Motoo Ishida

Aberrations of theAPC gene in primary breast carcinoma

Aberrations of theAPC gene, which plays an important role in the genesis of familial adenomatous polyposis and colorectal carcinoma, were investigated in 31 surgical specimens of primary breast carcinoma. These studies utilized the polymerase chain reaction followed by restriction-fragment-length polymorphism and single-strand-conformation polymorphism analyses combined with tumor cell enrichment by cell sorting. Loss of heterozygosity at theAPC locus was detected in 8 (38%) of 21 informative cases, but only 2 (6%) of 31 tumors carried a mutatedAPC gene. Direct DNA sequencing analysis confirmed mutations at codon 1081 (AGC to ATC) resulting in an amino acid substitution of serine for isoleucine, and at codon 1096 (CAG to CAT) resulting in a substitution of glutamine for histidine. There were no significant correlations between the loss of heterozygosity or mutation at theAPC locus and any clinicopathological characteristics. Our present observations suggest that the mutations of theAPC gene may play an important role in the genesis of certain breast carcinomas, and that another tumor-suppressor gene, which is the true target of frequent loss of heterozygosity, may exist near theAPC gene.

Improved detection of loss of heterozygosity at retinoblastoma gene locus in human breast carcinoma

Loss of heterozygosity (LOH) at the retinoblastoma (Rb) gene locus was investigated in 33 breast carcinomas by polymerase chain reaction single‐strand conformation polymorphism (PCR‐SSCP) analysis after tumor cell enrichment by cell sorting. The efficacy of cell sorting was evaluated by comparing the results of PCR‐SSCP with and without cell sorting. Ten of 17 (59%) informative cases showed LOH at this locus by cell sorting combined with PCR‐SSCP, although LOH was detectable in six (35%) cases without cell sorting. Flow cytometry and histologic examination revealed that this underestimation may occur when the tumor cell population is less than 50% in the specimens analyzed. It is concluded that LOH of the Rb gene occurs more frequently in human breast carcinoma than previously thought, and thus may contribute significantly to the development and/or progression of this tumor.

Frequent loss of heterozygosity at the deleted in colorectal carcinoma gene locus and its association with histologic phenotypes in breast carcinoma

Loss of heterozygosity (LOH) at the deleted in colorectal carcinoma gene (DCC), a tumour suppressor gene that encodes a protein with high homology to the neural cell adhesion molecule, was investigated in 42 surgical specimens of primary breast carcinoma. LOH was analysed in breast carcinoma by amplifying the DNA, spanning a variable number of tandem repeats site and a restriction fragment length polymorphism site within DCC, using the polymerase chain reaction (PCR). Cell sorting was used to enrich carcinoma cells. The expression of the DCC gene was also investigated using a reverse transcription-PCR method followed by Southern blot hybridization. LOH at the DCC locus was detected in 15 (51.7%) of 29 informative cases and 10 of 13 cases having DCC-LOH showed distinct reduction or loss of DCC expression. The DCC-LOH was closely associated with certain histological phenotypes; DCC-LOH was more frequent in scirrhous carcinomas than in solid-tubular ones (P<0.05), and was also more frequent in carcinomas with infiltration into fat tissue over the mammary gland than in those without infiltration (P<0.05). DCC-LOH was detected in invasive lobular carcinomas (2/2), but in none of the noninvasive ductal carcinomas (0/2). These observations suggest that malignant histological phenotypes are associated with DCC-LOH.

Well-differentiated neuroendocrine tumor of the breast with recurrence due to needle tract seeding

Dear Editor, Recently, percutaneous imaging-guided core needle biopsy (CNB) ensuring a high degree of diagnostic accuracy and minimal invasiveness has been widely practiced as an alternative to surgical biopsy [1]. However, the procedure itself can, very rarely, contribute to disease recurrence [1, 2]. The WHO classifies mammary carcinomas with neuroendocrine (NE) features as a special tumor entity, representing <1 % of invasive breast carcinomas, and recognizes three subtypes: (i) NE tumor (NET), well-differentiated; (ii) NE carcinoma, poorly differentiated; and (iii) invasive carcinoma with NE differentiation [3, 4]. Herein, we describe the first case of a mammary NE cancer (well-differentiated NET) showing intramammary relapse related to needle implantation. A 60-year-old postmenopausal Japanese woman presented with slight skin retraction in the upper inner portion of the right breast. Ultrasonography revealed an irregular, hypoechoic right breast tumor with an echogenic halo and posterior attenuation. Systemic CT detected no other suspicious lesions. We performed ultrasound-guided 16-G automated CNB of the breast mass after obtaining informed consent, and the histological diagnosis was (ductal) carcinoma. The cut surface of the lumpectomy specimen contained a poorly delimited, grey-whitish and focally brownish-red, solid tumor, measuring 12×10 mm in size. Histologically, this tumor was composed of invasive growing carcinoma cells in solid and/or trabecular clusters with a highly vascular fibrovascular stroma and focal hemorrhage (Fig. 1). Carcinoma cells were polygonal or, occasionally, spindle-shaped with finely granular cytoplasm and ovoid nuclei with a finegranular chromatin pattern (Fig. 1a). Six mitotic figures were counted in 10 high-power fields. In situ carcinoma components were locally observed near invasive cancer nests. Neither lymphatic nor vascular infiltration was detected. Lateral, including nipple-side, margins were negative for cancer. On the other hand, we noted small foci of scarring with fat necrosis and hemosiderin-laden macrophages in the subcutaneous tissues away from the main tumor (Fig. 2a) and identified sporadic epithelial clusters showing cancer cell morphologies within and around the scar tissues (Fig. 2b, c). No metastases were identified in the four excised right axillary lymph nodes. T. Kawasaki (*) :A. Sato :M. Suzuki : R. Sugimoto :Y. Mue : N. Uesugi :K. Ishida : T. Sugai Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan e-mail: tomonori@yamanashi.ac.jp

Well-differentiated neuroendocrine tumor of the breast with extensive lymphatic and vascular infiltration.

To the Editor: The World Health Organization (WHO) classifies mammary carcinomas with neuroendocrine (NE) features as a special tumor entity, representing<1 % of invasive breast carcinomas, and recognizes three subtypes: (i) NE tumor (NET), welldifferentiated; (ii) NE carcinoma (NEC), poorly differentiated, i.e. small cell carcinoma; and (iii) invasive carcinoma with NE differentiation. Recently, we reported an unusual case with hematogenous metastases due to a massive tumor embolus from a well-differentiatedmammary NET. Herein, we describe, to our knowledge, the first case of anNE neoplasmwith extraordinary intra-lymphatic embolization in the breast. The patient, a 46-year-old premenopausal Japanese woman, presented with a mildly painful palpable mass in the upper outer quadrant of the left breast. There was no medical or familial history of breast disease, although she had undergone left thyroidectomy for adenomatous goiter 25 months earlier. Ultrasonography revealed an irregularly-shaped (geographic), hypoechoic left breast area and enlarged regional lymph nodes. Systemic CT and bone scintigraphy detected no other suspicious lesions. We performed ultrasound-guided, core needle biopsy of the breast lesion, and the histologic diagnosis was invasive carcinoma. The cut surface of themastectomy specimen contained an illdefined, grey-whitish solid tumor, measuring 23 × 22mm.Histologically, the tumor was composed of a solid and/or trabecular invasive growth of carcinoma cells with focal luminal structures and a highly vascular fibrovascular stroma (Fig. 1a). Polygonal carcinoma cells had finely granular cytoplasm and oval or irregularly-shaped nuclei with fine-granular chromatins and occasional conspicuous nucleoli. Twenty-one mitotic figures were counted in 10 high-power fields (HPFs) (histological grade 2). Marked lymphatic permeation (i.e. carcinomatous lymphangiosis) as well as vascular infiltration were detected (Fig. 1b-d). In-situ foci consisting of similar carcinoma cells were locally observed near invasive cancer nests. Metastases were identified in 9 of 17 excised left axillary nodes, with extra-nodal invasion. Immunohistochemically, the carcinoma cells in the primary invasive, in situ and intra-lymphatic and metastatic regions were diffusely positive for synaptophysin [Fig. 1a (inset), d] and focally positive for chromogranin A. The rates of carcinoma cells showing reactivity for estrogen and progesterone receptors were 99%and 30% (Allred’s total scores: 8 and 6), respectively. The HER2 score was estimated to be 1+, and the Ki67 (MIB-1) labeling index was 61.4 % in the hot spot.

Esophageal carcinoma cases surviving for more than ten years in Japan.

食道癌手術後10年以上生存例についてアンケートによる全国集計を行い, 集計された症例を種々の面から分析検討したので報告する.10年以上長期生存例を有する施設は47で, 総症例数は387例であった.このうち非切除例は7例で, 切除例は380例であった.切除例はすべて昭和47年9月以前に手術が施行されたものである.男女比では2対1と男性が多かった.腫瘍長径では6～10cmが41%, 進行度ではstage IIIが40%, 組織型では扁平上皮癌が96%と多かった.術後最長生存者は28年で, 10年以上現在も生存しているのは237例 (62%) であった.生活状況は約88%が満足すべきものであった.