A case of radiation-induced mucosal melanoma in an immunohistochemically S-100-negative patient.

We report a case of radiation-induced mucosal melanoma in a 41-year-old woman with a history of childhood rhabdomyosarcoma of the nasal cavity that had been treated with radiotherapy. During the workup for the melanoma, the patient was found to be negative for S-100 protein on immunostaining. While many melanotic markers for the histologic confirmation of melanoma exist, they can be negative in some cases, such as ours. To the best of our knowledge, only 1 case of radiation-induced melanoma has been previously reported in the English-language literature, and in that case the patient was S-100-positive. Although our case is rare, it suggests another possible long-term adverse effect of radiotherapy. We also describe the morphologies and histology associated with diagnosing melanoma in an S-100-negative patient.

Chemical excitation of electrons: A dark path to melanoma.

Sunlight's ultraviolet wavelengths induce cyclobutane pyrimidine dimers (CPDs), which then cause mutations that lead to melanoma or to cancers of skin keratinocytes. In pigmented melanocytes, we found that CPDs arise both instantaneously and for hours after UV exposure ends. Remarkably, the CPDs arising in the dark originate by a novel pathway that resembles bioluminescence but does not end in light: First, UV activates the enzymes nitric oxide synthase (NOS) and NADPH oxidase (NOX), which generate the radicals nitric oxide (NO) and superoxide (O2(-)); these combine to form the powerful oxidant peroxynitrite (ONOO(-)). A fragment of the skin pigment melanin is then oxidized, exciting an electron to an energy level so high that it is rarely seen in biology. This process of chemically exciting electrons, termed "chemiexcitation", is used by fireflies to generate light but it had never been seen in mammalian cells. In melanocytes, the energy transfers radiationlessly to DNA, inducing CPDs. Chemiexcitation is a new source of genome instability, and it calls attention to endogenous mechanisms of genome maintenance that prevent electronic excitation or dissipate the energy of excited states. Chemiexcitation may also trigger pathogenesis in internal tissues because the same chemistry should arise wherever superoxide and nitric oxide arise near cells that contain melanin.

Protein oxidation, UVA and human DNA repair.

Solar UVB is carcinogenic. Nucleotide excision repair (NER) counteracts the carcinogenicity of UVB by excising potentially mutagenic UVB-induced DNA lesions. Despite this capacity for DNA repair, non-melanoma skin cancers and apparently normal sun-exposed skin contain huge numbers of mutations that are mostly attributable to unrepaired UVB-induced DNA lesions. UVA is about 20-times more abundant than UVB in incident sunlight. It does cause some DNA damage but this does not fully account for its biological impact. The effects of solar UVA are mediated by its interactions with cellular photosensitizers that generate reactive oxygen species (ROS) and induce oxidative stress. The proteome is a significant target for damage by UVA-induced ROS. In cultured human cells, UVA-induced oxidation of DNA repair proteins inhibits DNA repair. This article addresses the possible role of oxidative stress and protein oxidation in determining DNA repair efficiency - with particular reference to NER and skin cancer risk.

Keratoacanthoma: a distinct entity?

Keratoacanthoma (KA) are common but exceptional benign tumors, often appearing on sun-exposed areas of light skinned people and showing spontaneous resolution. The goal of this study was to review existing literature, to point out the etiological complexity of KA biology and to answer the controversial debate if or not KA is a distinct entity or a variant of squamous cell carcinoma (SCC). Relying on recent results, we highlight that KA is an individual lesion with a unique molecular signature caused by alterations in the TGFß signalling pathway. These recent findings will help to understand the nature of KA and to develop new reliable diagnostic tools, simplifying the discrimination of the histologically similar KA and SCC.

CNS Masson Tumors: Frequent Association With Therapeutic Radiation.

Masson tumor (MT, papillary endothelial hyperplasia) is an exaggerated form of thrombus reorganization rarely occurring in the central nervous system (CNS), where it presents as a mass or hemorrhage in parenchyma, meninges, or venous sinuses. MT is subclassified as type 1 arising within a histologically normal vessel, type 2 associated with a ruptured vascular malformation, and extravascular. Limited reports of CNS MT after radiosurgery, or especially external radiation therapy, have emerged. We searched our databases for cases reported from 2008 to present. Nine cases were identified, 6 of which were associated with receipt of therapeutic radiation for known lesions, with intervals of 1 to 25+ years to MT development (4 neoplasms=external beam radiation; 1 neoplasm=external beam radiation+radiosurgery, 1 arteriovenous malformation=radiosurgery). MTs were coassociated with radiation-induced vascular malformations (1 cavernoma-like, 1 massive) only in 2 of 6 irradiated patients, whereas the other 4 had MTs only. The 3 MTs in nonirradiated patients were extravascular, with 1 spontaneously developing in a hemangioblastoma. Seven of 9 MTs were intracerebral, 1 was within the spinal cord, and 1 was subdural. Papillary MT architecture was best appreciated by CD31 or CD34 immunohistochemistry, although ERG verified the endothelial monolayer population. Most CNS MTs at our institution have arisen in patients who have received therapeutic cranial radiation, many of whom received only external beam radiation. Although MTs could conceivably represent early, severe phases in radiation-induced cavernoma development, most were not found coassociated with the latter. This study further extends our knowledge of types of radiation-induced CNS vascular abnormalities.

Angiosarcoma (Stewart-Treves syndrome) in postmastectomy patients: report of 10 cases and review of literature.

AIMS: To study the clinicopathologic features of Stewart-Treves syndrome (STS) in postmastectomy patients including the epidemiology, presentation, morphology, differentiation, pathogenesis and therapeutic options. METHODS AND RESULTS: Ten cases of STS in postmastectomy patients were retrospectively identified in our archives, and immunohistochemistry for CD34, CD31, D2-40, HHV-8, CK, EMA and Ki-67 was performed. All ten patients presented with lymphedema after mastectomy as the first sign. Physical examination revealed multiple raised, pinkish-red papulo-vesicular lesions or ulceration as the early evidence of tumor in the field where radiation therapy was introduced. Microscopic examination revealed infiltrative proliferation of vessels and the heteromorphic tumor cells expressed CD34, CD31 and D2-40. Despite the various treatment modalities, 5 patients died in an average of 19 months, 4 patients survived to the last follow-up (9-31 months), and 1 patient got lost. CONCLUSIONS: STS is a fatal complication of postmastectomy lymphedema. Patients with STS have very poor prognosis. The key to improve patient's survival is the early diagnosis through a high alert of this disease by primary care physicians and comprehensive physical examination of patients with pertinent history and suspicious clinical presentations followed by prompt biopsy for definitive diagnosis.

Radiation-induced Sarcomas Occurring in Desmoid-type Fibromatosis Are Not Always Derived From the Primary Tumor.

Desmoid-type fibromatosis is a rare, highly infiltrative, locally destructive neoplasm that does not metastasize, but recurs often after primary surgery. Activation of the Wnt/ß-catenin pathway is the pathogenic mechanism, caused by an activating mutation in exon 3 of CTNNB1 (85% of the sporadic patients). Radiotherapy is a frequent treatment modality with a local control rate of approximately 80%. In very rare cases, this may result in the development of radiation-induced sarcoma. It is unclear whether these sarcomas develop from the primary tumor or arise de novo in normal tissue. In 4 tertiary referral centers for sarcoma, 6 cases of desmoid-type fibromatosis that subsequently developed sarcoma after radiotherapy were collected. The DNA sequence of CTNNB1 exon 3 in the desmoid-type fibromatosis and the subsequent postradiation sarcoma was determined. Sarcomas developed 5 to 21 years after the diagnosis of desmoid-type fibromatosis and included 2 osteosarcomas, 2 high-grade undifferentiated pleomorphic sarcomas, 1 fibrosarcoma, and 1 undifferentiated spindle cell sarcoma. Three patients showed a CTNNB1 hotspot mutation (T41A, S45F, or S45N) in both the desmoid-type fibromatosis and the radiation-induced sarcoma. The other 3 patients showed a CTNNB1 mutation in the original desmoid-type fibromatosis (2 with a T41A and 1 with an S45F mutation), which was absent in the sarcoma. In conclusion, postradiation sarcomas that occur in the treatment area of desmoid-type fibromatosis are extremely rare and can arise through malignant transformation of CTNNB1-mutated desmoid fibromatosis cells, but may also originate from CTNNB1 wild-type normal cells lying in the radiation field.

Can c-myc amplification reliably discriminate postradiation from primary angiosarcoma of the breast?

PURPOSE: Breast angiosarcomas are rare vascular malignancies that arise secondary to irradiation or de novo as primary tumours. The aim of this study is to know whether c-myc amplification can reliably discriminate these two entities. MATERIEL AND METHODS: Forty-seven patients treated for breast angiosarcomas were studied. Thirty-two patients were diagnosed with postradiation angiosarcomas after breast cancer treatment and 15 patients with primary angiosarcomas. Interphase fluorescence in situ hybridization (FISH) was performed by hybridization of probes covering C-MYC (chromosome 8q24.21) and CEP8 on tissue sections. RESULTS: Amplification (5- to 20-fold) of the c-myc oncogene was found in all breast radiation-induced angiosarcomas (32 tumours) but in none of the 15 primary angiosarcomas except one (7%). CONCLUSION: This study reinforces that there are true pathogenetic differences between the two types of breast angiosarcomas which are morphologically indistinguishable. These data point the pathways preferentially involved in the pathogenesis of post radiation angiosarcomas of the breast and may provide the basis for an additional targeted therapy.

MITF positivity in atypical fibroxanthoma: a diagnostic pitfall.

Microphthalmia transcription factor (MITF) is an established melanocytic marker originally credited with a high degree of specificity. We report a series of 11 atypical fibroxanthoma (AFX) from 2 laboratories showing positive MITF staining. Although there are multiple case reports illustrating MITF staining in a range of tumors, aberrant staining in AFX has not been previously reported. Awareness of the possibility of MITF positivity in AFX is important to avoid a misdiagnosis of melanoma. We also report positive MITF staining in 2 nonneural granular cell tumors and discuss the overlap with the granular subtype of AFX.

Desmoplastic nevus of chronically sun-damaged skin: an entity to be distinguished from desmoplastic melanoma.

Desmoplastic (sclerotic) nevus (DSN) can often be difficult to differentiate from desmoplastic melanoma (DM). This can be especially difficult when DSNs occur in a background of heavy solar elastosis. We have observed numerous examples of DSNs occurring in chronically sun-damaged (CSD) skin. In a subset of these cases, we have observed notable pleomorphism and nuclear atypia raising concern for the possibility of DM. In this study, we evaluated the clinical, histopathologic, and immunohistochemical findings in 23 cases of DSN occurring in CSD skin and compared them with 10 cases of DM. DSN on CSD skin is seen in adults (mean, 53.2 years) with a female predominance (70%) and upper (57%) and lower (17%) extremity anatomic locations. Most DSNs present as small flesh-colored macules or papules. Typical histologic features include symmetry, limited junctional growth, presence of a lentiginous component often with focal and limited pagetoid spread (extension across only a few rete ridges), and lack of deep extension. DSN and DM had a statistically significant difference in immunohistochemical staining for Melan-A and p75. Melan-A was positive in 18 of 20 DSNs and only 2 out of 10 DMs, whereas p75 was positive in all DMs (10/10) and was weakly positive in 11 of 20 DSN cases. We believe that our study offers some useful clinical, histologic, and immunohistochemical clues to help differentiate DSNs on CSD skin from DMs.

Radiation-induced synovial sarcoma of the lung diagnosed by gene analysis after the surgical resection of chondrosarcoma arising from the scapula.

The patient was a 62-year-old male who underwent wide resection and radiotherapy for right scapular chondrosarcoma 12 years ago. An abnormal shadow was detected in the right upper lung field included in the irradiated field on chest X-ray. Since the nodule tended to enlarge, a malignant lung tumor was suspected, and surgery was performed. On histological examination, spindle cells densely proliferated in a bundle pattern. Vimentin, bcl-2 protein, and CD99 were positive, and CD34, cytokeratin, AE1/AE3, and EMA were partially positive on immunohistochemical staining. The SYT-SSX (synaptotagmin- synovial sarcoma X) fusion gene was detected employing RT-PCR, based on which primary synovial sarcoma of the lung was diagnosed. The findings also matched the diagnostic criteria of radiation-induced sarcoma, suggesting radiation-induced primary synovial sarcoma of the lung. Primary synovial sarcoma of the lung is a rare tumor. It is difficult to diagnose based on cellular findings, and immunohistochemical and genetic investigations are essential. Radiation-induced sarcoma may develop through a long-term course, as seen in this patient, for which long-term follow-up after radiotherapy is important.

Radiation-associated meningiomas in children: clinical, pathological, and cytogenetic characteristics with a critical review of the literature.

OBJECT: Radiation-associated meningiomas (RAMs) arise after treatment with radiation to the cranium and are recognized as clinically separate from sporadic meningiomas. Compared with their sporadic counterparts, RAMs are often aggressive or malignant, likely to be multiple, and have a high recurrence rate. However, limited information exists about the clinical, pathological, and cytogenetic features of RAMs in pediatric patients. The authors report the findings in 9 children with meningiomas following therapeutic radiation to the cranium. In addition, they performed a critical review of the English language literature on pediatric RAMs. METHODS: Medical files were searched for patients who demonstrated meningiomas after a history of radiation to the brain. Only those patients in whom a meningioma occurred before the age of 18 years were included in this study. Clinical and demographic data along with the MIB-1 labeling index and cytogenetic studies were evaluated. RESULTS: The patients consisted of 5 males and 4 females with a median age of 5 years (range 2-10 years) at radiation therapy. The latency period was a median of 10 years after radiation therapy (range 6-13 years). The MIB-1 labeling index was a median of 6.6% (range 4%-10%). Five patients (55.6%) displayed multiple meningiomas at the first presentation. Histological types included clear cell meningioma in 1 patient, fibroblastic meningioma in 2, chordoid meningioma in 2, meningothelial meningioma in 7 (atypical in 2 cases), xanthomatous meningioma in 1, and chordoid meningioma in 1. Cytogenetic studies showed that the loss of 22q12.2 was the most common abnormality (3 patients), followed by complex cytogenetic abnormalities (2 patients) and rearrangements between chromosomes 1 and 12 (1 patient) and a 1p deletion (1 patient). CONCLUSIONS: In contrast to RAMs occurring in adults, those in pediatric patients show an increased incidence of multiplicity on first presentation and unusual histological variants, some of which are described here for the first time. There was no difference in the MIB-1 labeling index in children with RAMs as compared with that in children with non-RAMs.

A gene expression signature distinguishes normal tissues of sporadic and radiation-induced papillary thyroid carcinomas.

BACKGROUND: Papillary thyroid cancer (PTC) incidence increased dramatically in children after the Chernobyl accident, providing a unique opportunity to investigate the molecular features of radiation-induced thyroid cancer. In contrast to the previous studies that included age-related confounding factors, we investigated mRNA expression in PTC and in the normal contralateral tissues of patients exposed and non-exposed to the Chernobyl fallout, using age- and ethnicity-matched non-irradiated cohorts. METHODS: Forty-five patients were analysed by full-genome mRNA microarrays. Twenty-two patients have been exposed to the Chernobyl fallout; 23 others were age-matched and resident in the same regions of Ukraine, but were born after 1 March 1987, that is, were not exposed to ¹³¹I. RESULTS: A gene expression signature of 793 probes corresponding to 403 genes that permitted differentiation between normal tissues from patients exposed and from those who were not exposed to radiation was identified. The differences were confirmed by quantitative RT-PCR. Many deregulated pathways in the exposed normal tissues are related to cell proliferation. CONCLUSION: Our results suggest that a higher proliferation rate in normal thyroid could be related to radiation-induced cancer either as a predisposition or as a consequence of radiation. The signature allows the identification of radiation-induced thyroid cancers.

Pancreas-preserving segmental duodenectomy for gastrointestinal stromal tumor of the duodenum and splenectomy for splenic angiosarcoma.

BACKGROUND: Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract and occur rarely in the duodenum. Splenic angiosarcoma is an aggressive neoplasm with an extremely poor prognosis. METHODS: We report a case of a 70-year-old man hospitalized for abdominal pain in the upper quadrants, dyspepsia and nausea, previously treated for Hodgkin lymphoma 30 years ago. Abdominal CT showed a solid nodular lesion in the third portion of the duodenum, the presence of retropancreatic, aortic and caval lymph nodes, and four nodular splenic masses. (111)In-octreotide scintigraphy revealed pathological tissue accumulation in the duodenal region, and in the retropancreatic, retroduodenal, aortic and caval lymph nodes, suggesting a nonfunctioning neuroendocrine peripancreatic tumor. RESULTS: At exploratory laparotomy, an exophytic soft tumor was found originating from the third portion of the duodenum. Pancreas-preserving duodenectomy with duodenojejunostomy, splenectomy and lymphnodectomy of retropancreatic aortic and caval lymph nodes were performed. Pathological evaluation and immunohistochemical studies showed the presence of a duodenal gastrointestinal stromal tumor with low mitotic activity and a well-differentiated angiosarcoma localized to the spleen and invading lymph nodes. CONCLUSIONS: We speculated that the angiosarcoma and duodenal gastrointestinal stromal tumors of this patient were due to the treatment of Hodgkin lymphoma with radiotherapy 30 years ago. Pancreas-preserving segmental duodenectomy can be used to treat non-malignant neoplasms of the duodenum and avoid extensive surgery. Splenectomy is the treatment of choice for localized angiosarcomas but a strict follow-up is mandatory because of the possibility of recurrence.

Clinical, genetic, and immunohistochemical characterization of 70 Ukrainian adult cases with post-Chornobyl papillary thyroid carcinoma.

BACKGROUND: Increased incidence of papillary thyroid carcinoma (PTC) is observed as a consequence of radiation exposure in connection to the Chornobyl nuclear plant accident in 1986. In this study, we report a cohort of adult Ukrainian patients diagnosed with PTC from 2004 to 2008 following exposure at the age of 18 years or younger. METHODS: In total, 70 patients were identified and clinically characterized. The common BRAF 1799T>A mutation was assessed by pyrosequencing, the RET/PTC1 and RET/PTC3 (NCOA4) rearrangements by RT-PCR, and the expression of Ki-67 (MIB-1 index), BCL2, cyclin A, and cyclin D1 by immunohistochemistry. RESULTS: In total, 46/70 (66%) cases carried a BRAF mutation and/or a RET/PTC rearrangement. A BRAF mutation was detected in 26 tumors, RET/PTC1 in 20 cases, and RET/PTC3 in four cases. In four of these cases, BRAF mutation and RET/PTC rearrangement were coexisting. The BRAF mutation was underrepresented among PTCs with accompanying chronic lymphocytic thyroiditis (CLT) compared with PTCs without this feature (12 vs 44%). MIB-1 proliferation index determined by double staining with leukocyte common antigen was low (mean 0.8%; range 0.05-4.5%). Moreover, increased expression of cyclin A was observed in PTCs with a tumor size >2 cm compared with PTCs ≤2 cm (1.2 vs 0.6%). BCL2 and cyclin D1 showed frequent expression but without associations to clinical characteristics or amplification of the CCND1 locus. CONCLUSIONS: Our results suggest that this cohort has frequent BRAF mutation, RET/PTC1 rearrangement, and low proliferation index. Furthermore, BRAF 1799T>A was underrepresented in PTCs with CLT, and cyclin A expression was associated with increased PTC tumor size.

Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66 cases.

Postradiation cutaneous vascular lesions after treatment of breast carcinoma comprise a heterogeneous group of benign, atypical, and malignant lesions and are best regarded as points along a morphological spectrum. We analyzed a series of cutaneous angiosarcomas after treatment of breast cancer in comparison with control cases and cases of atypical vascular lesions with special emphasis on the expression and amplification of MYC. The 66 cases were divided into control cases (5), cases in which a slight vascular proliferation was seen after radiotherapy of breast cancer (12), cases of atypical vascular lesions after radiotherapy (16), cases of postradiation cutaneous angiosarcomas (25), and cases of angiosarcomas of skin and soft tissues unrelated to radiotherapy (8). None of the control cases (2 M, 3 F, 20-76 years), of cases showing slight vascular proliferation, dermal fibrosis and inflammation after radiotherapy of breast cancer (12 F, 48-79 years), of cases of atypical vascular lesions after radiotherapy (16 F, 29-81 years), and of cases of angiosarcomas of skin and soft tissues unrelated to radiotherapy (3 M, 5 F, 25-92 years) showed an amplification of MYC by FISH analysis. In striking contrast, in all cases of postradiation cutaneous angiosarcomas (25 F, 46-95 years), MYC amplification was found by FISH analysis in a variable number of counted nuclei. Immunohistochemically, strong positive nuclear staining for MYC and prox-1 was seen in cases of postradiation cutaneous angiosarcoma, whereas control cases and cases of atypical vascular proliferation after radiotherapy were negative for MYC, and stained only focally positive for prox-1 in a number of cases. In conclusion, the presence of MYC amplification represents an important additional diagnostic tool in the distinction of postradiation cutaneous angiosarcomas from atypical vascular lesions after radiotherapy. Immunohistochemical stainings for MYC are useful for mapping of these lesions and for careful tumor margin control.