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Markku Miettinen

Publications and source records attributed to Markku Miettinen.

At least 19 recordsLinked to original sources
PubMed2007

Calcareous lesions of the distal extremities resembling tumoral calcinosis (tumoral calcinosislike lesions): clinicopathologic study of 43 cases emphasizing a pathogenesis-based approach to classification.

Herein, we analyze the clinicopathologic features of 46 distal extremity lesions that have histologic features similar to conventional tumoral calcinosis (tumoral calcinosislike; TC-L). The study included 31 females and 12 males (whites:non-whites>3:1) ranging in age from 1 to 91 (mean, 39; median, 42) years. The lesions presented in fingers (n=20), feet (n=10), wrist (n=6), hands (5), toes (n=4), and ankle (n=1) were solitary in all but 5 patients and ranged in size from 0.3 to 4.5 (mean, 1.6; median, 1.4) cm. Chief initial complaints included presence of a painful (n=16) or asymptomatic (n=7) mass, and limitation of joint mobility (n=3). Pertinent clinical associations included antecedent trauma (n=7), scleroderma (n=3), long-standing osteoarthritis (n=3), bony deformities (n=5), including 2 infants with congenital hand malformations, and chronic renal failure (n=2). Patients were stratified into one of the 3 recognized clinical settings of TC: primary normophosphatemic (n=17), secondary (n=5), or primary hyperphosphatemic TC (n=1). The 20 remaining patients were placed in an "indeterminate TC" category. Most lesions were located in tenosynovial/fascial tissue, but 13 lesions involved dermis and 1 was intra-articular. Histologically, the process consisted of multiple cystic or cleftlike spaces bordered by histiocytes, osteoclastlike giant cells, and a variable inflammatory infiltrate and containing fibrin, granular calcific debris, and calcospherites. Pools of calcific debris bordered by sclerotic collagen and a sparse cellular element predominated in 4 cases. Cartilaginous metaplasia was identified in 10 lesions and evidence of hemorrhage or specific injury was observed in 12 examples. Follow-up data for 22 patients (interval range, 1 to 30 y; median, 6 y) revealed 17 individuals with no evidence of recurrent disease or the development of additional lesions after simple (local) excision. One patient (indeterminate TC) required reexcision of a thumb mass 1 year after surgery. All 3 scleroderma patients developed additional TC-L lesions. Acral TC-L lesions are histologically similar to conventional TC, but present as smaller size lesions. Most TC-L lesions are closely aligned with primary normophosphatemic or secondary TC. Acral TC-L lesions may be the first manifestation of scleroderma, where the process has the potential to follow an unrelenting course.

Adolescent↗
PubMed2006

A (9;11)(q34;q13) translocation in a hibernoma.

The diagnosis of hibernoma has historically been made by histopathologic examination and finding of characteristic brown fat cells with granular multivacuolated cytoplasm. The diagnosis of hibernoma may be complicated, however, because seemingly diagnostic cells could be mistakenly identified as lipoblasts, leading to the erroneous diagnosis of well-differentiated liposarcoma. Cytogenetic alterations in lipomatous tumors are well established and could be used for diagnostic purposes. Previous cytogenetic abnormalities reported in hibernomas have included alteration of 11q13 region. Here, we present a case of a hibernoma with a novel cytogenetic alteration involving a reciprocal translocation between 9q and 11q that was useful in establishing the final diagnosis.

Adult↗
PubMed2006

From morphological to molecular diagnosis of soft tissue tumors.

Cytogenetic discoveries of balanced translocations in soft tissue tumors have opened the way to molecular genetic definition of these translocations as gene fusions from the late 1980s. Many sarcomas are known to have such fusions, and the demonstration of the fusion transcripts in tumor tissue is of great value in specific diagnosis of synovial sarcoma (SYT-SSX), Ewing sarcoma (EWS-Fli1), clear cell sarcoma (EWS-ATF1), myxoid liposarcoma (FUS-CHOP), and other sarcomas. These translocations are believed to be disease-specific and pathogenetic forces, despite occasional observations to the contrary. Demonstration of SYT-SSX and EWS-ATF1 fusion assists in the diagnosis of synovial and clear cell sarcomas in unusual locations, such as the gastrointestinal tract, where these tumors occur with low frequency. Demonstration of sarcoma translocations and their fusion by different assays is well established; use of in situ hybridization is limited by availability of specific probes. In two exceptional instances, the same translocation and gene fusion occurs in two unrelated diseases: ETV6-NTRK fusion in infantile fibrosarcoma and secretory carcinoma of the breast, and ALK-TPM3 fusion in inflammatory myofibroblastic tumor and large cell anaplastic lymphoma. Thus, the target cell of the genetic change is an important factor to define the resulting disease. Activating mutations in two related receptor tyrosine kinases (RTKs), KIT, and platelet-derived growth factor receptor alpha (PDGFRA) is central to the pathogenesis of gastrointestinal stromal tumors (GISTs), and countering the mutational activation by specific tyrosine kinase inhibitors, such as Imatinib mesylate, is now standard treatment for metastatic GISTs. KIT exon 11 mutations (in frame deletions, point mutations, and duplications) occur in GISTs of all locations, whereas a characteristic exon 9 insertion-duplication AY502-503 is nearly specific for intestinal vs gastric tumors. In contrast, PDGFRA mutations are nearly specific for gastric GISTs, especially those with epithelioid morphology. Mutation type influences therapy responsiveness, but fortunately very few GISTs carry primarily Imatinib-resistant mutations. Secondary drug resistance acquired during Imatinib treatment based on new, Imatinib-resistant mutations is a major problem limiting treatment success. Loss of NF2 tumor suppressor gene in a biallelic fashion is believed to be central in the pathogenesis of neurofibromatosis 2 (NF2) associated and sporadic schwannomas and meningiomas. The mechanism includes nonsense or missense mutation in NF2 gene, and loss of the other NF2 allele as a part of losses in chromosome 22q. Schwannoma types may differ in their pathogenesis: gastrointestinal schwannomas lack NF2 changes suggesting a different pathogenesis. Intraneural and sclerosing perineuriomas display similar NF2 gene alterations as seen in meningioma, indicating a similar pathogenesis and molecular homology. Specific viral sequences of human herpesvirus 8 (HHV8) are diagnostic markers for Kaposi sarcoma (KS), and are absent in angiosarcoma. Despite discovery on simian virus SV40 sequences in mesothelioma as a possible pathogenetic factor, recent studies suggest that the presence of these sequences may be artifactual and based on common presence of some SV40 sequences as PCR contaminants.

Genetic Testing↗
PubMed2006

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology.

Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors of the gastrointestinal tract. Activating KIT or PDGFRA (platelet-derived growth factor receptor alpha) mutations have been shown to be a major force in GIST pathogenesis. Recently, a previously undescribed N659K PDGFRA exon 14 mutation has been reported in GISTs. The purpose of this study was to evaluate the frequency of GISTs with PDGFRA exon 14 mutations and define the clinicopathologic profile of such tumors. In all, 200 GISTs negative for mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were evaluated for PDGFRA exon 14 mutations by PCR amplification and direct sequencing. Mutations were found in 11 of 119 (9%) gastric GISTs. None of the 81 GISTs from other than gastric location had such a PDGFRA mutation. A majority of these mutations (eight cases) represented simple 2125C>A or C>G missense mutations, leading to substitution of the lysine for asparagine (N659K). However, in two cases, 2123A>T missense mutations leading to substitution of the tyrosine for asparagine (N659Y) was found instead. Of 11 PDGFRA N659-mutant GISTs, 10 had pure epithelioid morphology. One tumor had mixed, predominantly spindle and focally epithelioid cell morphology. Frequency of PDGFRA N659-mutant GISTs among pure epithelioid GISTs was almost 19%. Immunohistochemically, the majority (64%) of these tumors lacked KIT expression or showed only focal scattered KIT positivity. Tumor size ranged from 2.5 to 16 cm (average 7.1 cm). Low mitotic activity, 5 cm tumors. Based on mitotic activity and tumor size, six tumors were classified as probably benign with very low malignant potential. Low to moderate malignant potential and high malignant potential was suggested in three and two tumors, respectively. In four cases with moderate or high malignant potential GISTs, a long-term follow-up (average 235.5 months) showed favorable course of disease.

Base Sequence↗
PubMed2006

Keratin expression in schwannoma; a study of 115 retroperitoneal and 22 peripheral schwannomas.

Schwannomas have been variably observed to be glial fibrillary acid protein (GFAP) and occasionally keratin positive, with antibodies reacting with multiple keratins (pankeratins, keratin cocktail (CK), but specific keratin polypeptides (K) have not been examined for in schwannoma. Since we observed CK positivity in retroperitoneal schwannomas, we wanted to study a large group of retroperitoneal and peripheral schwannomas with GFAP, CK and Ks to explore the frequency and biologic background of this finding. We immunohistochemically evaluated a large number of retroperitoneal (n=115) and peripheral schwannomas (n=22) for GFAP, 16 individual K and AE1/AE3 keratin cocktail. The great majority (104/115, 90%) of retroperitoneal schwannomas were positive for GFAP, and 72/104 (69%) cases were positive for AE1/AE3, often extensively. Both markers highlighted the cellular Antoni A areas, particularly adjacent to the capsule, myxoid or degenerative areas, and perivascularly. Most cases 87/104 (84%) stained for both AE1/AE3 and GFAP at least focally. No tumors stained for keratins that were GFAP negative. None of the immunostains for individual K showed positivity comparable to that obtained with AE1/AE3 CK. However, 62% were focally positive for high molecular weight K1 and 8/61 (13%) for K7. None of the retroperitoneal schwannomas were positive for other keratins including K2, 4, 5, 8, 9, 10 and K14-20. Peripheral schwannomas showed GFAP-positivity in only three of 22 cases (14%), and all were negative for keratins, both cocktail and individual K. We conclude that crossreactivity of AE1/AE3 with other intermediate filament proteins, such as GFAP, as previously observed in brain and glioma tissue, probably accounts for the extensive keratin-positivity seen in some retroperitoneal schwannomas. However, focal expression of K1 and K7 cannot be ruled out. Keratin-positive schwannomas should not be confused with other keratin-positive tumors, such as sarcomatoid carcinoma, mesothelioma, and synovial sarcoma.

Adolescent↗
PubMed2006

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs).

Mutually exclusive KIT and PDGFRA mutations are central events in GIST pathogenesis, and their understanding is becoming increasingly important, because specific treatment targeting oncogenic KIT and PDGFRA activation (especially imatinib mesylate) has become available. KIT mutations in GIST are clustered in four exons. Most common are exon 11 (juxtamembrane domain) mutations that include deletions, point mutations (affecting a few codons), and duplications (mostly in the 3' region). The latter mutations most often occur in gastric GISTs. Among gastric GISTs, tumors with deletions are more aggressive than those with point mutations; this does not seem to hold true in small intestinal GISTs. Exon 9 mutations (5-10%) usually are 2-codon 502-503 duplications, and these occur predominantly in intestinal versus gastric GISTs. Lesser imatinib sensitivity of these tumors has been noted. Kinase domain mutations are very rare; GISTs with such mutations are variably sensitive to imatinib. PDGFRA mutations usually occur in gastric GISTs, especially in the epithelioid variants; their overall frequency is approximately 30% to 40% of KIT mutation negative GISTs. Most common is exon 18 mutation leading Asp842Val at the protein level. This mutation causes imatinib resistance. Exon 12 and 14 mutations are rare. Most mutations are somatic (in tumor tissue only), but patients with familial GIST syndrome have consitutitonal KIT/PDGFRA mutations; >10 families have been reported worldwide with mutations generally similar to those in sporadic GISTs. GISTs in neurofibromatosis 1 patients, children, and Carney triad seem to lack GIST-specific KIT and PDGFRA mutations and may have a different disease mechanism. Secondary mutations usually occur in KIT kinase domains in patients after imatinib treatment resulting in resistance to this drug. Mutation genotyping is a tool in GIST diagnosis and in assessment of sensitivity to kinase inhibitors. This is a US government work. There are no restrictions on its use.

Adolescent↗
PubMed2006

Gastrointestinal stromal tumors: pathology and prognosis at different sites.

Gastrointestinal (GI) stromal tumors (GISTs) are the most common mesenchymal tumors specific to the GI tract, generally defined as KIT (CD117)-positive tumors with a characteristic set of histologic features. These tumors, derived from Cajal cells or their precursors, most commonly occur at the age >50 years in the stomach (60%), jejunum and ileum (30%), duodenum (4-5%), rectum (4%), colon and appendix (1-2%), and esophagus (<1%), and rarely as apparent primary extragastrointestinal tumors in the vicinity of stomach or intestines. Their overall incidence has been estimated as 10 to 20 per million, including incidental minimal tumors. GISTs are rare in children (<1%) and almost exclusively occur in stomach. They are common in patients with neurofibromatosis 1, who have a predisposition to (multiple) small intestinal GISTs. GISTs contain a spectrum from minute indolent tumors to sarcomas at all sites of occurrence. Their gross patterns are diverse, including nodular, cystic, and diverticular tumors. External involvement of pancreas and liver can simulate primary tumor in these organs. In general, gastric tumors have a more favorable prognosis than the intestinal ones with similar parameters. Gastric GISTs < or =10 cm and < or =5 mitoses per 50 HPFs have a low risk for metastasis, whereas those with >5 per 50 HPFs and >5 cm in diameter have a high risk for metastasis. In contrast, all intestinal GISTs >5 cm independent of mitotic rate have at least moderate risk for metastases, and all >5 mitoses per 50 HPFs have a high risk for metastases. Intestinal GISTs < or =5 cm with < or =5 mitoses per 50 HPFs have a low risk for metastases. Gastric GISTs can be divided into histologic subgroups including 4 spindle cell and 4 epithelioid variants. Intestinal GISTs are a histologically more homogeneous group and often contain distinctive extracellular collagen globules, skeinoid fibers. Immunohistochemical demonstration of KIT, CD34, or protein kinase theta positivity helps to properly identify these tumors.

Adolescent↗
PubMed2006

Gastrointestinal stromal tumors: differential diagnosis.

Availability of KIT tyrosine kinase inhibitors for specific treatment of GISTs has magnified the importance of accurate differential diagnosis of GIST from other tumors occurring in the GI tract and abdomen. The general problems in this distinction include histological mimicry of other mesenchymal tumors with GIST, occasional KIT-negativity of GIST, and KIT-positivity of non-GISTs. Up to 5% to 10% gastric GISTs and <2% of intestinal GISTs can be KIT-negative. The identification of these tumors as GISTs is based on knowledge of the spectrum of GIST morphology, and can be supported by molecular diagnosis of KIT and PDGFRA mutations (the latter pertain to gastric tumors). True smooth muscle tumors (rare in GI tract except in esophagus and colon) can be separated from GISTs by the eosinophilic tinctorial quality of tumor cells, positivity for smooth muscle markers, and negativity for KIT. Desmoids can form large GIST-like masses, but are composed of spindled or stellate-shaped cells in a densely collagenous stroma. Negativity for KIT and nuclear positivity for beta-catenin are differentiating features. GI schwannomas, melanoma, and rare primary clear cell sarcoma are S100-positive, usually with characteristic histology. The latter two can be KIT-positive. KIT-positive non-GISTs include some sarcomas, especially angiosarcoma and Ewing sarcoma, extramedullary myeloid tumor, seminoma, and a few carcinomas, notably small cell carcinoma of lung. Spurious KIT-positivity, seen with some polyclonal KIT antibodies, has been a source of confusion leading to probable false-positive results in fibroblastic tumors and occasional other sarcomas, such as leiomyosarcomas. Integration of histological features with carefully standardized immunohistochemistry, supported by KIT and PDGFRA mutation analysis, is the cornerstone of state-of-the art differential diagnosis of GIST. To comprehensively capture all GISTs, KIT immunostains should be performed on all unclassified epithelioid and mesenchymal tumors of the abdomen. This is a US government work. There are no restrictions on its use.

Diagnosis, Differential↗
PubMed2006

Occurrence of other malignancies in patients with gastrointestinal stromal tumors.

Almost one-third of gastrointestinal stromal tumors (GISTs) are discovered incidentally during investigative or therapeutic procedures for unrelated diseases. In this regard, GISTs may coexist with different types of cancer, either synchronously or metachronously. The frequency of this association and the spectrum of neoplasms involved have not been sufficiently analyzed. We conducted a review of the literature and our own records for cases with sporadic GISTs and other malignancies, with emphasis on solid tumors. Neurofibromatosis 1 and Carney triad-associated tumors were excluded. Based on these data, there were 518 cancers in 486 GIST patients among 4813 cases with informative data. The overall frequency of second tumors in different series varied from 4.5% to 33% (mean, 13%). A total of 29 patients had multiple malignancies. GISTs of gastric location were most commonly involved with other neoplasms, reflecting their overall high frequency (60%) of all GISTs. The major types of GIST-associated cancers were gastrointestinal carcinomas (n=228; 47%), lymphoma/leukemia, (n=36; 7%), and carcinomas of prostate (n=43; 9%), breast (n=34; 7%), kidney (n=27; 6%), lung (n=26; 5%), female genital tract (n=25; 5%), and carcinoid tumors (n=13; 3%). Other cancers included soft tissue and bone sarcomas (n=15; 3%), malignant melanoma (n=12; 2%), and seminoma (n=6; 1%). Occurrence of collision tumors and metastases of carcinoma or sarcoma into a GIST (the latter noted in 4 cases) can be challenging diagnostic problems. The potential nonrandom association and causal relationship between GIST and other neoplasms remain to be investigated.

Bone Neoplasms↗
PubMed2006

Sclerotic (fibroma-like) lipoma: a distinctive lipoma variant with a predilection for the distal extremities.

This report details the clinicopathologic and immunohistochemical findings identified in 21 cases of a fibrosclerotic variant of lipoma from acral sites that is frequently misdiagnosed as a fibromatous (nonlipogenic) process. The study includes 12 males and 9 females; aged 7 to 72 (mean and median, 39). The patients presented with solitary, mostly asymptomatic, masses that ranged from 0.6 to 2.2 (median, 1.2; mean, 1.3) cm and involved fingers (n=17), hands or wrists (n=3), and toes (n=1). Microscopically, the lesions were well-circumscribed nodules that showed very low to moderately low cellularity and consisted of cytologically bland spindled and stellate-shaped cells and a minor component of randomly dispersed adipocytes embedded in a collagenous to myxocollagenous stroma. Eight tumors were "fibroma-like" owing to their paucity of spindled cells, dense fibrosclerotic stroma, and inconspicuous vasculature. One tumor showed features of spindle cell/pleomorphic lipoma, whereas another demonstrated a vague onion skin-like arrangement of collagen reminiscent of sclerotic (storiform) fibroma. In all cases, the mitotic activity was negligible. Nonlipogenic tumor cells were immunoreactive for CD99 (6 of 6 cases), CD34 (6 of 8), S-100 protein (4 of 7), and smooth muscle actin (2 of 6). Follow-up data on 8 patients (range, 1 to 20 years; median, 9.5 years) revealed no recurrence in 6, but indicated the possibility of persistent tumor in the remaining 2 individuals after simple excision. Despite histological overlap in 1 case with the sclerotic fibroma, no patient displayed definitive clinical features of Cowden syndrome. Our study indicates that fibrosclerotic lipomas demonstrate a broader histological scope than what was initially described.

Adolescent↗
PubMed2006

Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up.

Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. This study analyzed 1091 tumors originally classified as smooth muscle tumors of the small intestine (including jejunum or ileum and excluding duodenum), and found that 906 (83%) of these were GISTs. The GIST patients had 55:45 male-to-female ratio with a median age of 59 years (range, 13-94 years). Only 0.6% of tumors occurred before the age of 21 years and 13.6% before the age of 40 years. The tumors varied from 0.3 to 40 cm (median, 7.0 cm) and most commonly presented with GI bleeding or acute abdomen; 18% were incidentally detected. Histologically, the tumors were relatively monotypic with spindle cell (86%), epithelioid (5%), or mixed patterns (9%). Skeinoid fibers were present in 44% of cases, and their presence was associated with a favorable course. Most epithelioid tumors were malignant, and this morphology sometimes emerged from less cellular and less mitotically active spindle cell tumors, suggesting that it represented a transformation. KIT was immunohistochemically detected in 98%, CD34 in 40%, smooth muscle actin in 34%, desmin in 0.2%, and S-100 protein in 14% of the tumors tested. Outcome was strongly dependent on tumor size and mitotic activity, with an overall 39% tumor-related mortality, twice that for gastric GISTs. Only <3% of tumors <5 cm and < or = 5 mitoses/50 HPF metastasized, whereas 86% of tumors >10 cm and >5 mitoses/50 HPF metastasized. In stark contrast to corresponding gastric tumors, tumors >10 cm with mitotic activity < or = 5/50 HPF and those < or = 5 cm with mitoses >5/50 HPF had a high metastatic rate (>50%); tumors >5 cm < or = 10 cm with low mitotic rate had a 24% metastatic rate. The median survival times of patients with low mitotic rate tumors who died of disease decreased by increasing tumor size. KIT exon 11 mutations were detected in 90 cases, exon 9 mutation in 17 cases, and exon 17 mutation in 1 case; the presence of mutation or mutation type was not prognostically significant. There were no PDGFRA exon 12 or 8 mutations. Systematic data on prognosis of small intestinal GISTs of various size and mitotic activity categories can be helpful in management and surveillance of patients with these tumors.

Adolescent↗
PubMed2006

Reticulohistiocytoma (solitary epithelioid histiocytoma): a clinicopathologic and immunohistochemical study of 44 cases.

Reticulohistiocytoma and multicentric reticulohistiocytosis are designations for uncommon, incompletely characterized histiocytic proliferations of the skin or soft tissues. In this study, we analyzed a uniform group of 44 lesions composed of epithelioid histiocytes, comprising a subset of lesions originally designated as reticulohistiocytoma, and propose designating them as "solitary epithelioid histiocytoma" (SEH), in line with the recently published classification proposal for histiocytic disorders. There were 26 males and 18 females with a median age of 35 years (range, 2.5-74 years). All patients had a superficial, circumscribed, mildly elevated, solitary lesion (size range, 1.5-11 mm; median, 4 mm), located in the trunk wall (n = 16), lower extremity (n = 12), head and neck (n = 8, including 2 in the oral cavity), upper extremity (n = 6), penis (n = 1), and an unspecified site (n = 1). Histologically, the lesions typically involved upper and mid-dermis and were not ulcerated. They were composed of large epithelioid histiocytes with a varying number of lymphocytes and neutrophils. The histiocytes had abundant, typically densely eosinophilic, cytoplasm and mostly mild, if any, nuclear atypia. Multinucleated forms with randomly oriented nuclei were also present. The histiocytes had low mitotic activity (range, 0-4 mitoses per 10 wide HPFs; median, 1 mitosis per 10 HPFs). The lesions contained varying numbers of CD3-positive T cells, whereas B lymphocytes, plasma cells, eosinophils, and mast cells were scant, if present at all. Immunohistochemically, the epithelioid histiocytes were positive for CD163, CD68, lysozyme (variably), and vimentin. They often had focal nuclear immunoreactivity for microphthalmia transcription factor, and they sometimes had focal reactivity for Factor XIIIa and S-100 protein. Membrane positivity for CD31, CD43, and CD45 was variable. The epithelioid histiocytes were consistently negative for CD3, CD20, CD30, HMB45, and keratins. All 12 patients with follow-up information had an uneventful clinical course with no recurrences (median, 13 years). SEH is a benign, probably reactive, histiocytic proliferation of unknown etiology. It needs to be distinguished from Rosai-Dorfman disease, juvenile xanthogranuloma, a variety of granulomatous conditions, and some malignant neoplasms, including histiocytic sarcoma, melanoma, and epithelioid sarcoma.

Adolescent↗
PubMed2006

Minute synovial sarcomas of the hands and feet: a clinicopathologic study of 21 tumors less than 1 cm.

Synovial sarcoma, one of the most common types of soft tissue sarcomas, usually presents in the proximal or middle portions of the extremities, often as a large mass with an aggressive clinical behavior. Gland-forming biphasic and spindle cell fibrous monophasic tumors are the most common subtypes. In this study, we evaluated 21 minute synovial sarcomas, <1 cm in diameter, from the hands and feet. These tumors occurred in 14 females and 7 males with a median age of 29 years (range, 8-60 years). Clinically, all tumors were thought to be benign processes such as a ganglion cyst or glomus tumor, and on microscopic examination, they were also often initially misinterpreted as benign lesions such as nerve sheath or (myo) fibroblastic tumors. Histologically, 7 tumors were biphasic and 14 were monophasic spindle cell variants. Microscopic calcifications were present in 8 cases and were prominent in 3 tumors. All monophasic tumors tested had elements positive for EMA, and all but one had reactivity for a keratin cocktail. S-100 protein-positive neuroma-like neural proliferations were commonly present in the monophasic but not in biphasic tumors. SYT-SSX fusion transcripts were demonstrated in 5 cases studied by polymerase chain reaction assay. All tumors were enucleated, followed by local reexcision of the site, and often combined with postoperative radiation. Three patients had amputation of the involved digit or metatarsal. Four patients had local recurrences, 2 of which were successfully treated; 2 of these patients were lost to follow-up. Despite some variation in treatment, all 12 patients with complete follow-up were alive and well, 2 to 32.2 years after surgery (median, 14.7 years), including 2 patients who received neither amputation nor postoperative radiation. Minute synovial sarcomas of hands and feet are clinically favorable tumors if completely excised; there is some evidence to suggest that they may be managed more conservatively than larger tumors. These tumors should be recognized as part of the spectrum of synovial sarcomas.

Adult↗
PubMed2006

Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases.

Gastrointestinal stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, most commonly occur sporadically, but there seems to be some increased tendency for these tumors to develop in patients with neurofibromatosis 1 (NF1). The clinicopathologic profile, KIT, and PDGFRA mutation status and long-term prognosis of patients with GIST in NF1 are incompletely characterized. In this study, we analyzed 45 patients who had NF1 and GIST. There were 26 females and 19 males with a median age of 49 years (10 years lower than the median age of GIST patients in general). A great majority of tumors occurred in the jejunum or ileum, with multiple tumors occurring in 28 cases. Ten patients had a duodenal and one had a gastric GIST. The most common presentations were gastrointestinal bleeding and anemia, and many patients had intermittent bleeding over several years. The majority of the tumors were small and mitotically inactive; only 7 had mitotic activity >5/50 HPFs and 15 tumors were >5 cm. Associated Cajal cell hyperplasia was common. One patient had an intraabdominal peri-intestinal neurofibroma. Five of 35 patients with follow-up died of metastatic disease; all of these had a tumor >5 cm, mitotic rate >5/50 HPFs, or both; three of these tumors were located in the duodenum. The presence of multiple small tumors was not associated with progressive disease. Most patients with long-term follow-up enjoyed a good prognosis; 2 died of other NF1-associated tumors (malignant peripheral nerve sheath tumors, brain tumor). None of the 16 tumors from 15 patients had a KIT exon 9, 11, 13, or 17 or PDGFRA exon 12 or 18 mutation as is typically seen in sporadic GISTs, indicating that GISTs in NF1 patients have a different pathogenesis than sporadic GISTs.

Adult↗
PubMed2006

Pulmonary microcystic fibromyxoma: Report of 3 cases.

Three cases of pulmonary myxoid tumors showing a variable degree of microcystic change are described. They are presented as incidental solitary peripheral lung nodules on routine radiologic studies. The patients included 2 women, 45 and 65 years old, and 1 man, 33 years old. Clinical work-up showed no evidence of neoplasia in other sites. Following surgical resection, no evidence of disease was observed after a mean follow-up of 48 months. The tumors ranged in size from 1 to 2.3 cm (mean 1.4 cm). Microscopically, the lesions were well circumscribed with conspicuous cystic change and myxoid stroma. Innocuous, widely-spaced, spindled to stellate tumor cells showed minimal nuclear pleomorphism and absence of mitotic activity. The myxoid stroma contained acid mucopolysaccharides, sensitive to hyaluronidase digestion. No epithelial, chondroid, neural, myofibroblastic, lipomatous or vascular differentiation was evident on immunohistochemical studies. Although these cases display cytologic features, myxoid stroma and benign clinical course characteristic of pulmonary myxomas; the presence of microcystic architecture is unique to the current series, and thus a descriptive designation "microcystic fibromyxoma" is suggested.

Adult↗
PubMed2006

Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis.

CONTEXT: Gastrointestinal stromal tumors (GISTs) are specific, generally Kit (CD117)-positive, mesenchymal tumors of the gastrointestinal tract encompassing a majority of tumors previously considered gastrointestinal smooth muscle tumors. They are believed to originate from interstitial cells of Cajal or related stem cells. OBJECTIVE: To review current clinicopathologically relevant information on GIST. DATA SOURCES: Literature in Medline and authors' own experience. CONCLUSIONS: GISTs usually occur in older adults (median age 55-60 years) and rarely in children in the second decade (<1%) throughout the gastrointestinal tract: 60% in stomach, 35% in small intestine, and less than 5% in rectum, esophagus, omentum, and mesentery; most GISTs in the latter 2 sites are metastatic. Five percent of GISTs occur in patients with neurofibromatosis type 1 syndrome (multiple small intestinal tumors) and in Carney triad (gastric epithelioid GISTs in young females). Familial GISTs occur in patients with inheritable germline Kit or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Histologically GISTs vary from spindle cell tumors to epithelioid and pleomorphic tumors. Most GISTs (95%) express Kit (CD117), CD34 (70%), and heavy caldesmon (80%), whereas 25% are positive for smooth muscle actin and less than 5% for desmin. Tumor size and mitotic activity are best predictive prognostic features; small intestinal tumors behave more aggressively than gastric tumors with similar parameters. Mutually exclusive gain-of-function Kit or PDGFRA mutations occur in a majority of GISTs representing in-frame deletions, point mutations, duplications and insertions. Mutations in Kit juxtamembrane domain (exon 11) are the most common in GISTs of all sites, whereas rare Kit extracellular domain (exon 9) Ala502-Tyr503 duplication is specific for intestinal GISTs. Mutations in PDGFRA have been identified in juxtamembrane (exon 12) and tyrosine kinase domains (exons 14 and 18), nearly exclusively in gastric GISTs, mostly in epithelioid variants. Some Kit and PDGFRA mutations have a prognostic value. Kit/PDGFRA tyrosine kinase inhibitor imatinib has been successfully used in the treatment of metastatic GISTs for more than 5 years. However, primary and acquired secondary resistance linked to certain types of Kit and PDGFRA mutations is limiting long-term success necessitating the use of alternative treatments.

Biomarkers, Tumor↗
PubMed2005

Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study.

Despite clearly defined histologic criteria, the prediction of tumor behavior for patients with gastrointestinal stromal tumors (GIST) still poses a challenge to pathologists. Therefore, searching for alternative markers that allow for better prognostic evaluation is an important task. To determine the practicability of immunohistochemical staining for p16 in clinical cases, we examined p16 protein expression in a group of 284 GISTs, a subset of which had long-term follow-up (median, 45 months; range, 1-204 months). P16 protein expression was ascertained on tissue microarrays as well as on standard sections. Survival analyses were carried out in 157 patients. P16 loss was found in 50% of GISTs, there being no correlation with age, sex, histologic subtype, signs of necrosis, or metastases. Patients having p16-negative tumors had a worse prognosis than those with p16-positive tumors (P = 0.012) with a 2.3-fold relative increased risk of dying of disease. P16 loss identified a subgroup of gastric tumors with a worse prognosis (P = 0.03). The multivariate configural frequency analysis identified two "antitypes," whose observed frequency was found to be significantly lower than the expected frequency [i.e., marker combinations: p16 positive, no metastases, and death of disease and p16 loss, metastases, and still alive]. The "type" whose observed frequency was significantly higher than the expected frequency consisted of the following marker pattern: p16 loss, necrosis, and death of disease (P < 0.001). In the multivariate Cox regression analysis, p16 loss, necrosis, and metastases each had independent prognostic value. P16 loss is a common molecular abnormality in GISTs and might be used in routine diagnosis to identify patients with high-risk tumors.

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