Kyle Molberg

Physiologic versus neoplastic C-cell hyperplasia of the thyroid: Separation of distinct histologic and biologic entities

Although hyperplasia of C‐cells has been described in association with various pathologic and physiologic conditions, criteria for its diagnosis are poorly defined. Both neoplastic and physiologic C‐cell proliferations have been lumped together under the umbrella designation of C‐cell hyperplasia (CCH), creating considerable confusion among clinicians and pathologists.

Secondary syphilis: a histologic and immunohistochemical evaluation

Abstract:  The usual method for detecting spirochetes in tissue sections is the silver stain; however, they are often difficult to detect due to marked background staining commonly seen with this technique. In certain clinical settings, such as neurosyphilis, congenital syphilis, and immunosuppressive conditions including human immunodeficiency virus (HIV) infection, a better method of detecting spirochetes in tissue sections is needed. We compare immunohistochemistry (IHC) with a monoclonal antibody to Treponema pallidum to silver staining in 19 biopsies from 17 patients with serologic evidence of secondary syphilis. IHC demonstrated a sensitivity of 71%, which was superior to the 41% sensitivity of the silver stain (p = 0.084). Furthermore, specificity was improved with IHC, as background artifacts were markedly reduced. Dermal spirochetes were visualized in all 12 positive cases, while epidermal organisms were seen in only eight cases. This finding lies contrary to accepted teaching that organisms are most commonly seen at the dermal epidermal junction. Of interest, perineural plasmacellular infiltrates were frequently seen in our cases (74%). Spirochetes were not seen in any of 14 control cases with similar histopathologic patterns. Although serologic studies remain the gold standard, IHC is more sensitive and specific than silver stain for detecting T. pallidum in biopsies of secondary syphilis.

SALL4 is a novel sensitive and specific marker of ovarian primitive germ cell tumors and is particularly useful in distinguishing yolk sac tumor from clear cell carcinoma.

Ovarian primitive germ cell tumors (GCTs) are uncommon tumors and sometimes pose diagnostic challenges. Among them, yolk sac tumor (YST) poses the greatest diagnostic difficulty and can be mistaken for clear cell carcinoma (CCC). Current immunohistochemical markers such as alpha-fetoprotein (AFP), glypican-3, cytokeratin (CK) 7, and epithelial membrane antigen (EMA) used to distinguish YST from CCC lack adequate sensitivity and specificity. Here by immunohistochemistry, we investigated a novel marker SALL4 in 98 GCTs (29 YSTs, 18 dysgerminomas, 6 gonadoblastomas, 6 embryonal carcinomas, 15 immature and 12 mature teratomas, 7 carcinoid tumors, 3 strumal carcinoids, and 2 struma ovarii) with particular interest of exploring SALL4 to distinguish YST from CCC. One hundred sixty-three non-GCTs including 45 CCCs were also stained. We found that SALL4 is strongly positive in more than 90% tumor cells in all YSTs, dysgerminomas, gonadoblastomas, and embryonal carcinomas. Variable SALL4 staining is seen in 11 of 15 immature teratomas. All other GCTs included in this study are negative for SALL4. Except 3 CCCs with focal SALL4 staining (<15% tumor cells), SALL4 is negative in the remaining 160 non-GCTs. We also compared SALL4 with AFP, glypican-3, CK7, and EMA in all YSTs and CCCs. AFP and glypican-3 are positive in 24 (83%) and 20 (69%) YSTs, respectively, whereas 16 (35%) and 13(28%) CCCs show positive AFP and glypican-3 staining, respectively. Three (10%) and 4 (14%) YSTs show focal (<2% tumor cells) CK7 and EMA staining, respectively. CK7 and EMA are positive in all 45 CCCs but 3 (7%) and 1 (2%) cases show staining in less than 30% tumor cells, respectively. Our findings indicate that SALL4 is a novel sensitive and specific marker for ovarian primitive GCTs. SALL4 is particularly useful in distinguishing YST from CCC and better than AFP, glypican-3, CK7, and EMA.

Loss of Dpc4 Expression in Colonic Adenocarcinomas Correlates with the Presence of Metastatic Disease

DPC4 is a candidate tumor suppressor gene on chromosome 18q21, a region that shows high frequencies of allelic losses in pancreatic and colorectal adenocarcinomas. Biallelic inactivation of DPC4 has been reported in half of pancreatic cancers, but are relatively infrequent in other tumor types. The role of DPC4 inactivation in colorectal neoplasms has not been fully characterized. An immunohistochemical assay for Dpc4 protein expression has been recently developed and shown to be a sensitive and specific surrogate for alterations in the DPC4 gene. In this study we examined the expression of Dpc4 protein in formalin-fixed archival tissue from 83 colorectal lesions, including 19 adenomas and 64 sporadic adenocarcinomas (11 stage I, 13 stage II, 17 stage III, and 23 stage IV cancers). None of the adenomas or stage I adenocarcinomas showed loss of Dpc4 expression, whereas one of 13 (8%) stage II, one of 17 (6%) stage III, and five of 23 (22%) of stage IV cancers showed loss of Dpc4 expression. There was a borderline significant difference in loss of Dpc4 reactivity in colorectal tumors with distant metastasis at presentation (22%) versus primary tumors without distant metastasis (5%) (Fishers exact test, P = 0.05; chi(2) = 0.04). Poorly differentiated histology or status of pericolonic lymph nodes did not affect Dpc4 expression. Alterations in DPC4 are involved in the progression of a subset of colorectal carcinomas, especially those that present with advanced disease. In the sequential pathogenesis of colorectal tumors, inactivation of DPC4 is likely to be a late event.

Diagnostic utility of SALL4 in extragonadal yolk sac tumors: an immunohistochemical study of 59 cases with comparison to placental-like alkaline phosphatase, alpha-fetoprotein, and glypican-3.

Extragonadal yolk sac tumors (YSTs; primary and metastatic) are rare but are malignant germ cell tumors. Pathologic diagnosis of extragonadal YSTs can be challenging without immunohistochemical markers but markers used for diagnosing these tumors such as placental-like alkaline phosphatase (PLAP), alpha-fetoprotein (AFP), and glypican-3 lack adequate sensitivity and/or specificity. In earlier studies with gonadal germ cell tumors, SALL4 has been identified as a novel diagnostic marker for YSTs and other types of primitive germ cell tumors. Here, we investigated the diagnostic utility of SALL4 in 59 extragonadal YSTs (27 primary sacrococcygeal, 15 primary nonsacrococcygeal, and 17 metastatic) by immunohistochemical staining. We also compared SALL4 with PLAP, AFP, and glypican-3. In addition, we performed immunostains for pancytokeratin, epithelial membrane antigen, and OCT4 in these tumors. Our results showed that all 59 YSTs showed strong pancytokeratin staining (70% tumor cells in 1 case, >90% tumor cells in 58) and 10 (17%) of them also showed focal epithelial membrane antigen staining (<3% tumor cells). All 59 YSTs were negative for OCT4. Strong SALL4 staining was seen in all 59 YSTs (in more than 90% tumor cells in 54 and 70% to 85% tumor cells in 5 YSTs). Only 39 of 59 (66%) YSTs showed positive PLAP staining and the staining was often focal (in less than 30% tumor cells) (28 of 39 cases). Positive AFP staining was seen in the vast majority of YSTs (56 of 59 or 95%); however, 32 (54%) YSTs showed staining in less than 30% tumor cells. Although all 59 YSTs showed positive glypican-3 staining, 18 (30%) showed staining in less than 30% tumor cells, and additional 10 (17%) showed staining in between 30% and 60% tumor cells. In these 59 YSTs, the mean percentage of tumor cells stained with PLAP was 14% (range: 0% to 90%), with AFP 35% (range 0% to 95%), and with glypican-3 57% (range: 1% to 100%), whereas the mean percentage of tumor cells stained for SALL4 was 94% (range: 70% to 100%) (P<0.001). Our results indicate that SALL4 is a novel sensitive (100% sensitivity) diagnostic marker for extragonadal YSTs. SALL4 is a more sensitive marker than PLAP, AFP, or glypican-3 for extragonadal YSTs.

Clinicopathologic analysis of CD10+ and CD10- diffuse large B-cell lymphoma: Identification of a high-risk subset with coexpression of CD10 and bcl-2

We analyzed 53 cases of diffuse large B-cell lymphoma (DLBCL) to determine whether expression of CD10 is a relevant biologic parameter. Tumor morphologic features were assessed semiquantitatively. Bcl-2 protein expression was studied by immunohistochemical analysis. The presence or absence of CD10 by flow cytometry was correlated with clinical and pathologic characteristics. CD10+ (23 cases) and CD10- (30 cases) DLBCLs were indistinguishable based on age, sex, extranodal presentation, B symptoms, clinical stage, morphologic features, or bcl-2 expression. However, cases with a CD10+ phenotype showed a significantly lower rate of complete remission. Cases expressing bcl-2 showed trends toward a lower rate of complete remission and poorer overall survival. Examination of CD10 and bcl-2 interaction revealed that the prognostic effects for both of these antigens were due to a subset of CD10+ bcl-2-positive cases. Compared with cases expressing one or neither of these markers, patients with dual-positive tumors had a poorer complete response rate to initial therapy and strikingly worse overall survival. While CD10+ and CD10- DLBCLs are similar with regard to a variety of clinical and pathologic features, CD10 and bcl-2 coexpressing tumors are an extremely high-risk subset based on response to therapy and overall survival.

Increased expression of early growth response-1 messenger ribonucleic acid in prostatic adenocarcinoma.

PURPOSE We isolated genes whose expression differs between normal and malignant prostate. MATERIALS AND METHODS Differential display polymerase chain reactions revealed a messenger ribonucleic acid (mRNA) with higher expression in prostatic adenocarcinoma versus age matched normal tissue. Deoxyribonucleic acid sequencing identified this mRNA as the product of the early growth response-1 gene. RESULTS Early growth response-1 mRNA levels were elevated in 12 of 12 intraprostatic adenocarcinomas but not in breast or ovarian cancers, or in rapidly dividing rat ventral prostate cells. Early growth response-1 mRNA was detected in epithelial and stromal cells at tumor margins but not in lymph node metastases. CONCLUSIONS Early growth response-1, a nuclear transcription factor, is implicated in the growth and invasion of intraprostatic cancers.

Predictors of Invasion and Axillary Lymph Node Metastasis in Patients with a Core Biopsy Diagnosis of Ductal Carcinoma In Situ: An Analysis of 255 Cases

Abstract:  The diagnosis of ductal carcinoma in situ (DCIS) using core biopsy does not ensure the absence of invasion on final excision. We performed a retrospective analysis of 255 patients with DCIS who had subsequent excision. Clinical, radiologic, and pathologic findings were correlated with risk of invasion and sentinel lymph node (SLN) metastasis. Of 255 patients with DCIS, 199 had definitive surgery and 52 (26%) had invasive ductal carcinoma (IDC) on final excision. Extent of abnormal microcalcification on mammography, and presence of a radiologic/palpable mass and solid type of DCIS were significantly associated with invasion on final excision. Sentinel lymph node biopsy was performed in 131 (65.8%) patients of whom 18 (13.4%) had metastasis. Size of IDC and extent of DCIS on final pathology were significantly associated with positive SLN. Micrometastasis and isolated tumor cells comprised majority (71.4%) of the metastases in DCIS. SLN biopsy should be considered in those with high risk DCIS.

Ectopic prostatic tissue in the uterine cervix.

This is the first reported case of ectopic prostatic tissue in the uterine cervix, diagnosed in a 38-year-old woman. A cluster of benign prostatic glands with cribriform and papillary patterns and focal squamous metaplasia occupied the superficial endocervical stroma. The glands were immunoreactive for prostatic specific antigen and prostatic specific acid phosphatase. This lesion, which could be confused with microglandular hyperplasia, mesonephric rests, or adenocarcinoma in situ may represent an embryonic rest.

Decreased Androgen Receptor Expression Is Associated With Distant Metastases in Patients With Androgen Receptor-Expressing Triple-Negative Breast Carcinoma

To characterize prognostic values of androgen receptor (AR) in triple-negative (TN) breast cancers, we investigated AR expression status and levels, explored an association of AR expression with metastatic disease, and correlated AR expression with Ki-67 in TN invasive breast carcinomas. AR expression was analyzed with immunohistochemistry in 121 cases of TN tumors. Thirty-nine cases had distant metastatic disease and 82 had locoregional disease only. AR was positive in 38 (31.4%) of the 121 cases. Our results indicate that among the AR-positive TN tumors, distant metastases are significantly associated with lower expression of AR compared with cases with only locoregional disease, and that AR expression negatively correlates with Ki-67 expression. These findings suggest that decreased intratumoral AR expression may be predictive of distant metastatic disease and AR expression levels may have potential prognostic value in AR-expressing TN tumors.