The Pathology of Systemic Fibroinflammatory Disorders



Fig. 3.1
Sclerosing mesenteritis. (a) On low-power view, sclerosing mesenteritis consists of a diffuse replacement of the resident mesenteric soft tissues (mostly adipose tissue) by a dense fibrous tissue (arrow) and several foci of chronic inflammatory infiltrate (arrowheads). (b) This inflammatory infiltrate is mainly made of lymphocytes (arrow) and plasma cells (arrowhead). (c) Large bands of collagen (arrow) replace the normal mesenteric soft tissues. (d) Often, the lymphocytes are organized into follicles with a germinal center (arrow) (Courtesy of Dr. Andrew L. Folpe, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN)



The pathologic differential diagnosis includes lymphoma, well-differentiated liposarcoma (where, in addition to basic histopathology, immunohistochemistry for MDM2 and CDK4 or FISH for MDM2 may be helpful in diagnosing this mesenchymal neoplastic proliferation) [2], inflammatory myofibroblastic tumor, and a reactive process secondary to either carcinoma, foreign material or bowel perforation, fibromatosis, idiopathic retroperitoneal fibrosis and, sometimes, Whipple disease [1].



3.3 Nephrogenic Systemic Fibrosis


NSF – also known as “gadolinium-induced fibrosis” (GIF) – is an iatrogenic fibrosing disease primarily affecting patients with chronic kidney disease following exposure to gadolinium-based contrast agents in case of imaging procedures. GIF is characterized by skin thickening, tethering, and hyperpigmentation especially affecting the extremities; flexion contractures of joints; and extracutaneous fibrosis [3].

A skin biopsy is mandatory in order to confirm the clinical suspicion of GIF, and clinical data must be the guide for a correct histopathological interpretation of otherwise non-fully specific microscopic findings. The histopathologic picture largely depends on the timing in the disease course, with the general morphologic change of a fully developed lesion being a cell-rich dermal fibrosis that can sometimes extend to the underlying hypodermis. In the dermis there are thick and thin collagen bundles, which are often surrounded by clefts of CD34+, CD45RO+, and/or type I procollagen+ spindle cells, these findings suggesting their origin from circulating fibrocytes. In addition, factor XIIIa+ cells and CD68-KP1+ multinucleated histiocytes can be observed. Prominent elastic fibers interweave among the above-mentioned dermal collagen bundles and mucin deposits. Additional less common histological features include bone metaplasia, calcification, and a mild chronic inflammatory infiltrate [3].

The skeletal muscle is often modified in the areas just below the affected skin segments, thereby suggesting that muscle participation in GIF is closely related to superficial involvement. In a series of five NSF cases, Levine et al. [4] found by computerized tomography scan fibrosis of the fascia and muscles in the most severely affected patients, and by electromyography mild-to-severe myopathic changes. Histopathologically (Fig. 3.2), a spectrum of mild-to-severe fibrosis, degenerating fibers, nonspecific changes, and/or chronic inflammatory cells can be detected. However, it cannot be ruled out that secondary signs of uremic nephropathy may be superimposed on the above skeletal muscle myopathic changes [5].

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Fig. 3.2
Nephrogenic systemic sclerosis (skeletal muscle biopsy). (a) Medium-power view of a skeletal muscle in a patient with nephrogenic systemic sclerosis showing scattered atrophic fibers (black arrow), and occasional necrotic (black arrowhead) and regenerative fibers (white arrow). The small arteries (white arrowhead) and some capillaries have slightly thickened walls. (b) Immunohistochemical analysis showing HLA Class I overexpression in muscle fibers (Courtesy of Dr. Istvan Bodi, King’s College Hospital, London, UK)

Interestingly, gadolinium has been detected by electron microscopy in the affected skin as well as in skeletal muscle, lymph node, heart, lung, liver, adrenal gland, kidney, ileal wall, thyroid, eye, dura mater, and cerebellum of patients with GIF [3].

Using data from the Yale International NSF Registry, Girardi et al. [6] have compiled diagnostic criteria and a compendium of images to assist the clinician in making this diagnosis. With regard to the histopathologic interpretation, they proposed a 0–4 score (as “inconsistent with NSF,” “suggestive of NSF,” “consistent with NSF,” “highly consistent with NSF,” or “NSF excluded,” respectively) whose total is the sum of different histopathologic findings in a kind of weighted score: the presence of: (i) increased dermal cellularity, (ii) thick and thin collagen fibers, (iii) septal involvement, and (iv) CD34+ cells, each correspond to +1; the presence of osseous metaplasia corresponds to +3; the absence (or reduction) of elastic fibers corresponds to −1.

Given the relatively nonspecific histopathologic changes, pathologic differential diagnosis is obviously wide and includes scleromyxedema, morphea/scleroderma, eosinophilic fasciitis (Shulman syndrome), eosinophilia-myalgia syndrome, lipodermatosclerosis, dermatofibrosarcoma protuberans, stiff skin syndrome/congenital fascial dystrophy, septal panniculitis, pseudoxanthoma elasticum, and calciphylaxis [6].


3.4 IgG4-Related Disease


IgG4-RD is an immune-mediated fibroinflammatory disorder characterized by the development of sclerotic masses reportedly rich in lymphocytes and IgG4+ plasma cells. These masses may affect synchronously or metachronously the soft tissues and/or different organs such as pancreas, lacrimal glands, salivary glands, gallbladder, and many other target locations including the cardiovascular system [7].

Very recently, a panel of experts has issued current strategies for managing and treating patients suffering from IgG4-RD. According to these recommendations, careful clinical assessment, laboratory tests, and imaging studies are initially imperative but often unsatisfactory in differentiating IgG4-RD from tumors or other tumefactive nonneoplastic lesions. In view of this, adequate biopsy material is fundamental to make a diagnosis of this fibroinflammatory disorder [8].

According to current guidelines on morphological interpretation of IgG4-RD tissue samples [9], key histopathological findings (Fig. 3.3) that are relevant to the diagnosis of IgG4-RD are: dense lymphoplasmocytic infiltrate, storiform-type fibrosis, and obliterative phlebitis. It should be noted that there are some exceptions to these general microscopic findings, in particular anatomical locations such as the lymph node, lung, salivary glands, and lacrimal glands where storiform fibrosis or obliterative phlebitis may be modest or even absent, and the inflammatory infiltrate may be qualitatively different. In lungs, obliterative arteritis signs are often seen. Moreover, in lymph nodes five histological patterns (always in the presence of other IgG4-RD lesions) have been reported: (a) multicentric Castleman’s disease-like, (b) follicular hyperplasia, (c) interfollicular expansion, (d) progressive transformation of germinal center, and (f) nodal inflammatory pseudotumor-like [9].

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Fig. 3.3
IgG4-related disease. (a) Low-power view of a chronic periaortitis consisting of marked sclerotic replacement and expansion of the adventitial spaces (arrow), as well as foci of inflammation (arrowhead). (b) This inflammatory infiltrate (arrows) is mainly composed of lymphocytes and plasma cells. (c) Immunohistochemical analysis with an anti-CD138 antibody decorating the plasma cells. (d) Immunohistochemical analysis displaying the IgG4-positive plasma cells (overall, >50 % of the total plasma cells)

In addition to these qualitative characteristics, quantification of IgG4+ plasma cells by immunohistochemistry is crucial to make a diagnosis of IgG4-RD. IgG4 quantification should be performed in three histological fields – using a × 40 magnification objective lens – with the highest number of IgG4+ plasma cells by: (a) counting the absolute number of IgG4+ plasma cells (cut-off ranging from 10/hpf to 200/hpf, depending on the organ involved), or (b) calculating the IgG4+ plasma cell-to-IgG+ plasma cell ratio (with cut-off of 40 %). The above-mentioned board also proposed a terminology scheme – as “highly suggestive,” “probable,” or “insufficient” categories – for diagnosis of IgG4-RD, which is primarily based on the histopathological picture of the various biopsies [9]. In aortic biopsies, since some cases of atherosclerosis and giant-cell or infectious aortitis can sometimes display IgG4/IgG ratios close to 40 %, a cell ratio of >50 % should be considered as a threshold criterion for diagnosis of IgG4-RD [9, 10].

Overall, however, a number of vital points regarding IgG4-RD histopathological diagnosis are still pending. With regard to the general histopathological features in IgG4-RD, both storiform fibrosis and obliterative phlebitis cannot always be detected in the relevant biopsy material, even outside the above-mentioned organs that constitute an exception to the general rules. In fact the growth pattern of fibrosis may be different from one site to another and even from case to case, and the storiform pattern may merely be one of the possible morphologic manifestations of the newly formed fibrotic tissue. Furthermore, according to current understanding of IgG4-RD pathogenesis, IgG4 seems not to play a pathogenic role in the development of this disorder. In view of this, diagnostic criteria based on a pure dichotomic subdivision between IgG4-to-IgG plasma cell ratio of <40 % and >40 % would very likely miss a significant fraction of patients affected by this disease. Moreover, a distinction between organs in terms of different IgG4 cut-offs often seems somewhat arbitrary [11].


3.5 Idiopathic Retroperitoneal Fibrosis


IRF is a fibroinflammatory disorder included in the spectrum of “chronic periaortitis.” In the great majority of cases, it develops around the infrarenal tract of a nondilated aorta and the iliac arteries. IRF grows centrifugally and, in doing this, frequently entraps adjacent retroperitoneal structures such as the ureters and the inferior vena cava with obvious and severe sequelae [12, 13].

Grossly, IRF is a firm grayish noncapsulated mass, which stems from the adventitia of the aorta (or other arteries) and extends eccentrically towards the retroperitoneal soft tissues. Due to the infiltration of the resident adipose tissue, the peripheral areas of this mass often display a combination of grayish and yellow zones [12].

The histopathology of IRF is quite nonspecific (Fig. 3.4), especially if the various components are examined singularly. On the contrary, its microscopic picture as a whole bears morphologic characteristics which, when guided by informative clinicoradiologic information, very often allow the pathologist to make a correct diagnosis. Of course, the more adequate the biopsy (in terms of size and sampling site) the more accurate the diagnosis.

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Fig. 3.4
Idiopathic retroperitoneal fibrosis. (a) Low-power view of an idiopathic retroperitoneal fibrosis constituted of a fibrous tissue (arrow) which replaces the resident soft tissues and an inflammatory component (arrowhead). (b) The fibrous component consists of thick keloid-like and haphazardly distributed collagen bands (arrow) with a peculiar onionskin distribution around the blood vessels (arrowhead). The inflammatory infiltrate is composed of lymphocytes, plasma cells, macrophages, and scattered eosinophils. (c, d). The fibroinflammatory proliferation may infiltrate and entrap large nerve trunks (c, arrow) as well as small peripheral nerves (d, arrow). (e) The perivascular pattern of the inflammatory infiltrate is characterized by a nodular aggregation of lymphocytes and plasma cells around the adventitia of small blood vessels (arrow). Sometimes, this component shows a germinal center (arrowhead). (f) The diffuse inflammatory pattern (arrow) consists of dispersed aggregates of the above-mentioned inflammatory cells

In broad terms, IRF consists of fibrous tissue and inflammatory infiltrate in various proportions from case to case and even within the same lesion. The fibrous component is characterized by thick keloid-like and irregularly distributed collagen bands (both immunohistochemically and ultrastructurally consistent with type I collagen) with quite a peculiar organization around the adventitia of small-sized blood vessels with an onionskin appearance. In addition, some nerves entrapped in the fibrous proliferation may be found. Closely associated to these collagen bands, there is a mild (sometimes moderate) proliferation of medium-sized fibroblasts/myofibroblasts with elongated and normochromatic nuclei. These spindle-shaped cells are immunohistochemically positive for vimentin and often smooth muscle actin (with a mild-to-moderate staining intensity suggesting a myofibroblastic phenotype), but do not express citokeratins, caldesmon, S100, CD34, ALK-1, beta-catenin, desmin, myogenin, or myoglobin. In addition, the MIB1 proliferation index in these cells is always negligible. Mitoses are absent or exceedingly rare and there are no signs of necrosis. Typically, the interface between IRF and the preexisting adipose tissue is poorly demarcated and displays a combination of IRF findings and resident soft tissues; in addition, the collagen fibers are often thinner than the above-mentioned ones, this fact suggesting that these areas represent the more recent ones within the fibroinflammatory proliferation. Congo red staining does not reveal any amyloid material deposition [12].

The fibrous background shows varying degrees of inflammatory infiltrate consisting of small lymphocytes, plasma cells, macrophages, and rare eosinophils; this inflammatory component is characterized by two main patterns: perivascular and diffuse. The inflammatory perivascular pattern consists of lymphocytes tightly packed within and around the adventitia of the small blood vessels; in a significant proportion of IRF cases, it is possible to identify a vasculitic process consisting of inflammatory cells infiltrating the wall of the above-mentioned blood vessels. On immunohistochemistry, the perivascular inflammatory infiltrates consist of similar proportions of CD3+ and CD20+ lymphocytes, with a CD4+/CD8+ cell ratio of about 3:1. Most of the perivascular inflammatory infiltrates have a peculiar target-like appearance (or even a germinal center), with the central portion occupied by CD20+ lymphocytes, and the periphery mainly consisting of CD4+ and CD8+ lymphocytes. The diffuse pattern is characterized by dispersed aggregates of lymphocytes, macrophages, and rare eosinophils infiltrating the narrow spaces between the collagen bands. Immunohistochemically, in the inflammatory areas with a diffuse pattern, there are more CD3+ than CD20+ lymphocytes, and the CD4+ and CD8+ cell percentages are quantitatively superimposable [12].

The above-described morphologic picture is also observed in the other forms of chronic periaortitis (i.e., perianeurysmal retroperitoneal fibrosis and inflammatory abdominal aortic aneurysms) as well as in thoracic periaortitis and in most of the secondary forms of retroperitoneal fibrosis.


3.6 Sclerosing Forms of Autoimmune Thyroiditis


The sclerosing forms of autoimmune thyroiditis are chronic disorders characterized by varying degrees of fibroinflammatory replacement of the thyroid gland parenchyma. They mainly encompass Riedel’s thyroiditis, Hashimoto’s thyroiditis, and the IgG4-related disease. Owing to the common inflammatory nature of these disorders and the relative nonspecificity of the different histopathologic findings, especially if considered singularly, a specific diagnosis may be challenging. This is why clinicopathologic correlation is vital to achieve a correct identification of the disease.


3.6.1 Riedel’s Thyroiditis


Dr. Bernhard Riedel first described in 1896 this rare and – in some respects – still obscure thyroiditis [14]. Riedel’s thyroiditis (RT) presents as a painless enlargement of thyroid gland with signs and symptoms secondary to frequent tracheal and esophageal fibrotic involvement. Like in HT, hypothyroidism and hyperthyroidism may manifest as a result of progressive replacement of the thyroid parenchyma by the newly formed fibrosclerotic tissue.

Grossly, the thyroid gland is grayish, nonlobulated, woody, and hard; in addition, it is typically fixed to the surrounding anatomic structures without any detectable cleavage plane.

Histopathologically (Fig. 3.5a, b), there is total loss of thyroid parenchyma, which is replaced by thick bands of hyalinized collagen. Interestingly, various degrees of phlebitis with consequent luminal obliteration of the small and large thyroid and extrathyroid veins may also be found.

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Fig. 3.5
Sclerosing forms of autoimmune thyroiditis. (a) Low-power view of Riedel’s thyroiditis showing a significant and progressive replacement of the organ parenchyma by collagen fibers (arrow). Typically, this sclerotic tissue extends beyond the thyroid capsule (arrowhead) and is usually fixed to the surrounding structures. With time, the thyroid parenchyma is progressively replaced by the sclerotic tissue (b, arrow). (c) Hashimoto’s thyroiditis consists of a mainly lymphocytic inflammation (arrow) of the thyroid gland with some degree of sclerosis (arrowhead). The involved thyroid follicles (d) are atrophic (arrow) and may show some oncocytic metaplasia (arrowheads). (e) The “fibrous variant” of Hashimoto’s thyroiditis is characterized by marked sclerosis (usually, more than one third of the organ) which typically – unlike Riedel’s thyroiditis – is confined within the thyroid capsule. The collagen bands (f, arrow) are thicker than those of Riedel’s thyroiditis

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Sep 2, 2017 | Posted by in NEPHROLOGY | Comments Off on The Pathology of Systemic Fibroinflammatory Disorders

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