Sebastian Mannweiler

Cystic lymph node metastases of squamous cell carcinoma of Waldeyer's ring origin

SummaryWe analysed in a retrospective study the frequency of cystic lymph node (LN) metastases in neck dissection specimens of 123 patients with primary squamous cell carcinoma (SCC) arising in the palatine tonsils (62 M/14 F), the base of the tongue (38 M/5 F) and the nasopharynx (2 M/2 F). Eighty-two per cent of patients had metastases (64 tonsillar SCC, 33 base of tongue SCC and all four nasopharynx SCC) in 368 LN of a total 2298 sampled LN. Thirty-nine per cent of patients had exclusively solid metastases and 37% of patients had exclusively cystic metastases. A total of 62 patients had some signs of cyst formation in one or more metastatically affected LN (27 with only histological evidence of cyst formation with luminal diameters < 5 mm, 35 with clinically detectable cyst with luminal diameter > 5 mm). Cystic metastases were more common in patients with SCC of the base of the tongue (P = 0.005), while solitary clinically evident cystic metastasis with lumina > 5 mm were found exclusively in tonsillar carcinoma (P = 0.024). In comparison with solid metastases, cyst formation was associated with N-categories (N2b and N3, P = 0.005) in SCC of the base of the tongue origin. No such association was observed for tonsillar SCC (P = 0.65). The primary mechanism of cyst formation was cystic degeneration.

Two major pathways of penile carcinogenesis: HPV-induced penile cancers overexpress p16ink4a, HPV-negative cancers associated with dermatoses express p53, but lack p16ink4a overexpression

BACKGROUND Penile squamous cell carcinomas (SCC) arise either through transforming infections with human papillomavirus (HPV) or independent of HPV, often in the background of lichen sclerosus (LS) and lichen planus (LP). Despite impact on therapy and prognosis, etiologic stratifications are missing in most histological diagnoses and publications about penile cancers/precursors. OBJECTIVE Classification of penile lesions into HPV-induced or HPV-negative via immunohistochemical demonstration of p16(ink4a) overexpression, a surrogate marker for transforming HPV-high-risk infections, and p53 expression in the absence of p16(ink4a) overexpression. METHODS Archival formalin-fixed material of 123 invasive penile cancers and 43 pre-invasive lesions was evaluated for the presence of LS, LP, 28 HPV genotypes, and expression of p53 and p16(ink4a). RESULTS Seventy-two of 123 SCCs and 33 of 43 pre-invasive lesions showed p16(ink4a) overexpression independent of HPV-HR genotypes involved; 66 of 72 SCCs and 29 of 43 precursor lesions revealed a single HPV-high-risk-genotype (HPV-HR16 in 76% followed by HPV33, HPV31, HPV45, HPV18, HPV56); 5 of 72 SCCs and 4 of 43 precursor lesions revealed multiple HPV-HR-genotypes. One SCC revealed HPV-LR and HR-DNA. Fifty-one of 123 SCCs and 10 precursor lesions were p16(ink4a) negative, but showed nuclear p53 expression in tumor cells and basal keratinocytes. Forty-nine of 51 SCCs and 10 of 10 precursor lesions lacked HPV DNA. Two of 51 SCCs contained HPV18 and HPV45 DNA, respectively, but p16(ink4a) negativity classified them as non-HPV-induced. Twenty-seven of 51 SCCs showed peritumoral LS, 13 of 51 SCCs showed peritumoral LP, and 11 SCCs revealed no peritumoral tissue. Histologically, HPV-negative precursors showed hyperkeratotic, verrucous, atrophic, and basaloid differentiation. LIMITATIONS This was a retrospective study. CONCLUSIONS p16(ink4a) overexpression identifies HPV-HR-induced penile carcinogenesis independent of HPV-HR genotype. p53 expression along with p16(ink4a) negativity identifies HPV-negative cancers. Correct etiologic classification of penile lesions during diagnostic work-up allows optimal therapy decisions.

Trichoblastic Carcinoma (“Malignant Trichoblastoma”) with Lymphatic and Hematogenous Metastases

We report an aggressively behaving malignant trichogenic tumor arising in a trichoblastoma (TB) with widespread lymphatic and hematogenous metastases in a 55-year-old man with a concomitant B-cell chronic lymphocytic leukemia. The primary tumor had been present and unchanged for as long as 40 years before excision. Typical trichogenic TB with dystrophic calcification and even ossification was still present peripheral to the malignant transformation. The malignant neoplasm consisted of basaloid cells, spindle cells arranged in fascicles and densely packed rounded nests or “cell balls.” The metastases consisted of immature basaloid cells and cell balls, and the recurrences became successively more undifferentiated. The residual TB reacted with antibodies to cytokeratin (CK) 6, 8, 14, and 17 and focally to S-100; the malignant primary tumor reacted uniformly with antibodies to vimentin and only focally with antibodies to CK and S-100. The metastatic tumor had lost epidermal CK expression but maintained expression of S-100 in paraffin-embedded tissues. Trichoblastic differentiation was confirmed in frozen tissues with antibodies to hair keratins. No expression of p53 or bcl-2 was identified, but p-glycoprotein (MDR-1 gene related) was expressed by primary and metastatic tumor cells. We believe that this neoplasm is best classified as a trichoblastic carcinoma arising in a TB in association with a B-cell chronic lymphocytic leukemia. This case illustrates that TBs have the potential for malignant transformation and aggressive behavior.

A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen, prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second and third repeat prostate biopsy.

Study Type – Diagnosis (exploratory cohort)

Penile carcinogenesis in a low-incidence area: a clinicopathologic and molecular analysis of 115 invasive carcinomas with special emphasis on chronic inflammatory skin diseases.

BackgroundHuman papillomavirus (HPV) infections account worldwide for 50% of penile cancers. The role of lichen sclerosus and lichen planus in penile carcinogenesis needs further investigation. Materials and MethodsArchival formalin-fixed high-grade penile intraepithelial neoplasias, differentiated penile intraepithelial neoplasias, and invasive carcinomas from a single pathology institution in a low-incidence area for penile cancer were analyzed for 28 HPV low-risk and HPV high-risk genotypes, p16INK4a overexpression, presence of peritumoral lichen sclerosus, lichen planus, precursor lesions, and monoclonal rearrangement of the T-cell receptor &ggr; locus. ResultsA total of 29 penile intraepithelial neoplasias (100%) and 69 of 115 (60%) invasive cancers contained HPV high-risk genotypes with a single HPV high-risk genotype (80% HPV16, 6% HPV33, 2% HPV45 and HPV18, 1% HPV73). Multiple HPV high-risk genotypes were identified in 4% with and in 5% without HPV16/18. p16INK4a overexpression correlated in all but 1 case of HPV high-risk 45 cancer. No p16INK4a overexpression and HPV genotype was found in 6 differentiated penile intraepithelial neoplasias and 46 of 115 (40%) invasive cancers, 30% of which were pT2/pT3 cancers. For 35 cancers, peritumoral tissue was available for analysis. Advanced lichen sclerosus was identified in 26, lichen planus in 9, and differentiated penile intraepithelial neoplasia in 18 carcinomas. Dense T-cell-dominant lymphocytic infiltrates were identified in 22 of 46 carcinomas and in 3 of 6 differentiated penile intraepithelial neoplasias, with 6 of 13 analyzed carcinomas/penile intraepithelial neoplasias showing a monoclonal rearrangement of the T-cell receptor &ggr; locus. ConclusionsThe prevalence of HPV high-risk in penile cancers from a low-incidence area was slightly higher than the global distribution. HPV-negative carcinomas were associated with advanced lichen sclerosus and lichen planus, differentiated penile intraepithelial neoplasia, and accumulation of T lymphocytes with monoclonal rearrangement of the T-cell receptor &ggr; locus.

MUC1 and MUC2 expression in salivary gland tumors and in non-neoplastic salivary gland tissue.

The expression of MUC1 and MUC2 was studied in salivary gland tumors and non‐neoplastic salivary gland tissue. Formalin‐fixed paraffin‐embedded specimens from 101 patients (21 pleomorphic adenomas (PA), 22 Warthins tumors (WT), 26 adenoid cystic carcinomas (ACC), 13 acinic cell adenocarcinomas (ACA), 9 mucoepidermoid carcinomas (MC), and 10 specimens of non‐neoplastic parotid and submandibular gland tissue) were immunostained. All salivary gland tumors expressed MUC1. A strong immunoreactivity was noted in WT and MC, a moderate in ACC and ACA, and a weak in PA. Strong expression of MUC2 was noted in all WT, moderate expression in MC, and weak expression in PA and ACA. All cases of ACC except for two were negative for MUC2. In general, MUC1 expression was stronger than that of MUC2. Non‐neoplastic salivary gland tissue revealed a moderate MUC1 and MUC2 expression in excretory ducts and a strong expression in striated ducts. The apical plasma membrane of some serous acini expressed MUC1. Mucous acini were negative for both antigens. No change in immunoreactivity was noted in cases of chronic sclerosing sialadenitis. In conclusion, the different expression pattern of MUC1 and MUC2 in salivary gland neoplasia may be of additional value for the classification of salivary gland tumors.

Colliding/concomitant tumors of the intestine: Report of 3 cases

Collision/concomitant tumors of the intestine involving lymphomas are very rare. For these cases molecular genetic analyses are valuable diagnostic adjuncts. We report one collision tumor of the rectum (adenocarcinoma and peripheral T-cell lymphoma, unspecified), and two cases of concomitant tumors (carcinoma in the cecum and lymphoma in the ileum; carcinoma in the sigmoid and lymphoma in the ileum). The collision tumor (poorly differentiated adenocarcinoma and a peripheral T-cell lymphoma, unspezified) showed a variable proportion of the anaplastic tumor cells expressing lymphatic markers as well as cytokeratin. Only polymerase chain reaction (PCR) analysis revealing T-cell monoclonality of the anaplastic part of the colliding tumor allowed the correct diagnosis. In the second case, a moderately differentiated adenocarcinoma in the cecum with a concomitant B-cell Non-Hodgkin lymphoma in the ileum, PCR analysis was non contributary. In the third case (adenocarcinoma in the sigmoid colon and a follicular center lymphoma in the ileum) PCR analysis revealed gene rearrangement of the immunoglobulin heavy chain gene. We would like to emphasize that collision and concomitant tumors of the gut are rare and that molecular genetic analysis may be mandatory for correct diagnosis. It is our impression, that these tumors may be diagnosed more often in the intestinal tract if molecular genetic analysis and immunohistochemistry are used routinely, at least for all anaplastic tumors.

Clear-Cell differentiation and lymphatic invasion, but not the revised TNM classification, predict lymph node metastases in pT1 penile cancer: A clinicopathologic study of 76 patients from a low incidence area

OBJECTIVE Prediction of lymph node (LN) metastases in penile invasive cancer relies on clinical features and histologic characteristics of the primary tumor. Correct prediction, however, is difficult, as only 50% patients undergoing lymphadenectomies will have LN metastases. In 2009, the tumor, nodes, metastases (TNM) classification for staging of early penile cancers was revised. We tested the predictive accuracy of the revised TNM classification in a low incidence area for penile carcinoma. MATERIALS AND METHODS The presence of LN metastases in 76 men with pT1 penile cancers was correlated with the 2009 TNM subclassification, which is based on a combined evaluation of tumor grade and lymphatic invasion, but also with individual parameters, such as histologic grade, lymphatic invasion, perineural invasion, invasion depth, growth pattern and human papilloma virus (HPV) status. RESULTS 76pT1 penile cancers were reclassified into 31pT1a squamous cell carcinomas (SCC) and 45pT1b (41 SCC; 4 clear-cell carcinomas); 12/22 men (55%; 8 SCC, 4 clear-cell carcinomas) undergoing lymphadenectomy for enlarged inguinal lymph nodes had metastases, 54 patients without enlarged LN and lymphadenectomies had no LN metastases during follow-up of median 47 months. Statistically, clear cell differentiation of the primary carcinoma was highly associated with metastases (100% clear-cell carcinomas vs. 11% SCC) and poor survival (50% vs. 5.5%). Among conventional SCC, only lymphatic invasion showed a highly significant association with metastases with 100% specificity. The 2009 TNM classification, tumor grade alone, perineural invasion, growth pattern, invasion depth or HPV status could not predict LN status. Lymphadenectomy for enlarged LN resulted in 100% sensitivity and 42% predictive probability for identifying metastases and a 16% false positive rate. Statistically, survival correlated significantly with clear-cell differentiation and with lymphatic invasion in both clear-cell carcinomas and conventional SCC. CONCLUSIONS Penile clear-cell carcinomas are more aggressive cancers than SCC. Our observation suggests a benefit of a prophylactic lymphadenectomy for patients with clear-cell carcinomas. Among conventional SCC, only lymphatic invasion predicted LN metastases. Neither tumor grade alone nor perineural invasion, growth pattern, depth of invasion, and subgrouping according to the revised TNM classification correlated with metastases. Clinical evaluation of the LN status was superior to histologic risk stratification.

Multivariate karyometric approach in differential diagnosis of follicular thyroid neoplasms. A study of 31 cases.

Abstract A retrospective analysis of 19 follicular adenomas, 12 minimally invasive follicular carcinomas and 3 widely invasive follicular carcinomas of the thyroid was performed on 5-µm-thick Feulgen-stained paraffin sections by means of a semiautomatic system for picture analysis. The major aim was to assess the potential of multiparameter karyometry for separation of the first two tumour types. Sixteen planimetric and densitometric features were defined in each case on 200–300 randomly selected nuclei and processed by a number of uni- and multivariate statistical methods. Despite predominantly significant ANOVA results a substantial overlap between tumour groups limited the practical usefulness of any karyometric feature alone. Factor and cluster analyses indicated independence of planimetric and densitometric parameters from each other, which was of crucial importance in finding an optimal subset of variables for discriminant analysis. The classification rule derived from the latter procedure was checked by the ”jack-knife” method, by classification of 3 widely invasive cancers and by hierarchical tumour clustering. Sensitivity and specificity of the model for detection of malignancy were 100% and 94.7%, respectively. A multivariate karyometric approach, when applied correctly, can be a useful tool for differentiation between follicular adenomas and minimally invasive follicular carcinomas of the thyroid.

The flow cytometric DNA index can predict the presence of lymph node metastases in invasive ductal breast carcinoma.

Axillary lymph node (LN) dissection is an important staging procedure for invasive ductal breast carcinoma (IDC), but causes elevated morbidity. Reliable preoperative prediction of metastases is at present not possible. We investigated whether flow cytometric analysis of primary IDC can correctly predict the presence of LN metastases at the time of primary diagnosis. In 341 primary IDC, DNA index (DI) in absolute values, S‐phase fraction (SPF), size of the primary tumor, tumor grade (G), estrogen/progesterone receptors (ER/PR) expression and age were analysed and correlated with the axillary LN status with the aim of correctly predicting the LN status. No predictive value was identified for S‐phase fraction (SPF), tumor grade, or ER/PR expression. The DI correlated statistically with LN status in all patients. A practically useful association was, however, only observed in 37 women aged 45–58 years with an IDC >2 cm diameter: a DI>1.44 predicted the presence of LN metastases at the time of operation with a specificity of 100% and a sensitivity of 89%, a negative predictive value of 91% and a positive predictive value of 100%. Determination of the absolute values of the DI may be a useful adjunct to sentinel LN preparation when predicting the axillary LN status and may spare some women the morbidity associated with axillary LN dissection.