Malignant phyllodes tumor in Lynch syndrome: a case report.

BACKGROUND: Lynch syndrome, or hereditary nonpolyposis colorectal cancer, is an autosomal dominant genetic syndrome that predisposes individuals to multiple cancer types. The known cancers associated with Lynch syndrome include colorectal and endometrial cancers as well as cancers of the stomach, ovary, urinary tract, hepatobiliary tract, pancreas, small bowel, and brain. There are no searchable cases of malignant phyllodes of the breast associated with Lynch syndrome. CASE PRESENTATION: Our patient was a 43-year-old Caucasian woman who felt a lump in her left breast and was found to have a spindle cell neoplasm. Definitive surgery revealed a malignant phyllodes tumor. On the basis of her cancer diagnosis and family history of multiple cancers, a Myriad myRisk Hereditary Cancer® test panel of 25 genes was performed. This testing revealed that she had a heterozygous MSH6 mutation as part of the Lynch syndrome panel. Due to positive margins, the patient received adjuvant chemotherapy with doxorubicin and ifosfamide. She also had a subsequent total abdominal hysterectomy and a bilateral salpingo-oophorectomy for risk reduction. She remains in a high-risk surveillance program. Her family members have been tested, which revealed that her two brothers and daughter also carry the genetic mutation. CONCLUSIONS: This case highlights the importance of genetic testing with rare malignancies because the full scope of phenotypic sequelae for known hereditary syndromes has not been mapped.

BCL-2 expression aids in the immunohistochemical prediction of the Oncotype DX breast cancer recurrence score.

BACKGROUND: The development of molecular techniques to estimate the risk of breast cancer recurrence has been a significant addition to the suite of tools available to pathologists and breast oncologists. It has previously been shown that immunohistochemistry can provide a surrogate measure of tumor recurrence risk, effectively providing a less expensive and more rapid estimate of risk without the need for send-out. However, concordance between gene expression-based and immunohistochemistry-based approaches has been modest, making it difficult to determine when one approach can serve as an adequate substitute for the other. We investigated whether immunohistochemistry-based methods can be augmented to provide a useful therapeutic indicator of risk. METHODS: We studied whether the Oncotype DX breast cancer recurrence score can be predicted from routinely acquired immunohistochemistry of breast tumor histology. We examined the effects of two modifications to conventional scoring measures based on ER, PR, Ki-67, and Her2 expression. First, we tested a mathematical transformation that produces a more diagnostic-relevant representation of the staining attributes of these markers. Second, we considered the expression of BCL-2, a complex involved in regulating apoptosis, as an additional prognostic marker. RESULTS: We found that the mathematical transformation improved concordance rates over the conventional scoring model. By establishing a measure of prediction certainty, we discovered that the difference in concordance between methods was even greater among the most certain cases in the sample, demonstrating the utility of an accompanying measure of prediction certainty. Including BCL-2 expression in the scoring model increased the number of breast cancer cases in the cohort that were considered high certainty, effectively expanding the applicability of this technique to a greater proportion of patients. CONCLUSIONS: Our results demonstrate an improvement in concordance between immunohistochemistry-based and gene expression-based methods to predict breast cancer recurrence risk following two simple modifications to the conventional scoring model.

Invasive breast carcinomas with ATM gene variants of uncertain significance share distinct histopathologic features.

The increasing availability of next-generation sequencing for clinical research dramatically improved our understanding of breast cancer genetics and resulted in detection of new mutation variants. Cancer risk data relating to some of these variants are insufficient, prompting the designation of variants of uncertain significance (VUS). The histopathologic characteristics of these variants have not been previously described. We propose to depict these characteristics and determine if invasive carcinomas with similar VUS genes share similar histomorphologic features. In total, 28 invasive breast cancers with VUS were retrospectively identified. Tumor sections were reviewed and a predefined set of histopathologic characteristics were documented and compared. Nine of the 28 cases were variants in the ATM gene and were found to share similar histologic characteristics; all had tumor cells with low nuclear grade, absent tumor infiltrating lymphocytes, as well as a marked desmoplastic response. A subset of the above findings were identified in variants of other genes but none had all findings collectively. Furthermore, variants of ATM gene had smaller tumor size, lower pathologic T stage at presentation, and more favorable surrogate molecular subtype compared to variants of other genes. These findings could potentially be used to reclassify VUS and predict which patients may harbor ATM mutations, and hence could have implications in triaging toward ATM variant identification for potential future targeted therapy.

Myeloproliferative Neoplasm or Reactive Process? A Rare Case of Acute Myeloid Leukemia and Transient Posttreatment Megakaryocytic Hyperplasia with JAK-2 Mutation.

Myeloproliferative neoplasms (MPNs) are hematopoietic malignancies characterized by unchecked proliferation of differentiated myeloid cells. The most common BCR-ABL1-negative MPNs are polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The discovery of JAK2 V617F mutation has improved our understanding of the molecular basis of MPN. The high frequency of JAK2 mutation in MPN makes JAK2 mutation testing an essential diagnostic tool and potential therapeutic target for MPN. Here, we present a rare case of a 34-year-old patient who was initially diagnosed with acute myeloid leukemia (AML) with mutated NPM1. After chemotherapy treatment followed by granulocyte colony stimulating factor administration, the patient achieved complete remission of AML. However, the bone marrow showed hypercellularity with granulocytic hyperplasia, markedly increased atypical megakaryocytes (50.2/HPF) with focal clustering, and reticulin fibrosis (3/4). JAK2 V617F mutation was also detected. Considering the possibility of AML transformed from a previous undiagnosed MPN, patient underwent peripheral blood allogenic stem cell transplant. This case illustrates the diagnostic challenges of firmly establishing a diagnosis between similar, but distinct, disease entities and an accurate clinicopathological differentiation is crucial.

Thymidine phosphorylase expression in B-cell lymphomas and its significance: a new prognostic marker?

OBJECTIVE: To explore thymidine phosphorylase (TP) expression in B-cell lymphomas (BCLs). TP is expressed by tumor and stromal cells in a variety of cancers. STUDY DESIGN: Paraffin-embedded tissues from follicular lymphomas, diffuse large BCLs (DLBCLs), and benign lymph nodes were studied using immunohistochemical staining with antibodies for TP and CD68. Prognostic markers were used to stain DLBCLs. We correlated TP expression in DLBCL indirectly with prognostic immunomarkers and directly with survival data. RESULTS: TP expression in BCLs was noted in a subset of malignant B cells. TP expression in higher-grade lymphoma was identified in 66% of cases and 11% of lower-grade lymphomas. Macrophages/stromal cells demonstrated an intense cytoplasmic and/or nuclear staining pattern in both lymphoma and benign lymph nodes, confirmed by CD68 coexpression. Increased macrophage/ stromal cells in higher-grade lymphomas are associated with enhanced TP expression in neoplastic B cells (observation only). Sixty-eight percent of TP-positive DLBCLs were of nongerminal center origin, indicating poorer prognosis. CONCLUSION: TP is more likely expressed by malignant B cells in higher-grade lymphomas, and expression of TP possibly results from changes intrinsic to the tumor cells or interactions between microenvironment and tumor. TP positivity in DLBCL correlates with nongerminal center origin and worse outcome.

Radiotherapy in the treatment of gastrointestinal stromal tumor.

Gastrointestinal stromal tumors (GISTs) are uncommon mesenchymal tumors of the gastrointestinal tract. Up to one-third of GISTs are malignant with a high rate of metastasis. Surgical resection is the mainstay of care for patients with resectable disease. Imatinib mesylate, a selective tyrosine kinase inhibitor, is the current standard of care for GISTs that cannot be completely resected or in cases of metastatic GIST. Although often overlooked, radiation therapy is a viable option for select patients with GIST. We report the case of a patient with unresectable GIST who was treated with local radiotherapy and achieved long-term response. We also present a review of the literature regarding the use of radiotherapy in the treatment of GIST. GIST has been shown to be a radiosensitive tumor. Radiotherapy can offer long-term local control and should be considered in the adjuvant or palliative setting. The role of radiotherapy delivered concurrently with imatinib in the treatment of GIST may warrant further investigation.