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Bone neoplasms, not of bone but in bone

  1. Gastroepato
  2. Oncology
  3. Bone neoplasms

notes by  dr. Claudio Italiano

Bone tumors are subdivided into primary tumors (ie, bone-like ones) and secondary tumors (that is, they derive from the metastasis of other neoplasms). The latter lesions are certainly more frequent than the primary lesions, as different tumors, as is well known, can metastasize into bone tissue (bone secondarism). Today, compared to the past, the approach to bone tumors, especially those primitive, has changed significantly: in the face of a clinical suspicion of bone cancer we proceed to accurate imaging and the execution of incisional biopsies.

The biopsy indications are reflected in the fact that a cyto-reductive therapy can often be carried out, because sometimes an "exeresis" (surgical removal) of the bone portion affected by the neoplasia can entail considerable complications, so the idea is that to carry out treatments that can reduce the damage on the bone segment as much as possible, trying to limit the amount to be removed and above all trying to make the remaining segment compatible with any prosthetic structures that can be implanted.
Another characteristic feature of bone tumors is represented by the fact that from the histogenetic point of view they derive from the proper components of bone and cartilage, while in reality other neoplasms present in the bone and are developed in the bone from an epidemiological point of view a superior relief of the neoplasms of the osteocartilaginous tissue proper. So while we need to document in the neoplasms the presence of cartilaginous matrix or the presence of a newly formed osteoid matrix, we know that there are a whole series of neoplasms in which we have to go elsewhere to look for the clinical signs of the neoplasia because it does not c 'neither the production of osteoid matrix nor of cartilaginous derivation substances'. Therefore a bone lesion must be sought in a phase as early as possible precisely because many of these neoplasms give extra bone / extra-articular signs. Another fundamental element consists in conducting a sampling in correspondence of the bone and cartilage with particular techniques: not being able to fix it in formalin, it is necessary to proceed towards a progressive demineralization and decalcification of the bone through descaling substances one of the best known is acid 1% formico but also EDTA, and then set up histological sections on a regular basis.
Once the diagnosis has been made and the therapy performed, including perhaps a surgical exeresis involving even significant portions of the osteoarticular apparatus, it is appropriate to proceed to a sort of mapping of the lesions to determine how effective the therapy has been. For example, in the case of an extensive bone neoplasm, it should be tested if the pre-surgical treatment (generally mixed both radiotherapy and antiblastic) produced a neuropathy necrosis, with reduction of the neoplastic mass and at the same time reduced the ability to give metastases.

Another element is the great extra-compartmental aggressiveness and the simultaneous demonstration of a distant metastasis, so sometimes the first filter will be at the pulmonary level. 

Practical classification of bone neoplasms

Referring to multiple myeloma, Edwing's sarcoma, non-Hodgkin's malignant lymphoma, we can state that although it is not bone grafting in the narrow sense, we still understand that of these 3 tumors that these tumors of the bone are tumors in the bone. bone, in the sense that they are inside, they grow well. These are the locations in which they manifest themselves in a recurrent manner.


CLASSISICATION OF SMALL CELLS TUMORS:

 Multiple myeloma
 Ewing's sarcoma
 Non-Hodgkin malignant lymphoma


The most common bone tumor in all, much more common than cartilage lesions and bone tissue itself is represented by MIELOMA MULTIPLO. Well over a third of all bone tumors, even almost half of the malignant tumors in the bone, is known because it is the most frequent among the malignant neoplasms of the bone. Another important aspect for diagnostic purposes is the patient's age, the first manifestations and the locations that are strongly indicative; it is basically difficult to think that a patient who is under 40 has a myeloma, precisely because the latter is characteristic of old age (50-60 years). The other extremely characteristic element is that this tumor invariably presents itself with osteolytic lesions, that is the emptying of the bone structure and in particular of the flat bones.

Once again, the seat becomes an element of reference because the localizations typical of myeloma are the cranial case, the sternum, the ribs, the vertebrae, that is, where we have flat bones. The other fundamental elements are linked to the fact that, if we consider histogenesis, the cell of origin has nothing to do with a cell of bone or cartilaginous origin, because the tumor consists of a monomorphic proliferation of plasma cells. In reality they are largely immature plasma cells, often plasmocytoid, plasmablasti, etc. they remind the plasma cells somehow, and this proliferation produces a series of side effects:
a) The plasma cells produce a high amount of cytokines, of light chains of monoclonal immunoglobulins that are absolutely ineffective from the functional point of view and therefore the humoral immunity of these patients is reduced, does not work (it is one of the first signs that pushes the patient to go to the doctor, are patients who complain of recurrent infections even trivial). This excess of immunoglobulins is then filtered into reality as if we had a constant proteinuria which then leads to Bence Jones proteinuria.
b) The accumulation of proteins ends up in determining an amyloidosis, a deposition of amyloid substance also in correspondence with the bony lamellae which are visibly altered and fragmented.
c) The altered lamellae determine another starting element which is the pathological fracture. There is indeed the possibility that this tumor in absolute clinical silence suddenly wakes up with a fracture
d) Since there is a non-functioning humoral immunity, the mechanisms of immunosurveillance tend to be completely altered: this is the reason why patients with multiple myeloma often develop a second neoplasm.

These second neoplasia in general are bothersome in the sense that they are rather aggressive (es.carcinoma of the pancreas, carcinoma of the extrahepatic biliary tract), tumors that already in themselves are in condition to determine the patient's exitus. The risks of a patient with myeloma are therefore numerous, as you can imagine all these proteins that are filtered by the kidney in the long run will determine a renal failure (when we do the renal pathology we will find that there is an amyloidosis kidney kidney because the excess amount of amyloid does not stop only the damaged bone but goes into the kidney determining first the increase of recurrent and saprophytic infections and then a second neoplasia.

The lesions are determined in the bone precisely for this hyperactivity of the plasma cells that overproduce protein substances of nature mostly non-effective immunoglobulin, which in turn stimulate a wide range of interleukins including TNFalpha: all these substances play an activating action against osteoclasts, this is the link that leads us to understand why this lesion develops in the bone, basically that equil The balance between bone remodeling and the juxtaposition of bone, osteoid and mineralized matrix is ​​actually unbalanced, there is an hyperactivation of osteoclasts which clearly determine a negative balance with respect to bone resorption. This is the reason why radiographs are often appreciated osteolytic lesions that are also called nummular, coin-shaped.

These lesions are due to the action of the osteoclasts that go to erode the lamellae. The most common site is the cranial case, again for the hyperactivation of osteoclasts. In the histological correspondent we should expect an organization of the bone tissue, and in fact we see that the lamellae are only on the right, now reduced in the periphery and all the rest is replaced by a uniform proliferation of plasmocytes. Looking at them at a higher magnification than if they are plasma cells, we notice even more not so much, and only for the appearance, because the nucleus that polarizes and lateralises in the cell is evident, the carriage-wheel nuclear chromatin is described, but the other aspect it is striking that this cytoplasm is blue, strongly basophilous violet precisely because it has this large production of protein substances that end up being stored inside the cytoplasm. This excess of basophilia of the cytoplasm is not even indirectly indicative of synthetic hyperactivity of proteins that actually corresponds to what these plasma cells do. Obviously when the picture is more widespread it is extremely simple, in other cases it can be more difficult in the sense that especially in the elderly people in whom there has been a partial transformation of the yellow marrow into a less working marrow can happen to find some elements in the form of infiltrated spilled (rather than in the form of diffuse infiltrate) in the middle of the yellow adipose tissue component and in these cases we can help with a specific plasma cell marker that allows us to identify them with an obvious cytoplasmic reactivity that is CD138. In the histology, what we can see again is not only the presence of the lamella that has all the absolutely irregular and jagged margins, but what strikes us most, beyond the amount of plasma cells that are present here, are these cells more large osteoclasts; activated cells which, upon thrust of the plasma cells, are arranged around the lamellae and begin to eat them up to the fracture; there is a deposition of amyloid substance; in fact the amyloid substance is revealed with the Congo red, an absolutely characteristic streaming color gives this orange-red color, often in the perivascular structures in the interstitial tissue there is a real deposition in the bone region. Of course, amyloid can also be demonstrated with polarized light, but today more often the diagnosis of amyloid is made with periumbilical fat biopsy which is much easier to take; and it is sufficient to have positive red congo structures of the periumbilical area, interstitial structures to make a diagnosis.

The curiosity has remained to understand if indeed this hyperproduction of proteins inside these cells is documented not only from the chromatic point of view with basophilia but if one can have a certainty that this has happened from a structural point of view, for this reason wants to run to an ultrastructural analysis of this tumor (going to do the electron microscopy not for diagnostic purposes but for purposes of study / deepening or even sometimes to have the verification of what was suspected), we can see that next to the core there is a huge amount of RER with many ribosomes that represents the workshop open day and night. In the long run this material that accumulates inside the cells tries to make space, and the cell makes it take on a characteristic digital impression distribution; so these profiles of the RER are as if they were wrapped around each other to simulate the shape of the fingerprint. In doing so it becomes necessary to proceed to a real packaging / stacking of these proteins according to a periotic structure giving rise to the formation of these geometric crystals represented by pseudo-triangles, rectangles in which, however, if you look well down inside this triangle there is a 'utmost technicality because as they are brought in there these proteins are always folded in the same way. The secondary and tertiary structures are assembled together and the final result is to have many more proteins inside the cells occupying a smaller space; obviously we can remove the superfluous space and we set up a logic of periodicity that tells us that inside there is a large quantity of packaged immunoglobulins even if they are not functionally suitable.
In MIELOMA MULTIPLO we will have:
 Peak of monoclonal immunoglobulins
 Bence-jones proteinuria
 Multiple district amyloid deposition
 Pathological fractures
 Increased susceptibility to infections
 Increased risk of second neoplasia

This is therefore the most frequent and common cancer in the bone. However, in the field of small cell tumors there are other tumors, even those with a completely different provenance from that of the osteocartilaginous tissue. Both Ewing's sarcoma and non-Hodgkin's lymphoma are extremely rare cancers, unlike the frequent myeloma; they are in the order of 5-6% no more than the malignant tumors of the bone. Also this time especially for the SARCOMA DI EWING useful information about age, as well as for myeloma which is absolutely a neoplasm of maturity, with the same certainty we can say unfortunately instead that Ewing's sarcoma is a neoplasia of young people not to mention children; above the age of 20 is practically an unknown neoplasm unless it is extra-skeletal but this is an even rarer neoplasm. Being a young tumor it is often accompanied by a demonstrable translocation at the chromosomal level 11-22; from a histogenetic point of view it is a neuroendocrine tumor that takes origin from the neural crest cells and in their migration, instead of going where they should, they end up inside the bone. These are small cells certainly but as we will see these are also densely packed cells, cells that have a high fraction of growth and as such are cells that say they can not carry with them a share of tumor neoangiogenesis and therefore are cells that very often they accompany areas of necrosis (the characteristic is "a festoon"). The clinician in fact asks us after treatment to check how much they have extended, how much of the tumor these areas have succeeded in replacing. It is a tumor practically having a ubiquitous distribution, it covers every kind of bone portion (while in myeloma we had seen that it preferred flat bones), however, tends to favor the localization in the long bones, not only the lower limbs also of the forearm for one thing. We can therefore define it as a ubiquitous, widespread and rapidly growing lesion. Here we have a first evaluation element (which we will also see later on in osteosarcoma the malignant tumor of the bone properly) that gives a further important meaning, and it is the imaging survey because basically in these cases especially at the time of the first diagnosis imaging becomes not only for us but also for clinicians, for all a macroscopic morphological aspect. In some way we have to imagine and represent the macroscopic aspect of this neoplasia through what imaging allows us, this is true because otherwise we should have the limb in hand, we should have a deprivation or amputation, all conditions that we try to avoid even more because we are talking about subjects of school age and adolescence. Work is done to ensure that the exeresis is the minimum possible and eventually there is the replacement of that portion or with a bone to be re-implanted or with prosthetic material.

The tumor manages to infiltrate and overcome this layer of periosteum and again the bone tries to limit it with another affixing). The more events of these occur the less resistant the bone and consequently it is easier for the pathological fracture to happen but also understand that if the pathological fracture is opened, that material that is under the periosteum exits the bone then exceeds the tumor it becomes extra-compartmental. Worse is the situation on this side that we could not grasp is that from this portion begin real bone discontinuity; the bone is completely erased.

The tumor started from the inside of the bone but all the periosteum was completely destroyed and even the surrounding portions were taken away; in fact it is called block excision, the whole district is taken away with the muscles attached with the bands attached. Because? It is obvious, the tumor is very advanced; however, they are conditions that we should not see because this cancer should be diagnosed before arriving at this stage. Otherwise, unfortunately, these situations involve extensive mutilations and as you understand they are very difficult to make children accept children, imagine yourself to family members. Our task must be to reduce the removal as much as possible. So the main things we have said are:

 The decoupling between imaging and the real picture that then emerges
 Need to check these areas of necrosis very carefully


which are the effect of poor vascularisation and therefore a defect of the vasculature. You see how the lesion that initially seemed small inside the canal then expands becoming a polypoid lesion that infiltrates all the surrounding tissue and you also see in the other photo all those portions that are darker inside the vertebral bodies show polyostotic diffusion (replacement of bone tissue with the tumor).

We can find small, densely packed cells with a modest vascular share and the other interesting element is the presence of these small elements with these band-shaped tape-like necrosis, precisely because the vascular structure can not stay near the tumor that is made from round, small and all the same cells that very often contain glycogen granules inside them. We can also document these granules through a histo-chemical staining that is the FAS reaction that gives you a view of the slide with a vertical development at the top we see the equivalent hematoxylin-eosin, in the center of that field there are at least 4 or 5 achylic mitosis that say how aggressive the tumor is and on the other hand the corresponding color in FAS and inside the cells there is this small powdery red-magenta color that are nothing more than the granules of glycogen. You can see more in the varieties we have on the other side where the cells take this clear cell aspect at the start and then actually the red tells us that there are these granules inside. If we want to verify the purely structural aspect of these granules, we see in this slide that the little black dots are nothing more than the micro-aggregates of glycogen which are the ones just demonstrated with the red color. Today, among other things, this tumor identifies it very well because for this malignant neuroendocrine tumor we have a marker that is represented by CD99. We have the opportunity for many of these tumors without the need to conduct an ultrastructural investigation that is a much more expensive thing, which also needs a lot of time etc. we can do directly if we suspect the CD99, obviously within the clinical reasoning mentioned above: the young patient, localization in long bones and with these characteristics of apparently minimal radiological damage and then with a series of markers including CD99 and so Street.

LINFOMA NON HODGKIN would still have to be analyzed to complete the topic of small cell tumors. Now it is clear that here we are talking about primitive lymphomas of the bone even if 99% of the lymphomas are primitive of the lymph nodes, they are nodal lymphomas. We are not in the bone localization of a lymphoma in general but it is a primitive bone localization. The patient has nothing but the bone lesion. It is always in small cells but this time it is not neuroendocrine it is not made from plasma cells but it is made by B lymphocytes and this too is not at all surprising because most of the lymphomas (even nodal ones) are represented by B lymphocytes and bone lymphoma it is no exception. The characteristic aspect of these tumors is that very often they have a strange and unusual onset such as bone marrow compression because it realizes a real osteolysis of one or more portions of the vertebrae and the other characteristic aspect is the macroscopic one that we define boiled fish or "fishflesh" because it has a soft, whitish, milky appearance that contrasts strongly with the stiff rigid nature of specific bone tissue. Characteristically what does a lymphoma do? It is as if it were erasing the bone: it very closely resembles an osteomyeloma; because the tumor has an action of direct aggression and, as usual, an overproduction of cytokines which usually move the bone resorption so that these portions of bone are reduced and only the neoplastic clone is extended and that it is a two-sided neoplastic clone. Also in this case we have a marker that is the CD20, something that certainly goes to add to what is a clinical suspicion a radiological demonstration a traditional morphological histological study to complete the diagnosis.

Surgical treatment

The surgical treatment of the column lesions must prevent (preventive osteosynthesis) or treat (osteosynthesis with nails or plaques +/- cement, tumor prostheses) pathological fractures. Mininvasive techniques such as kyphoplasty in the lesions with collapse of the vertebral bodies are indicated to restore the height of the vertebral body and avoid further collapses. If there is bone marrow involvement, laminectomy and vertebral stabilization may be indicated. Localization of myeloma in D12 with collapse of the vertebral body; kyphoplasty treatment. Myeloma in D12 with vertebral body collapse; treatment with kyphoplasty. Localization of myeloma in D12 with collapse of the vertebral body; treatment with kyphoplasty.
Radiotherapy
Radiation therapy should always be associated with surgery and is the treatment of choice of solitary lesions that are not at risk of pathological fracture. Radiotherapy is also useful because it affects pain or is able to reduce compression on vital structures such as viscera or marrow.

Chemotherapy

Systemic chemotherapy (cyclophosphamide, melphalan and cortisone) is indicated in multiple lesions with systemic involvement. High-dose treatment with bone marrow autotransplant is currently used in younger patients.
LYMPHOMA MALIGNO NOT HODGKIN
 7% of malignant bone tumors
 Slight prevalence in male sex
 Vertebral involvement with medullary compression
 Osteolysis and osteosclerosis
 Macroscopically fish-flesh
 B-cellular origin
 Diffuse pattern
 Cellular pleomorphism (immunohistochemistry)

In this way we have cleared the field from this first part of objectively convenient classification, for which we had to distance ourselves from the criterion that most interests us, which is histo-genetic, to try to put together different things among themselves tumors that have completely different histogenesis but which are represented by small cells with a homogeneous and widespread distribution.

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