Urology Department, University of Turin, Turin, Italy
Etiologic and pathogenetic data are useful if not necessary if we are to understand the segmentary nature of some malformative conditions, including cystic diseases of the kidney. As mentioned earlier, the development of the kidney and urinary tracts occurs over a series of stages that take place within a limited space and time. If this development is abnormal it can cause malformative nephrouropathies. The most serious of the malformative nephrouropathies is renal dysplasia: primitive tubules, embraced by stroma and a muscular collar surrounded by areas of nephrogenic mesenchyme together with undeveloped or less developed renal tissue and with non-renal structures like cartilage, muscles, and other structures, termed mesenchymal metaplasia [41, 42].
The human nephroureterogenetic process starts at about the fifth intrauterine week as a result of the connection of the ureteral bud of the Wolff duct to the metanephric mesenchyme. This develops into a definitive kidney. This mesenchyme triggers a process of gene transcription that induces on the one hand the prolongation of the excretory system, ureter, pelvis, and collecting ducts, and on the other hand the differentiation and proliferation of metanephric blastema cells. From that differentiation and proliferation some vesicles will form, that with prolongation, differentiation, and segmentation will make the nephron from the glomerulus to the distal tube.
With regard to development time, it has been established that while the ureteric branching progressively decreases from week 15 onwards, formation of the new nephrons continues up to the 34th week and beyond.
Any alterations to these series of events, which are so intimately connected to one another, causes different anomalies depending on a number of issues. These issues include when the anomalies begin, the metanephric mesenchyme maturity, the tubular immaturity at the time, the different kinds of cyst formations and localizations, and the existence or absence of other excretory system anomalies. In terms of a timescale it would seem clear that, for example, the absence of the ureteric bud induction on the metanephrons causes agenesia, while stopping the ureteric branching and the epithelial differentiation would cause different kinds of dysplasia, ranging from a multicystic kidney to cortical or peripheral cysts .
Generally speaking, developmental failures are caused either by insufficient protoplasmic evolutive potential or, contrarily, by insufficient protoplasmic involutive potential. The consequence of the first cause is the developmental failure of the parenchyma and/or of the excretory system, such as agenesis, hypoplasia, and aplasia. A consequence of the second cause would be the excessive development and persistence of transitory elements that would ordinarily be destined to disappear. An absence of reduction in epithelial cell abundance in (solid) cords destined to become patent tubes, like the distal nephronic tubes, leaves them occluded, causing dilations or cysts (some readers may recall the Kemperer and McKenna theory on the involution failure of overabundance of primitive urinary tubules caused by the overabundance of nephrogenic blastemas, with respect to the numeric availability of collectors coming from ureterogenic gem; resulting in a lack of tubulo-collectorial meeting and consequentially cysts) .
Renal cysts are sac-like, epithelium-lined protrusions that have developed into renal parenchyma. They consist of liquid and start as expansions of pre-existing nephrons or collecting ducts of both embryonal structural elements. At this point they are a nephro-ureteric fusion anomaly. The inside liquid seems to derive from proximal and distal segments of primary nephrons. The epithelium that lines their surface is similar to that observed in the same segments of the nephron: functionally it retains the secretory activity. In some cases, over time, the cysts may lose all their connections with the original structures. Their pathogenesis is summarized in two predominant phenomena: epithelial hyperplasia of tubules and new or different secretive processes. Both contribute to the creation of endotubular hyperpression and the accumulation of similurinary liquid that develops tubular obstructions and cysts.
The aforementioned pathogenesis does not refer to the major numbers of renal cysts that occur in patients over a long period of time (5 and more years) that are treated with hemodialysis. In such circumstances cysts are generally small, subcapsular or at the cortico-medullary junction and, as part of the amyloid nephropathy, their content is liquid. In the majority of patients, the source of cystic liquid is not well understood. The obstruction of tubules seems to be caused by peritubular fibrosis or by calcium oxalate tubular occlusion. Given that the kidneys of dialytic patients are commonly small and retracted, their sudden enlargement indicates cystic complications, such as hemorrhage or tumors. Renal tumors, solid or papillary, frequently arise from the cystic epithelium and have a clear renal cell appearance .
In adults simple cysts are commonly acquired as a result of two principal factors: The first is the congenital presence of a small tubule diverticula, well illustrated by the microdissection technique , where the lesion starts. The second factor is precipitating substances and this is consistent with the obstruction of the urinary tract together with the normal involution of the basement membrane, typical of aging. With regard to aging, it is important to remember that in people under 40 years of age, simple renal cysts are rare, while from that age on almost 24 % of people have renal cysts in increasing numbers and size with age [56, 57]; 30 % of those cyst seem to be 2 cm or less, and are extra- or intra-parenchymal on abdominal CT.
The indications for renal segmentectomy (or partial nephrectomy) are exceptional for cystic diseases that concern only one single area of the kidney.
For completeness, it should also be noted that the same definition of a cyst could seem inaccurate compared to the total or partial excretory endorenal system dilation and their genesis. It is believed that the majority of kidney cyst formations (sporadic, acquired, congenital) originate from nephrons or collecting ducts either normally or not normally formed. An exception is multicystic dysplasia formed before nephron development from the lack of ureteral gem induction on the metanephric cap.
Much importance has been recently given to “ciliopathy” etio-pathogenesis for the manner in which it is involved in congenital cysts [59–61].
The sections below discuss only cystic diseases that, independent of their genesis, may occur as area- circumscribed and are therefore suitable for conservative surgery.
4.1 Cysts: Solitary, Typical, Atypical, Complicated
Surgical therapy for these cysts is not frequently indicated, is nearly exclusively for atypical or hemorrhagic or suppurated forms of puncture treatment . In such cases segmentectomy, rather than extracapsular removal, can be considered when and if nearly all of the segment is involved (which is exceptional).
4.2 Multilocular Cyst or Cystic Nephroma
This is a rare kind of non-hereditary, organogenetic, dysembryogenetic, malformative disease, considered similar to benign neoplasia. It is relatively rare, but not excessively so given that recently five cases have been reported in Piedmont alone (an Italian region of 4,400,000 inhabitants) [62, 65]. Part of the renal parenchyma is replaced by a cluster of cysts that do not communicate between themselves and are not connected with the pelvis and calyces. A capsule envelops the cluster. It is always monolateral, and almost exclusively in women. What remains of the renal parenchyma is normal. There are often other malformations.
An infantile form also exists. It is generally considered to be one of the following: benign cystic Wilms’ tumor, cystic nephroblastoma, or differentiated nephroblastoma. The diagnosis of this is generally on the basis of the presence of an abdominal mass.
Surgical treatment is by no means the rule, as especially in adulthood, patients are often symptomless, so surgery is reserved for large, complicated masses protruding in the abdomen. When the cyst bunch concerns one or more lobes, complicated by inflammation or hemorrhage, segmentectomy is indicated and the remainder of the kidney is considered normal and sound. Obviously preoperative or intraoperative tumor lesions have to be excluded.
As mentioned earlier, the cystic nephroma is often associated with other genitourinary malformations or the pathologies of different organs.
A possible, though very rare, association with endometriosis makes the diagnosis even more difficult, as in the case of C. Boccafoschi, in which this disease was associated with cystic lymphangioma involving the bladder and sigmacolon. The lymphangioma was presumably caused by a diffuse lymphatic obstruction at the pelvis level, which consequentially created lymphatic dilations and cysts. A type of lymphangioma was then at least partially acquired .
As mentioned above, since multilocular renal cysts may be considered neoplastic lesions, this was suggested as a more appropriate name . This definition must be reserved particularly for cystic tumors that have been formed from entirely differentiated tissues, without blastema, or other embryonal elements. The designation of “nephroblastoma partially differentiated” defines cystic lesions as lacking in a solid, nodular area, while blastema or other embryonal tissues are present in cystic septa. They are not especially aggressive and never result in metastasis.
The reason for the lesion being known by such a variety of names, such as multilocular renal cysts, partially polycystic kidney, renal cystadenoma, polycystic nephroblastoma, differentiated nephroblastoma, and cystic nephroma, is the result of different etio-pathogenetic interpretations. Essentially there are two contrasting theories: neoplastic and dysplastic. The first seems to be more accredited today, supported by the fact that in dysplasic skeletal muscle, spots of metanephric undifferentiated blastema and immature mesenchyme such as that of nephroblastoma have never been found. The absence of typical elements of dysplasia, such as cartilage and embryonal ducts, support the neoplastic hypothesis.
The dysplastic-malformative theory relies on the idea of an autonomous vascularization that is independent from the renal vessels and originates in the lumbar vessels. This contention has appeared in the same literature and it assumed that cystic nephroma is a species of renal sequestration similar to pulmonary sequestration . The latter is also a cystic malformation of the lung that does not communicate with the bronchial system and pulmonary vessels, but is nurtured by a systemic few vessels that it captures from the rest of the lung.
Another group of renal neoplastic cysts is the group of multilocular cystic renal-cell carcinomas, which represents a sub-group of renal cell carcinomas with proper macro- and microscopic characteristics. The features of these cysts include a variable quantity of neoplastic clear cells, with nuclear grade 1, and small or no mitotic activity. The cystic wall is fibrotic and often has no epithelium. Tumors are diploic at flux-cytometry and experience very low proliferative activity. Joshi et al.  believe this group of cyst to be a variant of low-grade clear cell renal tumors.
Finally, in order to avoid confusion, it is necessary to remember that the diagnosis of cystic nephroma is mainly based on the following characteristics: unilateral, isolated, multilocular, and unconnected to the pelvis or calices. The different cysts do not communicate with each other, and all the have a lined, defined epithelium, whilst normal and mature renal tissue is absent in them, and, importantly, the adjacent kidney is normal . With regard to conservative therapy and then renal segmentectomy, it is very important to reach the diagnosis preoperatively, demonstrating that a good amount of normal paremchyma can be saved. One should also be aware of the possible presence of adenocarcinama or nephroblastoma foci in the lesion; however, this does not exclude conservative surgery with favorable results [67, 68].
4.3 Unilateral Segmentary Cystic Disease of the Kidney
About 50 cases of this disease have been published. They are differentiated from polycystic autosomic diseases (recessive or dominant) by the absence of familiarity, unilaterality, and segmentarity. This is a benign form that does not have the tendency to evolve into renal insufficiency and for which surgical treatment is not generally necessary, except in cases of space-occupying masses and pain .
The literature provides examples of nephrectomies being carried out due to the suspicion of the presence of a tumor, despite a good biopsy result. The anatomic specimen showed that the normal parenchyma was lesion free. Thus we now know that when a surgical indication exists, segmentectomy or another partial resection can be considered.
4.4 Cysts Associated with Renal Neoplasms
Two typical cyst-tumor associations are those of von Hippel-Lindau and tuberous sclerosis. Von Hippel-Lindau disease is transmitted by an autosomal dominant character. Cerebellar and retinal hemangioblastomas, pancreatic cysts and carcinomas, and renal cysts and tumors represent such a serious problem]. that the issue of the cyst itself is completely non-existent. Surgical treatment, which takes into account the complete or partial nature of the tumor, will be indicated. It is well known that maximum effort should be extended toward preserving the not-yet invaded parenchyma. For tumors that are less than 3 cm in size, nonsurgical renal-spearing strategies (radiofrequency, percutaneous ablation, and selective trans-catheter arterial embolization) have shown promise in short-term trials. For tumors that are more than 3 cm in size, conservative surgery, such as partial nephrectomy or even segmentectomy, should be considered.
In multiple tuberous sclerosis, which is transmitted via an autosomal dominant character, the hamartomas of the skin, brain, retina, skeleton, lungs, and kidneys are often associated with cysts. Sometimes the cysts are big and cause arterial hypertension. Indication for surgery is exceptional and nearly always based on the angiomyolipomas situation (present in 50 % of cases) and its clinical scenario is as follows: hematuria, hemorrhage, flank-loin pain, and life-threatening retroperitoneal hemorrhage. Bleeding complications create an emergency and require urgent surgery. For this reason, conservative treatment, which would otherwise always be desirable, becomes in practice impossible. In that sense renal segmentectomy in cases of tuberous sclerosis represents just a theoretical indication.
It must be remembered that the first manifestation of tuberous sclerosis, though extremely rare, being unilateral, could be segmental cysts found in children, as in the case of the segmental cysts reported in 1997 by Wel Lara et al. .
Indeed, with regard to the relationship between renal cysts and tumors, interesting research is beginning to clarify the co-responsibility of proliferative activity of the cystic epithelium and genes regarding the induction of tuberous sclerosis. In this regard it was strongly suspected that the two major genes of tuberous sclerosis and polycystic kidney disease, TSC2 and PKD1, respectively, are adjacent in chromosome 16p, 13.3. It is on this basis that Sampson et al. believe that PKD1 has a role in the etiology of tuberous sclerosis .
Apart from von Hippel Lindau and tuberous sclerosis diseases, with regard to the cyst/tumor association, clinically the problem of identifying the presence of neoplastic tissue in cysts appears predominantly in complex cysts, where the occurrence of malignancy is greater. Imaging with radiologic follow-up and guide biopsy is able to reach the correct diagnosis and avoid unnecessary surgery in 39 % of cases of cystic renal masses, the second category of Bosniak, according to Hansinghani et al. . Apart from complex cysts, CT imaging shows some cysts with unusual content, now known as hyperattenuating renal masses. These cysts are wholly or predominantly filled with CT attenuation, higher than the surrounding parenchyma. Protein or iron concentration, hemorrhage, colloids, infections, and occasional iodine accumulation are the most frequent reasons for the hyperattenuation of simple cyst content. Hyperattenuating renal masses may also be constituted by hematoma, vascular aneurysm, malformations, malignant cysts, benign hyperattenuating cysts, and other hyperattenuating solid masses. As a consequence, the importance of recognizing the etiology and pathogenesis of the lesion is essential for correct clinical diagnosis. In the majority of cases the cysts are benign, and it must be emphasized that when neoplastic, the small cysts, with homogeneous enhancement hyperattenuating, should be considered to be of benign origin [80, 81].