Significance of transcriptionally-active high-risk human papillomavirus in sinonasal squamous cell carcinoma: Case series and a meta-analysis.

Sinonasal cancers represent a highly heterogeneous group of head and neck cancers, for which etiological and prognostic significance of high-risk human papillomavirus (HPV) infections has not yet been conclusively established. We investigated the presence of transcriptionally-active high-risk HPV in a series of 34 sinonasal squamous cell cancer (SNSCC) cases and evaluated the effect of transcriptionally-active HPV on the overall survival. In addition, we performed a meta-analysis of previously published studies, including this study, to summarize the prevalence of HPV positivity across histological subtypes of SNSCC. The presence of transcriptionally-active HPV was detected by HPV mRNA using the polymerase chain reaction (PCR) or in situ hybridization (ISH). p16 expression was evaluated as a surrogate marker for transcriptionally-active HPV infection by immunohistochemistry (IHC), the presence of high-risk HPV DNA was tested by PCR and the HPV genotypes were determined by sequencing of PCR amplicons. Transcriptionally-active HPV infections were found in ~25% of the SNSCC cases. The role of HPV infection in keratinizing SNSCC may be higher than previously reported (~32% in our study vs. ~0-6.3% in all other studies). Patients with transcriptionally-active HPV-positive SNSCCs were more likely to be diagnosed at earlier stages (p<0.05) and displayed better mean overall survival, although the difference between HPV-positive and HPV-negative groups was not statistically significant. In contrast to other non-oropharyngeal squamous cell carcinomas (non-OPSCCs) of the head and neck, in SNSCCs, p16/IHC and p16/IHC+HPV DNA displayed high specificity as surrogate markers of transcriptionally-active HPV infections. However, p16/IHC may have significantly lower sensitivity as a surrogate marker of transcriptionally-active HPV in SNSCCs compared to OPSCCs. Furthermore, in our group of SNSCCs, all cases positive for high-risk HPV DNA by PCR were also transcriptionally-active (causative) infections with positive HPV mRNA by ISH. Our results imply a possible different role of HPV-mediated carcinogenesis of squamous cell epithelium in oropharyngeal and sinonasal sites with the latter displaying a lower proportion of causative HPV infections; nevertheless, most cases positive for high-risk HPV DNA, p16/IHC or combination thereof were also found positive for transcriptionally-active HPV. The prognostic significance of HPV status in SNSCCs remains inconclusive and future studies should investigate the presence of transcriptionally-active HPV by direct HPV testing.

[Breast Cancer in Young Women - Correlation of Clinical Histomorphological, and Molecular-genetic Features of Breast Carcinoma in Women Younger than 35 Years of Age]. / Karcinom prsu u mladých zen - korelace klinických, histomorfologických a molekulárne-genetických nálezu karcinomu prsu u zen mladsích 35 let.

BACKGROUND: Worldwide, breast cancer is the leading type of malignancy in women. For premenopausal women, the disease brings much higher risk as it is usually more aggressive with worse prognosis. PATIENTS AND METHODS: In this retrospective study, 92 women treated at the Department of Oncology and Radiotherapy in Pilsen were selected from a basic cohort of 356 women under 35 years of age with breast cancer who were diagnosed between 2006 and 2015. The control group comprised 100 postmenopausal women over 65 years of age who were treated for invasive breast cancer. RESULTS: Overexpression of HER2/neu protein and a triple-negative immunoprofile and basal-like phenotype of cancer were more frequently seen in the women under 35 years of age. In addition, malignant cells were poorly differentiated and more aggressive, and prognostically favourable types were not often seen, in these women. In terms of the course of disease, the outcome was worse for the younger patients, and complete remission was reached less frequently and more cases of advanced disease and death due to the malignancy were detected. CONCLUSION: The incidence of invasive breast cancer in young women is low, representing around 2% of all cases of the disease, but this group of patients is prognostically very important. The cancers at such a young age are usually more aggressive (higher mitotic activity and higher grade), and prognostically worse types, such as triple-negative or basal-like, are seen significantly more often in younger patients. This retrospective study confirmed this premise. Moreover, breast cancer in young women is more often associated with genetic predisposition (e.g., hereditary mutations in BRCA1 and BRCA2 genes) than in older women.Key words: breast cancer - young women - triple negative breast cancer - BRCA mutation - basal-like - tumor-suppressor genes This work was partially supported by the Charles University research fund (project number SVV-2016-260 282). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 10. 1. 2017Accepted: 15. 3. 2017.

Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a non-endemic eastern european population.

Nasopharyngeal carcinoma (NPC) is a rare malignancy in the Czech Republic and Slovakia, with the standardized incidence rate of < 1:100000 person-years. Viral status of NPC in these non-endemic Eastern European regions is currently unknown. In a retrospective study, we evaluated the presence of EBV and HPV in 62 NPC cases. EBV status was determined by the use of in situ hybridization (ISH) for EBV encoded small RNA 1 (EBER1). HPV status was examined with p16 immunohistochemistry, DNA ISH and DNA polymerase chain reaction. Sixty-one studied cases showed non-keratinizing morphology and one was keratinizing squamous cell carcinoma. Only one NPC with non-keratinizing morphology was scored as p16-positive (nuclear and cytoplasmic staining ≥ 70% of tumor cells). This case was positive for high-risk HPV by ISH and the DNA PCR confirmed the presence of HPV18 type. At the same time, this case was found negative for EBV. Remaining sixty-one cases that were scored as p16-negative were all found HPV-negative by ISH and the DNA PCR. EBV was detected in 85.5% (53/62) of cases and 9 cases were EBV-negative, including the case of keratinizing NPC. In contrast with previous reports on the prevalence of EBV-positivity in Caucasian patients with NPC, the majority of patients coming from this non-endemic region show EBV-positivity; therefore, they may be candidates for novel EBV-targeting therapies. Conversely, HPV-positive NPC is very rare and HPV does not seem to play a significant role in the etiopathogenesis of NPC in these Eastern European populations.

Salivary acinic cell carcinoma: reappraisal and update.

Epidemiologic and clinicopathologic features, therapeutic strategies, and prognosis for acinic cell carcinoma of the major and minor salivary glands are critically reviewed. We explore histopathologic, histochemical, electron microscopic and immunohistochemical aspects and discuss histologic grading, histogenesis, animal models, and genetic events. In the context of possible diagnostic difficulties, the relationship to mammary analog secretory carcinoma is probed and a classification is suggested. Areas of controversy or uncertainty, which may benefit from further investigations, are also highlighted.

Renal clear cell carcinoma metastasis to salivary glands - a series of 9 cases: clinico-pathological study.

Metastatic tumors involving salivary glands arising from the non-head and neck area are very rare. Renal cell carcinoma (RCC) is known for its high propensity for metastasis to unusual localizations. RCC metastasis to the maxillofacial area is an uncommon event (16%), but metastasis to salivary glands is extremely rare. We report a series of 9 such cases retrieved from two institutions. The group included 6 females and 3 males. The age at diagnosis ranged from 60 to 97 years (mean 72.6 years). The tumors involved the parotid gland in 7 cases, and the submandibular and small salivary gland of the oral cavity in 1 case each. The size of tumors ranged from 0.4 to 5 cm. Total parotidectomy with selective neck dissection was performed in 4 cases, while superficial parotidectomy was performed in 1 case and simple resection in 3 cases. Histologically, all the tumors were clear cell renal cell carcinomas, and therefore the differential diagnosis mainly included clear cell variants of salivary gland carcinomas. The parotid gland was the initial manifestation of renal malignancy in 4 of the cases, while in the remaining 5 cases a history of RCC had been known. The salivary gland involvement developed from 11 months to 13 years after the time of diagnosis of the primary tumor. In 2 cases it was the first site of dissemination. Pathologists need to maintain a high index of suspicion for the possibility of metastasis when confronted with oncocytic or clear cell neoplasms developing in salivary glands. RCC, although rare, should be included in this differential diagnosis.

Giant cribriform adenocarcinoma of the tongue showing PRKD3 rearrangement.

Cribriform adenocarcinoma of the tongue and minor salivary glands (CAMSG) was first described 16 years ago. It typically presents as a mass at the base of the tongue with early spread to lymph nodes, but without potential for distant metastases. In the 2005 World Health Organization Classification of Tumors the entity was classified as a possible variant of polymorphous low-grade adenocarcinoma (PLGA). Since then, more than 40 cases have been described in the English literature. Recently, PRKD1-3 translocation was found in more than 80% of CAMSGs. In some of those cases ARID1A or DDX3X was the translocation partner. We reviewed 183 primary carcinomas of major and minor salivary glands, resected at the Medical University of Gdansk, Poland, in the period 1992-2012, and identified only one case of CAMSG. A giant tumor developed at the base of the tongue in a 76-year-old man. The primary tumor was resected with multiple bilateral cervical lymph node metastases. The patient received radiotherapy but died 10 months after the surgery due to causes not related to the primary cancer. The tumor presented PRKD3 rearrangement as confirmed by FISH. As the tumor is extremely rare (it represented only 0.5% of salivary gland tumors in our series), the controversy on its nosological status is still unresolved. This is the first report in the world literature of a patient who died in the course of CAMSG.

Alveolar soft part sarcoma in a child - a case report.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a very rare mesenchymal malignancy of uncertain origin. It mostly affects young people, with about a quarter of cases being diagnosed in children. CASE: An 11-year-old girl had a painless subcutaneous "lump" in the left elbow area. Imaging exams revealed a solid soft-tissue intramuscular mass of suspicious appearance. A surgical excision of lesion was performed. The biopsy consisted of a lobular tumor measuring 35 × 20 × 12 mm. Histology revealed an epithelioid-cell population arranged in organoid pseudoalveolar pattern. It immunohistochemically expressed TFE3 and harbored the ASPSCR1:: TFE3 gene fusion. A diagnosis of ASPS was established. Subsequently, a wide re-excision of the scar was performed without microscopic residual tumor. The patient is currently without evidence of local recurrence or metastasis. CONCLUSION: ASPS is considered an aggressive and prognostically unfavorable chemoresistant neoplasm. Children have a better prognosis compared to adults. Early detection of tumor in a localized stage with complete surgical removal remains a mainstay therapeutic option. Due to its tendency to late metastases, a long-term thorough follow-up of the patient is necessary.

[Pleomorphic adenoma of salivary glands: diagnostic pitfalls and mimickers of malignancy]. / Pleomorfní adenom slinných zláz: diagnostická úskalí a histologické nálezy budící podezrení z malignity.

Pleomorphic adenoma is the most common salivary gland tumor, characterized by a complex biphasic proliferation of epithelial and myoepithelial cells intermingled with a mezenchymal component with frequent metaplastic changes and protean histomorphology of the cells. This review describes several unusual histological findings in pleomorphic adenoma that may mimic malignancy, and therefore they represent a diagnostic pitfall. Intravascular invasion of tumor cells is generally suspicious of malignancy; however, intravascular tumor deposits may be rarely found within the capsule of clinically benign salivary pleomorphic adenomas. It is important not to render a malignant diagnosis in such neoplasms, in the absence of other evidence of malignancy. Pleomorphic adenomas, particularly of minor glands of palate, may contain large areas of squamous and mucinous metaplasia suspicious of mucoepidermoid carcinoma (MEC). In contrast to MEC, metaplastic pleomorphic adenomas do not harbour the distinctive translocations t(11;19) and t(11;15), they are not invasive, in contrast they reveal at least focally myxochondroid stroma. Cribriform structures in pleomorphic adenoma may mimic adenoid cystic carcinoma. Oncocytic metaplasia in cellular rich pleomorphic adenoma/myoepithelioma may be associated with significant nuclear polymorphism and hyperchromasia suspicious of malignancy. The most common pitfall in diagnosis of pleomorphic adenoma is so called "atypical PA" that must be distinguished from early malignant transformation to in situ-carcinoma ex pleomorphic adenoma.

Pseudotumors and mimickers of malignancy of the head and neck pathology.

We are summarizing some of the difficult pitfalls in tumors of the head and neck, which we have encountered in our biopsies referred for consultation as well as from our routine praxis in the last 20 years. Shortly we are presenting the following lesions of head and neck: multifocal sclerosing thyroiditis, mucoepidermoid carcinoma of the thyroid, solid cell nests, Chievitz organ, rhomboid glossitis, ectopic parathyroid, signet ring cell change of salivary glands, mucocele, epithelial misplacement of the vocal cord squamous cell epithelium, and angiomatoid nasal polyps.

[Sarcomatoid (metaplastic) spindle cell carcinoma arising in a phylloid tumor with massive squamous metaplasia - a case report and review of the literature]. / Sarkomatoidní (metaplastický) vretenobunecný karcinom prsu vznikající ve fyloidním tumoru s rozsáhlou skvamózní metaplázií - kazuistika a prehled literatury.

UNLABELLED: A 76-years-old woman underwent a partial mastectomy and a low-grade malignant homologous phyllodes tumor measuring 45 mm in maximum diameter was diagnosed. Beyond its typical dual composition the tumor displayed extensive intraductal squamous metaplasia. Approximately in one third of the lesion the original mesenchymal component cytologically and structurally changed which ultimately led to seeming stromal overgrowth. The loose storiform background contained isolated larger atypical elements with ample eosinophilic cytoplasm and obvious mitotic activity. This final fibromatosis-like arrangement was completed either by multiple dispersed abrupt squamous morules or just by pearl-like abortive form of squamous differentiation. Conventional in situ or invasive ductal carcinoma was not present. A combined expression of both low and high molecular weight cytoketatins, S100 protein, p63, CD10 and GFAP confirmed the incomplete basal/myoepithelial phenotype and ultimately led to the diagnosis of a spindle cell metaplastic carcinoma arising in a phyllodes tumor - a neoplasm unpublished so far. A review of the literature concerning epithelial malignancies originating from a milieu of phyllodes tumor guides discussion/speculation over the possible histopathogenesis of this vanishingly rare lesion. KEYWORDS: breast - phylloid tumor - phyllodes tumor - spindle cell sarcomatoid/metaplastic carcinoma - squamous metaplasia.

Biphenotypic sinonasal sarcoma - a case report.

BACKGROUND: Biphenotypic sinonasal sarcoma (BFSS) is a topographically specific low-grade sarcoma that was first described only 10 years ago. The term biphenotypic comes from the co-expression of markers of muscle differentiation and neural crest that is characteristic for this tumor. CASE: A 78-year-old woman manifested with prolonged breathing difficulties through the left nasal passage. Rhinoendoscopy and CT scans showed an obturation of the middle and posterior part of the left nasal cavity by a polypoid tumor mass with a stalk in the ethmoid sinus. It spread into the nasopharynx. The tumor was resected and extracted from the nasopharynx through the oral cavity. Grossly, it was a compact polyp measuring 6 × 3,5 × 3cm. Histology revealed a uniform neoplastic spindle cell population arranged in a fascicular pattern. It expres-sed S100 protein, smooth muscle actin, calponin and muscle-specific actin. Molecular genetic analysis of the tissue showed PAX3:: MAML3 gene fusion. The findings confirmed a dia-gnosis of BFSS. CONCLUSION: BFSS is a very rare, locally aggressive malignant tumor without metastatic potential. In contrast to other malignancies in a given locality, it possesses a relatively favorable prognosis. In bio-psy practice, the pathologists knowledge of this unique histopathological entity is principal because it should be always considered when encountering a low-grade spindle cell neoplasia arising in the sinonasal region.

[Predictive diagnosis of HER2 in gastric adenocarcinoma]. / Prediktivní diagnostika HER2 v adenokarcinomu zaludku.

Trastuzumab is a monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2). This receptor is overexpressed in approximately 20% of gastric adenocarcinomas. The overexpression is associated with a worse prognosis, but on the other hand, patients with HER2-positive cancers were shown to benefit from the addition of trastuzumab to standard chemotherapy. To begin the targeted therapy with trastuzumab, HER2 testing is now mandatory with immunohistochemistry being the primary test followed by in situ hybridization analysis of HER2 amplification in cases with equivocal immunopositivity (score 2+). The immunohistochemical HER2 scoring system has been modified to include incomplete basolateral and lateral membrane staining, and to differentiate between surgical and endoscopical samples of the tumor. Benefit from trastuzumab treatment can be expected in tumors showing an immunohistochemical score 3+, and in cases with score 2+ and a positive finding of HER2 amplification. Clinical trials with further monoclonal antibodies and receptor tyrosine kinase inhibitors are recently ongoing to broaden the spectrum of possibilities of a multitargeted approach to the treatment of gastric cancer.

[Metastases to the breast from primary extramammary tumors--real diagnostic dilemma]. / Metastázy extramamárních solidních tumoru do mlécné zlázy--skutecný diagnostický problem.

OBJECTIVE: To address the difficulty and possible pitfalls in diagnostics of breast mtttstases from extramanmnary primaries--a pathobiological phenomenon that is not always thought of. To underline the open-minded differential diagnostic algorithm that is naturally weakened by dominant straightaway logistics in a routine contemplation. To emphasize the importance of complete and relevant clinical data including the anamnesis. To evaluate the effectiveness velocity and cheapness of imunuohistochemistry at reaching the correct diagnosis. DESIGN: Comprehensive study of the unusual pathogenetic setting based on personal experience with eight observations and literature review. SETTING: Biopsy Lab s.r.o. and Sikl's Department of Pathology, Charles University and Faculty Hospital, Pilsen. METHODS: Detailed clinicopathologic characteristics and review of morphologic spectrum in nine cases of extramammary tumors metastatic to the breast (three melanomas, two small cell carcinomas, one carcinoma from salivary gland, ovary, kidney and prostate). Standard immunohistochemistry was used as a reliable tool for phenotypic evaluation. RESULTS: In total nine cases, eight women and one man, were identified among 3238 of malignant breast tumors in the years 2005-2010. There were three melanomas, two small cell carcinomas and by one carcinoma from salivary gland, ovary, kidney and prostate. The age ranged from 43 to 81 years and maximum size of lesion spanned 7-31 millimeters. All specimens were core needle biopsy and only in one patient the past medical history concerning the nonbreast malignancy was known (ovarian serous carcinoma). Two neoplasms (one of the melanomas and small cell carcinomas) were the first sign of underlying malignant process ever; in this melanoma the clinical workout to disclose primary skin lesion failed. These two tumors were also the only ones, where the multiple or bilateral involvement of breast was clinically documented. There was evident other organs spread in three cases at the time of diagnosis (generalization in melanoma and prostate carcinoma; skin metastasis in salivary gland carcinoma) and axillary lymph nodes involvement in two melanomas. In five patients where follow-up was available, three died of tumor in interval from five to eighteen months (in turn melanoma, small cell and prostate carcinoma). Four original pathologic verdicts turned out to be wrong (two melanomas, salivary gland and prostate carcinoma); in three of them final correct diagnosis was established even after additional clinical information about morphologically verified malignancy in the past.

[Muir-Torre syndrome--a phenotypic variant of Lynch syndrome]. / Muir-Torre syndrom--fenotypická varianta Lynchova syndromu.

Muir-Torre syndrome (MTS) represents an autosomal dominantly inherited condition and is considered a phenotypic variant of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC), or Lynch syndrome. MTS combines at least one cutaneous neoplasm with sebaceous differentiation (e.g. sebaceoma, sebaceous adenoma, and sebaceous carcinoma), and at least one visceral malignancy. MTS is a genetic disorder caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Tumors in MTS patients are characteristically associated with the loss of MMR protein expression and/or microsatellite instability (70%). Patients who are suspected to have MTS/Lynch syndrome are often identified by dermatologists, dermatopathologists/pathologists, gastroenterologists and gynecologists. If MTS is suspected on a clinicopathological ground, necessary additional laboratory investigations should be performed only in specialized pathological departments providing immunohistochemistry and molecular biologic analysis service.

Angiosarcoma of the parotid gland.

Angiosarcomas of the major salivary glands are rare tumours. The authors describe a case of the tumour located in the right parotid gland of a 77-year-old woman. Histological examination revealed a poorly differentiated tumour made up of epithelioid and spindle cells. These two types of cells intermingled. In some parts, primitive mutually anastomosing irregularly shaped vascular spaces with atypical endothelial cells were found. The tumour cells were positive for CD31, CD34, EMA and FVIII (focally). Due to the relatively short follow-up period the prognosis of the disease is difficult to estimate.

Endolymphatic sac tumor (aggressive papillary tumor of middle ear and temporal bone): report of two cases with analysis of the VHL gene.

Endolymphatic sac tumor (Heffner tumor) (ELST) is a very rare nonmetastasizing, locally aggressive low-grade adenocarcinoma of endolymphatic sac origin, which is linked to von-Hippel-Lindau disease (VHLD). VHLD is an autosomal dominant disorder characterized by an inherited genetic abnormality of the VHL gene located on the short arm of chromosome 3 (3p26-p25). VHL gene mutations have been shown both in ELSTs associated with VHLD and in sporadic cases. Because of the rarity of ELST, only a small number of cases have been subjected to molecular genetic analysis. We have encountered two patients with ELST, one of whom presented with a medical and family history of VHLD. The second was a sporadic case, the patient having no symptoms of VHLD. The tissues obtained from Heffner tumor and cerebellar hemangioblastoma from the patient with inherited VHLD possess a point mutation in exon 1 of VHL gene. This mutation is a C to T exchange at position 194, resulting in amino acid exchange S65L. No mutation was found in any of the three exons analyzed and in the exon-intron junctions of the VHL gene in the sporadic case.

Role of ancillary techniques in profiling unclassified laryngeal malignancies.

Laryngeal biopsies, contrary to biopsies from many other sites of the body, very often contain minute amounts of tumour tissue that may consist of morphologically undifferentiated tumour only. In haematoxylin- and eosin-stained sections, there may be no indicative features of what specific tumour entity that is present. In the larynx, particularly small round cell neoplasms, primary or metastatic, often cause a diagnostic dilemma and where an incorrect diagnosis can induce substantial clinical consequences for the patient (e.g., primary neuroendocrine carcinomas vs metastatic variants, certain sarcomas). If sufficient/representative material has been obtained, the application of immunohistochemistry and/or molecular techniques should in virtually every case reveal the true nature of the malignancy. In cases with sparse amount of material, and therefore a limited number of sections to be cut, a careful and thoughtful stepwise approach is necessary to ascertain a reliable diagnosis, or at least guide the clinician to the most likely diagnoses. With today's advanced and widely available technology with an abundance of markers to discriminate different tumours, the use of the term "undifferentiated" should be largely unnecessary. In the exceptional, and indeed exceedingly rare cases, when a classification is not possible, even after repeat biopsy, we suggest that the laryngeal neoplasm is better termed "unclassified malignant neoplasm" rather than "undifferentiated malignant neoplasm".

The importance of prognostic factors in premenopausal women with breast cancer.

BACKGROUND: Basic conventional prognostic factors for breast cancer include the age of the patient, tumor grade, regional lymph nodes status, and estrogen (ER) and progesterone (PR) receptor status. Positivity of the HER2 receptor (c-erbB-2) seems to be a new prognostic and predictive factor. Prognostic factors seem to be more important in the high-risk group of the premenopausal females. We evaluated individual prognostic factors (age, histology, TNM classification, ER, PR, CA 15-3, CEA, HER2) and their impact on disease-free survival (DFS) and overall survival (OS) during the 5-year follow-up period. PATIENTS AND METHODS: Forty-two patients were monitored after standard oncology treatment for a period of at least 5 years. The statistical significance of the individual prognostic parameters was evaluated in relationship to the time to progression (DFS and OS). RESULTS: The following were evaluated as statistically significant prognostic parameters for DFS: PR positivity (p = 0.0036), proliferative marker MIB1 (p = 0.0108), pre-operative level of CA 15-3 (p = 0.0425), ER negativity (p = 0.0507). The following were evaluated as statistically significant prognostic parameters for OS: PR positivity (p = 0.0003), MIB1 (p = 0.0005), ER (p = 0.0440), pre-operative level of CEA (p = 0.0495). Positivity of immunohistochemically performed test of c-erbB-2 was not statistically significant for DFS os OS (p = 0.6361 and 0.9323, respectively). CONCLUSION: The statistically significant prognostic importance of the levels of tumor markers CA 15-3 and CEA for prognosis in breast cancer of premenopausal females was proven. So far, these factors have been underestimated. The prognostic parameters of ER, PR and MIB1 were statistically significant. While no prognostic importance was confirmed for c-erbB-2 positivity; this factor cannot be evaluated in premenopausal females separately from the other prognostic factors due to the predictive value in relation to the adjuvant therapy (patients with HER+, ER+, PR-).