Retrograde lymphatic spread definition in betting

Patients: Twenty-seven patients underwent surgery. The decision to perform either an ampullectomy or pancreaticoduodenectomy PD was based on the size of the lesion, the presence of a "field defect" ie, familial polyposis , depth of invasion determined by preoperative endoscopic ultrasound, and extent of pancreatic and bile duct involvement seen on endoscopic retrograde cholangiopancreatography. Interventions: Fourteen patients underwent ampullectomy, 12 patients underwent PD, and one patient had a retroperitoneal node biopsy performed without resection of the primary tumor.

Main Outcome Measures: Resectability, morbidity, and mortality. Results: Depth of invasion was accurately determined in nine of 12 patients studied by preoperative endoscopic ultrasound. Preoperative endoscopic biopsy specimens were obtained in 21 patients and were inaccurate in seven of 21 cases. The length of stay following local resection was One patient died following PD, and there were no deaths following ampullectomy. The implication of field effects may have potentially important implications for the understanding of prostate cancer development.

These observations suggest that HGPIN is only a distant precursor of adjacent invasive prostatic adenocarcinoma [ 16 ]. Many studies have attempted a comparative molecular genetic characterization of HGPIN and its corresponding prostate cancer to study this tumor progression and transformation. Furthermore, a study by Haffner and coworkers provided some evidence inducing caution in the interpretation of the data related to the molecular relationship between HGPIN and adjacent prostate cancer [ 18 ].

In fact, these authors suggest that invasive prostate adenocarcinoma may morphologically mimic HGPIN through retrograde colonization of benign glands with cancer cells; the same would apply also to intraductal carcinoma adjacent to invasive adenocarcinoma [ 18 ].

These observations suggest that the HGPIN lesion adjacent to invasive carcinoma does not necessarily represent its respective precursor lesion and additional studies based on single-cell molecular analysis and lineage tracing studies are required to define such a relationship [ 7 ]. In spite all the limitations in the definition and identification of precursor lesions of prostate cancer, the search of prostate cancer precursors lesions is of fundamental importance because offers the unique opportunity for disease prevention and treatment [ 19 ].

PIN-like carcinoma is a rare and is a variant of acinar carcinoma that is morphologically characterized by large cancer glands lined with pseudostratified epithelium similar to HGPIN [ 21 ]. Ductal adenocarcinoma is a histologic subtype of prostate carcinoma with large glands lined with tall columnar pseudostratified epithelium [ 20 ]. In line with this interpretation, Lindberg and coworkers tracked the origin of metastatic prostate cancer in a patient with prostate cancer comprising an intraductal carcinoma lesion: the analysis of breakpoint of genetic abnormalities leads to the conclusion that the IDC-P component is phylogenetically closer to lymph node metastases than most areas of an adjacent carcinoma [ 29 ].

A recent study helped to understand the possible origin of intraductal carcinomas. Taylor and coworkers have investigated prostate cancers occurring in men bearing germline BRCA2 mutations [ 30 ]. Germline mutations in the BRCA2 tumor suppressor gene are associated with an increased lifetime risk of developing prostate cancer and increased risk of aggressive disease [ 29 ]. Also, in sporadic prostate cancers with evidence of IDC, there was no evidence of multiple independent tumors: the IDC and IC components arose from a common ancestor and there is no clear evidence as to which compartment this ancestor arose in [ 30 ].

Although the origin of IDC remains unclear, it was clearly shown that the presence of IDC, particularly with a cribriform morphology was associated with a poorer disease-specific survival and represents an independent negative prognostic factor [ 31 ]. Another study performed detailed analysis to define the molecular features of cribriform prostate cancer using the TCGA data, compared to that of GS4 non-cribriform tumors and to that of metastatic patients [ 32 ].

The results of this interesting study showed distinctive features of cribriform, compared to non-cribriform tumors: i increased somatic copy number alterations, such as deletions at 6q, 8q encompassing both PTEN and MAP3K7 losses, and gain 3q; ii increased frequency of SPOP and ATM mutations; iii enriched gene expression pattern of mTORC1 and MYC pathways; and iv increased methylation of some genes [ 32 ].

The comparison with metastatic tumors, showed a higher similarity with metastatic than with non-cribriform GS4 prostate cancers [ 33 ]. Although the problem of the definition of prostate cancer precursor lesions and of their potential evolution to high-grade tumors remains an open problem, it is certainly true that some patients display tumor lesions at an initial stage of development and that these lesions may be heterogeneous, with a variable tendency to tumor progression.

Follow-up biopsy is the only available method to directly determine the tumor evolution and whether continued surveillance or active intervention is most appropriate. The use of this approach allowed to follow in the time a specific cancer clone and to analyze its potential evolution. It is evident that IDCP-inv must be treated with radical surgery, while there is no consensus whether pure IDCP in needle biopsies should be recommended for surveillance rebiopsy or radical therapy.

Genetic Abnormalities of Prostate Cancer 3. Intertumor and Intratumor Heterogeneity Prostate cancer is a multifocal disease since at diagnosis primary tumors contain multiple and genetically distinct foci of disease. In fact, exome sequencing of prostate cancer foci provided evidence for the presence of somatically independent tumors within the same prostate [ 35 ]. This conclusion was confirmed also in more recent studies showing the comparison of genomic landscape in both interrelated and spatially distant regions within prostates has revealed independent tumor origins [ 14 ].

Distinct tumor foci from the same tumor were subjected to whole genome sequencing showing no shared copy number alterations and very few shared punctual mutations between tumor foci, thus supporting the existence of a multiclonal disease [ 36 ]. These findings have important implications at two different levels: a biopsy-based diagnostic assay may miss some genetic alterations, thus leading to a misclassification of the tumor at molecular level, thus precluding optimal treatment, particularly those with new targeted agents, and b evaluation of the contribution of the different clones to tumor progression [ 36 ].

Using radical prostectomy specimens from patients with localized prostate cancer, several recent studies have performed genomic and transcriptomic studies aiming to evaluate the extent of intratumoral i. A study by Wei and coworkers, based on the study of four prostate cancer patients, showed a considerable intratumoral and intertumoral heterogeneity [ 37 ].

These findings have important practical implications in the context of the proposed molecular taxonomy for prostate cancer [ 38 ]. Interestingly, the majority of foci could not be ascribed to any of the proposed subgroups [ 37 ]. The extension of this analysis to other studies assessing intratumoral and intertumoral heterogeneity showed that only a minority of tumor foci can be molecularly classified [ 37 ]. These findings suggest that the specific tumor foci and tumor regions sampled differentially impact risk classification.

Finally, consistent intertumoral transcriptomic heterogeneity was observed, largely reflecting a concomitant genomic and grading heterogeneity [ 40 ]. These findings were confirmed also using the recently introduced Spatial Transcriptomic method which allows for quantification of the mRNA population in the spatial context of intact tissue [ 41 ]. This methodology allowed detection of transcriptomic heterogeneity in the tumoral foci, with gene expression gradients in stroma adjacent to tumor regions [ 41 ].

These studies have sequenced bulk tumor samples, comprising at least thousands of individual cells and therefore tend to underestimate the number of subclones. To bypass these limitations, single-cell whole genome profiling of localized prostate tumors is required. Using this methodology, Su and colleagues analyzed two patients, showing consistent intercell variability in mutations: one these patients showed a classical linear evolutionary profile, while the other showed early tumor branching; thus, in the first patient, all the cells shared the same TP53 mutation, implying a monoclonal origin, while in the second patient, only a subpopulation of cells contained the TP53 driver mutation, while other cells carried different driver mutations, supporting a polyclonal origin of prostate cancer [ 42 ].

Another great limitation of the studies until now performed for the characterization of intratumoral genomic heterogeneity is that these studies were based on the analysis of only few prostate cancer patients. In conclusion, studies at genomic, histopathological and molecular levels have identified tumor heterogeneity as a key biological property of prostate cancers, greatly contributing to a considerable complexity in the diagnosis, prognosis and treatment of these tumors.

This consistent heterogeneity of primary prostate cancers implies a consistent vulnerabiolity of diagnosis and targeted therapy guided by the results of a single tumor biopsy limited to a single tumor area. The understanding of prostate cancer heterogeneity is essential in developing new improved diagnostic criteria, tools, and biomarkers, and in guiding the choice of ptimalized therapies. In contrast, metastatic prostate cancer, in spite of its consistent molecular heterogeneity, at the level of the single patient is clonally homogeneous: i.

In fact, through a high-resolution genome-wide single nucleotide and polymorphism and copy number survey it was shown that the large majority of metastatic prostate cancer have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell, while accumulating a variable number of separate subclonally sustained changes [ 45 ].

The ensemble of these observations suggest that the prostate gland can be, at the beginning of the neoplastic process, the site of multiple neoplastic transformation events, the majority of which give rise only to latent prostate cancer that does not progress to clinically relevant disease.

However, in spite this initial multifocality and heterogeneity, when the disease progresses and becomes metastatic only individual clones with selective survival and growth advantage are selected and drive tumor progression. Through this analysis, in few patients, it was possible to follow the evolution of the lethal clone from the primary tumor to metastases through samples initially collected at diagnosis, then during disease progression, and finally at the time of death.

These studies showed that the lethal clone originated from a small, apparently low-grade cancer focus already present in the primary tumor, and not from the bulk high-grade tumor or from metastases [ 45 ]. After metastasis, tumor cells undergo clonal evolution and continuously change their properties through a process of metastasis-to-primary and metastasis-to-metastasis reseeding [ 47 , 48 ]. These tumor exchanges promote a process increasing tumor heterogeneity and competition between various clones in function of their microenvironment.

Tumor heterogeneity decreases when an emergent clone has developed a high potential for local and at distance metastatic growth and is able to survive to cancer treatments [ 47 , 48 ]. The analysis of metastatic development allows describing phylogenetic trees of tumor development involving three different patterns: linear evolution, branched evolution, and independent evolution [ 47 , 48 ]. A recent study explored the relation between lymph node metastases and primary tumor lesions [ 49 ]. These findings have important implications for the focal ablation therapy, which, when based on the ablation of the sole index lesion, may represent an undertreatment of a significant proportion of prostate cancer patients.

In conclusion, the studies on metastatic disease suggest that the metastatic process does not uniformily originate from the index lesion, but may also originate from small, secondary non-iundex primary lesions. Under the selection exerted by treatment with androgen receptor targeted androgen deprivation therapy, rare subpopulations of cells present in origin tumor foci that reactivate androgen receptors through a variety of molecular processes from the acquisition of mutations; copy number alterations to synthesis of constitutively active androgen receptor splice variants acquire the capacity to evade androgen deprivation therapy, while other cells acquire alterations in MYC and CTNNB1 and develop the capacity to seed and reseed multiple sites through a metastatic process [ 47 , 48 , 49 , 50 ].

These studies imply the potential clinical utility of performing a detailed genomic analysis at the level of multiple metastatic sites. In this context, Bova and coworkers have performed a combined analysis of whole genome sequencing and transcriptome sequence analysis of multiple prostate cancer metastases in a single patient: liver metastases displayed the presence of AR pLH mutation, associated with increased expression of AR-regulated genes; the metastases displayed truncal mutation in PIK3CG, homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1 [ 51 ].

From a histopathological point of view prostate cancers are highly homogenous, in that the large majority corresponds to acinar adenocarcinomas, while other histotypes such as ductal adenocarcinoma and mucinous carcinoma are very rare. Although prostate cancer is relatively homogeneous at histological level, recent genomic profiling studies have shown a consistent degree of heterogeneity and have supported the existence of molecularly distinct subtypes.

However, despite having relatively few mutational events, prostate cancer is characterized by a high level of genomic instability and chromosomal rearrangements. In prostate cancer, gene abnormalities have been detected as single nucleotide variants SNVs , small insertions or deletions, rearrangements, aberrant methylation, and changes in gene copy number.

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All rights reserved. This is an open access article distributed under the Creative Commons Attribution License 4. However, no adequate data currently exist to illustrate the pathology of the retrograde lymphatic metastasis of cancer cells in human bodies. To shed light on this phenomenon, we report a case of a year-old Japanese man who underwent an esophagectomy and lymph node dissection for early-stage esophageal cancer.

The patient's clinical information was evaluated by board-certified surgeons and internists. Surgically excised materials were histopathologically evaluated by attending pathologists. Postoperative pathological examination revealed that the patient's tumor was a well-differentiated squamous cell carcinoma with negative surgical margins T1N0M0, stage I. Apart from the primary lesion, a single lymphatic vessel invasion was found between the lamina propria and lamina muscularis of the esophagus where intralymphatic cancer cells had spread against the direction of backflow prevention valves and skipped beyond these valves without destroying them.

The present case demonstrated that the retrograde lymphatic spread of cancer cells can occur in valve-equipped lymphatic vessels. Our study may not only provide a scientific basis for the concept of retrograde lymphatic metastasis but also explain a portion of the complexities associated with the lymphogenous metastasis of esophageal cancer. To shed light on this phenomenon, we report a case of a year-old Japanese man who underwent an esophagectomy and lymph node dissection for early-stage esophageal cancer.

The patient's clinical information was evaluated by board-certified surgeons and internists. Surgically excised materials were histopathologically evaluated by attending pathologists. Postoperative pathological examination revealed that the patient's tumor was a well-differentiated squamous cell carcinoma with negative surgical margins T1N0M0, stage I.

Apart from the primary lesion, a single lymphatic vessel invasion was found between the lamina propria and lamina muscularis of the esophagus where intralymphatic cancer cells had spread against the direction of backflow prevention valves and skipped beyond these valves without destroying them.

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