Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients.

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication.

Gastric Cancer in BRCA1 Germline Mutation Carriers: Results of Endoscopic Screening and Molecular Analysis of Tumor Tissues.

INTRODUCTION: There is some evidence suggesting a link between BRCA1/2 germline mutations and increased risk of gastric cancer. METHODS: Endoscopic screening for stomach malignancies was performed in 120 BRCA1 mutation carriers in order to evaluate the probability of detecting the tumor disease. RESULTS: No instances of gastric cancer were revealed at the first visit. The analysis of atrophic changes performed by OLGA (Operative Link for Gastritis Assessment) criteria revealed that OLGA stages I-IV alterations were observed in 26 of 41 (63%) subjects aged >50 years as compared to 29 of 79 (37%) in younger subjects (p = 0.007, χ2 test). One BRCA1 mutation carrier developed gastric cancer 4 years after the first visit for endoscopic examination. We performed next-generation sequencing analysis for this tumor and additional 4 archival gastric cancers obtained from BRCA1/2 mutation carriers. Somatic loss of the remaining BRCA1/2 allele was observed in 3 out of 5 tumors analyzed; all of these carcinomas, but none of the malignancies with the retained BRCA1/2 copy, showed chromosomal instability. CONCLUSION: Taken together, these data justify further studies on the relationships between the BRCA1/2 and gastric cancer.

Extraosseous osteosarcoma arising in recurrent ossifying fibromyxoid tumor of soft tissue: a case report.

We present a case of an osteosarcoma arising in ossifying fibromyxoid tumor. The patient was a 50-year-old man when an initial tumor was identified. It was a soft tissue mass in the left popliteal area, measuring 14x9 cm. The tumor was surgically removed. Histologically, the primary tumor had the appearance of a conventional ossifying fibromyxoid tumor, although there were cellular areas with pleomorphism and high mitotic rate. The neoplasm recurred 4 times over the next 8 years, involving underlying tissues, including skeletal muscle and bone. The recurrent lesions features areas of osteoid, which increased with each recurrence and in the fourth recurrence the tumor had an appearance of extraskeletal osteosarcoma lacking the ossifying fibromyxoid tumor. The tumor generalized that killed the patient with widespread metastatic disease.

Cutaneous hidradenocarcinoma: a clinicopathological, immunohistochemical, and molecular biologic study of 14 cases, including Her2/neu gene expression/amplification, TP53 gene mutation analysis, and t(11;19) translocation.

We present a series of 14 cases of cutaneous hidradenocarcinomas. The patients included 6 women and 8 men ranging in age at diagnosis from 34 to 93 years. All but 1 patient presented with a solitary nodule. There was no predilection site. One patient presented with multiple lesions representing metastatic nodules. Of 12 patients with available follow-up, 2 died of disease, whereas the remaining 10 patients were alive but 3 of them experienced a local recurrence in the course of the disease. Grossly, the tumors ranged in size from 1.2 to 6 cm. Microscopically, of the 14 primary tumors, 9 showed low-grade cytomorphology, whereas the remaining 5 neoplasms were high-grade lesions. The residuum of a hidradenoma was present in 5 of the 14 primaries. The mitotic rate was highly variable, ranging from 2 to 64 mitoses per 10 high-power field. The cellular composition of the tumors varied slightly, with clear cells, epidermoid cells, and transitional forms being present in each case. In 1 case, there was metaplastic transformation into sarcomatoid carcinoma. Glandular differentiation varied from case to case and appeared most commonly as simple round glands or as cells with intracytoplasmic lumens. Necrosis en masse was detected in 8 specimens. One specimen represented a reexcision and was unusual as it showed a well-demarcated intradermal proliferation of relatively bland clear cells accompanied by an overlying intraepidermal growth of clear cells resembling hidradenoacanthoma simplex. Despite the bland appearance, the tumor metastasized to a lymph node. Immunohistochemically, 5 of the 8 specimens studied for Her2/neu expression were negative, whereas 3 specimens from 2 cases yielded score +2, but all the 3 specimens with score 2+ subsequently proved negative for Her2/neu gene amplification by fluorescence in situ hybridization. Of 10 primaries studied, 4 tumors showed positive p53 immunoreaction in more than 25% of the cells comprising the malignant portion of the lesions, in 2 cases, a minority of the neoplastic cells (10%-20%) demonstrated nuclear staining, whereas the remaining 4 cases were negative. Of 9 specimens of hidradenocarcinoma studied for TP53 mutations, 2 harbored mutations, whereas the remaining 7 specimens showed the wild-type sequence. Of 11 specimens studied for translocation t(11;19), 2 cases harbored the translocation. It is concluded that cutaneous hidradenocarcinomas show some microscopic heterogeneity and comprise both low- and high-grade lesions that cytologically are similar to their benign counterpart, the hidradenoma. Within the spectrum of low-grade lesions, there seem to exist tumors almost indistinguishable from hidradenomas but still being capable of regional or distant metastasis. Similar to hidradenomas, hidradenocarcinomas show a t(11;19) translocation, but it is a significantly rarer event. Even rarer is the amplification of the Her2/neu gene. Of note is the relatively low frequency of TP53 mutations despite a high rate of p53 protein expression at the immunohistochemical level.

Vascular changes in merkel cell carcinoma based on a histopathological study of 92 cases.

Although prominent vascular proliferation is a known feature of various neuroendocrine tumors, it has not been systematically studied in Merkel cell carcinoma (MCC) of the skin. The purpose of this study was to fully characterize the light microscopic, immunohistochemical, and ultrastructural features of vascular changes associated with MCC and to determine their frequency and differential diagnostic implications. Additionally, the presence of human herpesvirus 8 DNA in the lesional tissue was investigated. Of 92 studied cases of MCC, 18 cases (20%) were found to exhibit foci of prominent vascular changes which were classified into the following 6 patterns: pericyte hyperplasia, pyogenic granuloma-like, hemangioendothelioma-like, epithelioid hemangioma-like, peliosis-like, and follicular dendritic cell tumor-like pattern. In addition, Azzopardi phenomenon was observed. These changes occurred singly or in combination. Human herpesvirus 8 DNA was identified by polymerase chain reaction in none of the 18 cases. It is concluded that prominent vascular proliferations may be seen in 20% of MCC, and thereby, MCC resembles neuroendocrine tumors in other organs. When unduly prominent and encountered in a limited biopsy specimen, vascular alterations may represent a potential diagnostic pitfall, but, on the other hand, they themselves may serve as a clue to the correct diagnosis. Human herpesvirus 8 does not play a role in angiogenesis in MCC.

Morphological variations of scar-related and spontaneous endometriosis of the skin and superficial soft tissue: a study of 71 cases with emphasis on atypical features and types of müllerian differentiations.

BACKGROUND: Seventy-one cases of scar-related and spontaneous endometriosis of the skin and superficial soft tissue were studied, with a focus on atypical features and types of müllerian differentiation. All patients were women, whose ages ranged from 22 to 65 years (median, 32 years). METHODS: Histological, immunohistochemical, and electronmicroscopic studies were performed. Clinical information was ascertained via a questionnaire solicited by the referring physicians. RESULTS: All types of metaplastic changes of müllerian epithelium were found, including tubal (61%), oxyphilic (15%), hobnail (10%), mucinous (4%), and papillary syncytial (3%) metaplasia. Atypical features included reactive atypia (23%) and atypical mitoses in glandular epithelium (6%). Stromal changes included smooth muscle metaplasia (31%), decidualization (<1%), stromal endometriosis (<1%), and elastosis (<1%). Other features recognized included lipoblast-like cells (15%), some with intranuclear inclusions; atypical/degenerative myocytes (10%); spiral arteries (4%); and perineurial invasion (<1%). CD56 staining identified large granular lymphocytes in 15 of 20 studied specimens. Ultrastructurally, these cells showed cytoplasmic granules, some with a delimiting membrane. LIMITATIONS: This study utilizes tissue specimens that mainly were received as consultations; therefore some inherent selection bias exists. Specimens were randomly selected for CD56 immunostaining, leading also to potential sampling error. CONCLUSIONS: All types of müllerian metaplasia can be encountered in cutaneous endometriosis. In addition, so-called atypical features described in endometriosis affecting other anatomic sites may be seen in the skin. Some features may represent a diagnostic pitfall.