human melanoma.

BACKGROUND: Several studies suggest that melanoma may be resistant to treatment because of resistance to apoptosis and that this may be the result of activation of the extracellular signal regulated kinase (ERK1/2) pathway. AIMS: To test this hypothesis by examining the expression of ERK1/2 and its activated form in histological sections of melanoma and its relation to known prognostic features of the disease. MATERIALS/METHODS: Immunohistochemistry with antibodies to ERK1/2 and phosphorylated ERK (p-ERK) was performed on formalin fixed sections from 42 primary melanomas, 38 metastases, and 20 naevi. Fourteen of the primary melanomas were in the radial and 28 in the vertical growth phase. RESULTS: ERK1/2 was widely expressed (100%) in all the (pigmented) lesions studied. p-ERK1/2 expression was much lower in compound (32.4%) and dysplastic (54.5%) naevi than in primary melanoma (nodular 78.8%, superficial spreading 67%) and subcutaneous metastases (76.3%). p-ERK expression was much lower in lymph node metastases (48.5%), suggesting that the microenvironment may influence the activation of ERK. There was a (non-significant) trend for p-ERK expression to be higher in thick (>1.0 mm) versus thin (< or =1.0 mm) melanoma (p = 0.23). There was a trend for overall survival to be related to p-ERK expression in patients with melanoma over 1 mm in thickness. CONCLUSIONS: Expression of activated ERK1/2 in melanocytic lesions appears to be related to malignant potential so that activation of ERK1/2 may be important in melanoma progression. These results provide important histological support for the proposal that inhibition of this signalling pathway may be useful in treatment of melanoma.

En-bloc resection, extracorporeal irradiation, and re-implantation in limb salvage for bony malignancies.

We treated 50 patients with bony malignancy by en-bloc resection, extracorporeal irradiation with 50 Gy and re-implantation of the bone segment. The mean survivor follow-up was 38 months (12 to 92) when 42 patients were alive and without disease. There were four recurrences. The functional results were good according to the Mankin score (17 excellent, 13 good, nine fair, three failures), the Musculoskeletal Tumour Society score (mean 77) and the Toronto Extremity Salvage score (mean 81). There was solid union, but bone resorption was seen in some cases. The dose of radiation was lethal to all cells and produced a dead autograft of perfect fit. Extracorporeal irradiation is a useful technique for limb salvage when there is reasonable residual bone stock. It allows effective re-attachment of tendons and produces a lasting biological reconstruction. There should be no risk of local recurrence or of radiotherapy-induced malignancy in the replanted bone.

Immunocytochemical analysis of the cellular infiltrate in primary regressing and non-regressing malignant melanoma.

Spontaneous regression occurs in a small proportion of malignant melanomas, and it is important to understand the processes involved in its induction as this may give a guide to future therapies for this disease. We have examined 36 primary malignant melanomas (19 regressing, 17 non-regressing) and identified the cellular phenotypes and activation states of the cells infiltrating regressing and non-regressing primary melanomas by immunochemistry. We have found a significantly increased number of CD3-positive cells and an increased ratio of CD4/CD8-positive cells infiltrating regressing compared to non-regressing tumors. In addition, the expression of the interleukin 2 receptor, an activation marker for T cells, was increased. However, there were no significant differences in class II MHC, CD1, intercellular adhesion molecule 1 (ICAM1), or melanoma-associated differentiation-antigen expression in these tumors. These data are consistent with melanoma regression being induced by activated CD4 T cells and do not seem to be related to the differentiation markers we have examined on these tumors.

Prevalence and distribution of ret/ptc 1, 2, and 3 in papillary thyroid carcinoma in New Caledonia and Australia.

The world's highest incidence of thyroid cancer has been reported among females in New Caledonia, a French overseas territory in the Pacific located between Australia and Fiji. To date, no molecular genetic studies in this population are available. Over the past few years, the oncogenic rearrangement of the ret protooncogene (ret/ptc) has been studied in papillary carcinomas in different populations. In this study, we investigated the prevalence and distribution of ret/ptc1, 2, and 3 in papillary thyroid carcinoma from the New Caledonian population and compared the pattern with that of an Australian population. Fresh-frozen and paraffin-embedded papillary carcinomas from 27 New Caledonian and 20 Australian patients were examined for ret rearrangements by means of RT-PCR with primers flanking the chimeric region, followed by hybridization with radioactive probes. ret/ptc was present in 70% of the New Caledonian and in 85% of the Australian samples. Multiple rearrangements were detected and confirmed by sequencing in 19 cases, 4 of which had 3 types of rearrangements in the same tumor. This study demonstrates a high prevalence of ret/ptc in New Caledonian and Australian papillary carcinoma. The findings of multiple ret/ptc in the same tumor suggest that some thyroid neoplasms may indeed be polyclonal.

Cutaneous melanomas that defy conventional prognostic indicators.

Tumor thickness is usually an accurate prognostic indicator for the patient with melanoma. However, very thin primary melanomas occasionally recur locally or metastasize, whereas some patients with very thick primary melanomas survive far longer than expected. There is also a group of patients with primary melanomas of various thicknesses who relapse after a very long disease-free interval. The large database of the Sydney Melanoma Unit which now contains comprehensive long-term follow-up on more than 13,000 patients treated over a 45-year period, has provided a unique opportunity to study melanomas that defy conventional prognostic indicators. Recurrence developed in 2.8% of melanoma patients classified as stage I (pTNM staging system) and with very thin lesions (< 0.50 mm). These recurrences developed more frequently in women than men and histologically were found to be associated with ulceration, high mitotic activity, and invasion to Clark's level IV, but not with regression. Concurrent lymph node metastases (stage III) were present in 3.1% of patients with very thin lesions (< 0.50 mm). In this group, most patients were men, and every lesion displayed regression. Total survival exceeded 15 years in 15.7% of stage II and III patients with very thick lesions (> 5.5 mm). In 1.7% of patients with lesions of any thickness, the disease-free interval before relapse was > 15 years. Neither in patients with very thick lesions surviving for > 15 years, nor in those with a disease-free interval of > 15 years was it consistently possible to show the presence or absence of any of the histological features usually considered to be of prognostic significance.

Thin malignant melanomas and recurrence potential.

Of 846 patients with stage I malignant melanoma that was less than 0.76-mm thick who were followed up for two to 31 years, 61 (7.2%) developed a recurrence. For those patients who did not initially undergo an elective lymph node dissection, the majority of first recurrences were at regional lymph nodes. Attempts have been made to identify those patients at risk of relapsing. Axial lesions, particularly those on the scalp, had the highest recurrence rate, with 15% of all thin scalp lesions recurring compared with only 4% of all thin extremity lesions. Three histological features proved to be useful prognostic indicators when analyzed by single-factor analysis. Evidence of ulceration in the primary lesion increased the recurrence rate from 6.7% to 26.1%. While only 4.3% of lesions displaying low mitotic activity recurred, this rate rose to 23.8% for those lesions of a high mitotic grade. Only 5% of Clark's level II lesions recurred, compared with about 12% of lesions at either level III or IV. Evidence of regression in thin lesions had no deleterious effect on prognosis. This study defines a small subset of patients who may benefit from elective lymph node dissection.

Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes.

The value of elective lymph node dissection (ELND) for melanoma patients with clinically uninvolved regional nodes remains controversial. However, it has been proposed that selective 'sentinel' lymph node biopsy reliably identifies individuals with micrometastases, who are most likely to benefit from full ELND. The aim of this study was to confirm that metastatic melanoma cells travelling in lymphatics do not bypass the sentinel node. After preoperative lymphoscintigraphy and intraoperative injection of blue dye around the primary melanoma site, sentinel node biopsy was performed in 118 melanoma patients for whom full ELND was planned as part of their definitive surgical treatment. A confidently identified sentinel node was tumour positive in 22 out of 105 regional lymph node fields (21%). In 18 cases the sentinel node was the only node found to be involved and in four cases, additional nodes were positive. In two other patients a positive node was found when the sentinel lymph node had been negative. However, in each case an avoidable error of technique had occurred and definite blue staining indicated that the positive node was in fact another sentinel node. This study thus confirms that sentinel lymph node status reliably indicates whether metastatic melanoma is present in regional lymph nodes.

Malignant pilomatrixoma of the scalp.

A 33 yr old man with a history of pilomatrixoma of the scalp, presented 5 mths later with a metastatic undifferentiated carcinoma in a submandibular lymph node. The cutaneous and lymph node tumors showed close histological similarity and features of malignancy. Investigations over 30 mths excluded a primary neoplasm elsewhere and consequently led to the diagnosis of malignant pilomatrixoma. These tumors are rare and most often located on the scalp. Most of the affected patients are middle age males. Wide excision is advised to avoid recurrences.

Unusual mycobacteria in 5 cases of opportunistic infections.

Five cases of infection due to an unusual mycobacterium are recorded, and the growth requirements and histological findings are discussed. On initial culture, these mycobacteria could be grown only on Lowenstein-Jensen medium containing ferric ammonium citrate, and the histology of the skin lesions was not always typical of mycobacterial disease.

Osteofibrous dysplasia of the tibia and fibula.

Osteofibrous dysplasia (ossifying fibroma of long bone) is an uncommon disorder of bone affecting the tibia and, rarely, the fibula of children and adolescents. It has been delineated from monostotic fibrous dysplasia, from which it can be distinguished by its radiological and histological characteristics and by its clinical course. We report 11 patients with osteofibrous dysplasia whose ages ranged from 10 months to 22 years. Four presented with a pathological fracture and in 2 a pseudarthrosis developed. A circumscribed area of intracortical lucency and expansion in the diaphysis is the characteristic radiological finding. Histologically there is a similarity to fibrous dysplasia but the trabeculae are lamellar or have a lamellar surface and most show osteoblastic rimming. Treatment may be difficult but more recent experience strongly favours a conservative approach wherever possible.

Hyalinising spindle cell tumour with giant rosettes: report of a case with unusual features including original histological and ultrastructural observations.

Hyalinising spindle cell tumour with giant rosettes (HSCTGR) is an uncommon, recently described low-grade sarcoma which shares many histological features with low-grade fibromyxoid sarcoma (LGFMS). We report a case of HSCTGR occurring in the deep soft tissues of the thigh of a 46-year-old woman, that presented as a slowly growing, painless mass. Microscopically the tumour was composed of spindled stromal cells amongst which were scattered so-called collagen rosettes. The distinctive feature of this case was the previously unreported finding of lymphoid cells of T-cell phenotype admixed with fibrohistioctyic cells in the cellular cuff surrounding the collagenous core of the rosettes. The case was further unusual in that it included focal areas of increased cellularity with a mitotic count of up to three per 10 high-power fields. While the latter feature has been associated with increased recurrences and metastases in LGFMS, it is not known whether the significance is similar in HSCTGR. The spindled stromal cells showed ultrastructural features of poorly differentiated fibroblasts, while those at the edges of the rosettes showed features of altered fibroblasts, some with a fibrohistiocytic appearance. These findings support the interpretation that HSCTGR forms part of the spectrum of sarcomas showing fibroblastic differentiation.

Perineural fibrous thickening within the dental pulp in type 1 neurofibromatosis: a case report.

A case of type 1 neurofibromatosis is presented that illustrates oral manifestations and their role in the diagnosis of this condition. The oral lesions may be overlooked in the diagnosis of intraoral swellings. This case documents the finding of perineural fibrous thickening within the dental pulp. Such changes may indicate pulpal involvement in neurofibromatosis and the effect of a genetically transmitted disorder upon the pulp.

[Cutaneous malignant melanoma in New Caledonia (South Pacific) 1973-1991. A study of 97 cases]. / Le mélanome malin cutané en Nouvelle-Calédonie (Pacifique Sud) 1973-1991. Etude de 97 observations.

The Cancer Registries have been operational in the South Pacific since 1958 (Papua New Guinea), Fiji (1965) and New Caledonia (1977) and complete cancer incidence rates are available, based on histologic data. We studied 97 melanomas, histologically confirmed, which were diagnosed in New Caledonia from 1973 to 1991. New Caledonia is located in the same latitude as Queensland in Australia, known for having the highest incidence of melanoma in the world. Standardised incidence rates (world population) were 9.82 and 7.65/100,000/year for European males and females, compared to 1.65 and 1.05 for Melanesian and Polynesian males and females. The European population is exposed and Melanesians/Polynesians are relatively protected as are black Americans or Africans. The mixed populations are protected, but no study is available as to the exact proportion of mixed people (20%?) in the entire population. For Europeans, among males, the main areas in which melanomas occur are the trunk (45%) the arm (13%) and the leg (13%). Among females, the main areas are the leg (27%), the trunk (20%) and the head (18%). Screening for melanoma has been more effective in the last 6 years, a period in which we diagnosed half the total cases and generally at earlier stages. Prognosis was poor for this period (1973-1991): the five year survival rates were 64% +/- 8%, not as good as in Europe or Australia, but these lesions were diagnosed between 1973 and 1985 and were generally more invasive. A better prognosis will probably be observed in a few years, and another evaluation of melanoma screening should be made in the future as well the study of precursors and early lesions.

Nasopharyngeal cyst simulating Kaposi's sarcoma in an HIV-infected patient.

A case of nasopharyngeal cyst in a 30-year-old male homosexual intravenous drug user infected with the human immunodeficiency virus (HIV) is presented. The similarity in clinical presentation of nasopharyngeal cyst and Kaposi's sarcoma is discussed.

Melanocytic lesions of the face: diagnostic pitfalls.

The pathologist often has a difficult task in evaluating melanocytic lesions. For lesions involving the face the consequences of misdiagnosis are compounded for both cosmetic and therapeutic reasons. In this article, the pathological features of common and uncommon benign and malignant melanocytic lesions are reviewed and pitfalls in their diagnosis are highlighted. Benign lesions resembling melanomas include regenerating naevus, "irritated" naevus, combined naevus, "ancient naevus", Spitz naevus, dysplastic naevus, halo naevus, variants of blue naevi, balloon and clear cell naevi, neurotised naevus and desmoplastic naevus. Melanomas that can easily be missed on presentation include desmoplastic, naevoid, regressed, myxoid and metastatic types as well as so-called malignant blue naevi. Pathological clues to benign lesions include good symmetry, V-shaped silhouette, absent epidermal invasion, uniform cellularity, deep maturation, absent or rare dermal mitoses and clustered Kamino bodies. Features more commonly present in melanomas include asymmetry, peripheral epidermal invasion, heavy or "dusty" pigmentation, deep and abnormal dermal mitoses, HMB45 positivity in deep dermal melanocytes, vascular invasion, neurotropism and satellites. Familiarity with the spectrum of melanocytic lesions and knowledge of the important distinguishing features should assist in interpretation. Occasionally, the use of ancillary studies may also provide additional useful information. Application of standard criteria for diagnosing such lesions should enable the correct diagnosis to be established in most cases.

Cancer occurrence in Vanuatu in the South Pacific, 1980-86.

A total of 269 pathologically confirmed carcinoma cases (118 male, 151 female) were recorded in the seven year period 1980 to 1986 in Vanuatu, an island nation within the Melanesia region in the South Pacific. Cervical cancer was numerically the most important malignancy in females (25% of all female cancers). In males, liver cancer was the most commonly observed (14.4% of all male cancers). Almost one-half (44.4%) of the available paraffin blocks from liver carcinoma cases (18 cases) demonstrated positivity of HBV antigens in liver tissue. The most interesting feature was the high proportion of thyroid cancers, especially in females. It represented 12.1 percent of all cancers in female and 5.2 percent in male Melanesians in Vanuatu. These percentages were found to be even higher than among Hawaiians for whom the highest incidence rates in the world have been recorded. Since our study was based solely on pathologically diagnosed cases, the findings should be regarded as minimum estimates.