Abstract
The orbital area contains a variety of anatomical structures including the eyelids, tarsal conjunctiva, caruncle, lacrimal gland, lacrimal drainage system, skin, skin adnexa, and soft tissues. It is surrounded by bone and cartilaginous structures and is highly vascularized and interspersed by the cranial nerves. This complex of neighboring, highly specialized tissues results in a large spectrum of inflammatory, benign, and malignant conditions. An extensive blood supply of the richly vascularized orbital area explains the occurrence of metastases from various organs, commonly from breast and lung neoplasms in adults and neuroblastoma in children. Fine-needle aspiration (FNA), by its simplicity and accuracy, can serve as an important diagnostic tool, solving some of the various clinical dilemmas in this complex anatomic area.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
Introduction
The orbital area contains a variety of anatomical structures including the eyelids, tarsal conjunctiva, caruncle, lacrimal gland, lacrimal drainage system, skin, skin adnexa, and soft tissues. It is surrounded by bone and cartilaginous structures and is highly vascularized and interspersed by the cranial nerves. This complex of neighboring, highly specialized tissues results in a large spectrum of inflammatory, benign, and malignant conditions. An extensive blood supply by the richly vascularized orbital area explains the occurrence of metastases from various organs, commonly from breast and lung neoplasms in adults and neuroblastoma in children. Fine-needle aspiration (FNA), by its simplicity and accuracy, can serve as an important diagnostic tool, solving some of the various clinical dilemmas in this complex anatomic area.
The role of FNA is to confirm the existence of primary, recurrent, or metastatic malignancies and to distinguish inflammatory from neoplastic lesions. FNA is particularly useful to assess nonresectable orbital lesions, such as hematolymphoid neoplasms and metastatic deposits, avoiding unnecessary surgery [1, 2]. In addition, FNA will provide crucial information in cases where surgery is being considered, e.g., before a major surgical or oncologic procedure is undertaken. Moreover, FNA may serve as the preferable technique to access and diagnose intraocular tumors and noncharacteristic clinical settings [3].
The most common malignant lesion in the orbit is orbital lymphoma. Valuable diagnostic modalities in such instances include aspiration cytology, in addition to ultrasound, computed tomography (CT) (see Fig. 18.1), and magnetic resonance imaging (MRI). Diagnosis based on routinely stained smears alone may be difficult. Combination of smears with ancillary techniques such as immunocytochemistry, flow cytometry, and molecular genetic techniques provide a reliable diagnosis and accurate typing in most cases [4,5,6].
Neoplasms of the lacrimal gland comprise a spectrum of lesions similar to primary major salivary gland neoplasms [7]. Roughly 50% of lacrimal gland tumors are of epithelial origin, 50% of epithelial tumors are benign pleomorphic adenoma, and 50% of malignant tumors are adenoid cystic carcinoma.
Primary or secondary sinonasal tract malignancies that first present as orbital lesions are rare, with a broad range of cytological findings in FNA smears. Specific features most often allow an accurate diagnosis in tumors such as in carcinoma similar to transitional and squamous cell carcinoma, carcinoma with specific differentiation, sarcoma, or melanoma [8].
There are a few case reports and review series [9,10,11] of orbital metastasis. The most frequently reported primaries are breast, lung, melanoma, and prostate cancer, but even metastasis from the liver, ovary, sacrococcygeal chordoma, thymic carcinoma, and skin has been reported. As indicated in a review of 80 patients with a mean age of 60 years [11], orbital metastases occurred usually in the late stages of a known malignancy. However, in some cases orbital metastasis may be the initial presentation of malignant disease. Char et al. [9] reported that metastasis was the first presentation of an unknown malignancy in 35% of the cases, whereas Valenzuela et al. [11] found that 15% of orbital metastasis had no known primary tumor.
Sampling Technique
Orbital and intraocular FNA was initially accepted with enthusiasm [12], but some authors later underlined the possibility of complications and argued against this technique [13]. Significant series of orbital and periorbital lesions with cytological evaluation began to appear about 60 years ago [14,15,16,17,18,19,20]. In the Institut Curie in Paris, FNA examination of orbital tumors was introduced in 1970 [21].
The technique of cytological sampling is not more complicated than in other settings, but an experienced operator improves the results of the procedure. Palpable tumors in the orbit and palpebra may be assessed by palpation-guided FNA with 23–27-gauge needles (see Fig. 18.2). Gentle aspiration should be applied to obtain a representative material, but in many cases more vigorous aspiration is not recommended to avoid hemorrhagic smears. Many patients describe the procedure as “unpleasant,” but they do not complain of pain, and anesthesia is not necessary in the case of most aspirations. In addition, injection of local anesthetic is not advocated because it usually leads to distortion of orbital and tumoral tissues. After the sampling is finished, a moderately forceful pressure with bandages is recommended to avoid hematoma. The rich vasculature of the orbit and the rigid bone structures around it tend to lead to hematomas.
FNA of nonpalpable tumors is performed under ultrasound guidance. In children and uncooperative patients, or in cases of intraocular tumor, general anesthesia is necessary. A 27-gauge butterfly needle is used and suction is applied (see Fig. 18.2). One drop of sample is smeared, and the remaining material is collected in ethylenediaminetetraacetic acid (EDTA) for molecular purposes. Cytological sampling of orbital lesions should be performed by either a cytopathologist or an ophthalmologist, occasionally by a radiologist, but the cooperation of both during the sampling procedure is preferred to secure representative samples. As in many other settings, on-site evaluation of aspirated material prevents a high percentage of nondiagnostic smears.
Diagnostic Accuracy and Complications
In a series of 286 aspirates of palpable orbital and eyelid tumors reported from the Curie Institute, FNA was a highly accurate diagnostic procedure with a concordant diagnosis of malignancy and tumor type achieved in 87% of cases. False-positive diagnoses were made in 1.6% and false-negative diagnoses in 1.8% cases [20]. Sensitivity of orbital FNA ranging from 75% to 99% in other larger series has been reported [14, 17, 22,23,24].
Complications of FNA of intraorbital lesions are minor and usually consist of hematoma in surrounding tissues. More severe potential complications may be puncture of the eyeball, vitreous or subretinal hemorrhage, and retinal detachment, but such complications have never occurred in this author’s institution where more than 40 years of experience with FNA of orbital, paraorbital, and viral lesions has been accumulated. To minimize this hazard, Liu [25] recommended that the needle should be inserted in the quadrants of the orbit only and not directly above or below the globe. Other reported complications constitute vitreous hemorrhage, transient visual loss, and ocular motility disturbance.
Tumor Classification
A classification according to the anatomical structures of the orbital region may be useful from a practical point of view. We systematize the tumors as palpebral, intraorbital, or intraocular.
Palpebral Tumors
Palpebral tumors correspond to skin tumors described in Chap. 14. The most common malignant tumor of the eyelid is basal cell carcinoma, and it is a relatively frequent target for FNA [26, 27]. The diagnosis is obvious if smears from a superficial eyelid tumor display cytological features such as well-formed and often cohesive sheets and nests of relatively uniform basaloid cells in palisades (see Fig. 18.3). Larger, dyscohesive cells, differentiation toward squamous epithelia, and keratinization favor primary squamous cell carcinoma, the second most common malignancy of the eyelid (see Fig. 18.4). Palpebral eccrine spiradenoma (see Fig. 18.5), pilomatrixoma (see Fig. 18.6), and other skin appendix tumors comprise important differentials to basal cell carcinoma and squamous cell carcinoma. Classical and diagnostic features of pilomatrixoma are its three components: basaloid cells, ghost cells with an admixture of amorphous keratin deposits, and multinucleated giant cells. Sebaceous carcinoma is the third most common eyelid malignancy and most commonly arises from the Meibomian glands.
Orbital Tumors
Reactive and Inflammatory Conditions
Granulomatous lesions, including Wegener’s granulomatosis, sarcoidosis, chalazion, xanthogranuloma, and aspergillosis [28], may be encountered in the orbit and the orbital adnexa. Wegener’s granulomatosis may be identified as a necrotizing granulomatous inflammation, whereas sarcoidosis and chalazions are identified as non-necrotizing granulomatous inflammations. Other inflammatory lesions include pseudotumors [29], histiocytosis X (see Fig. 18.7), and rare in this location Rosai-Dorfman disease [30, 31]. Benign cystic lesions in the orbit mainly include epidermal inclusion cysts, mucoceles, and dermoid cysts. Anucleate and occasional nucleate squames represent microscopic findings in smears from epidermal inclusion cysts and admixture of debris in dermoid cysts.
Benign Neoplasm
Meningioma
Meningothelial neoplasms in smears can be readily identified due to the presence of cohesive clusters with a whorling pattern of relatively uniform cells with bland, ovoid nuclei and moderate to abundant cytoplasm. Intranuclear pseudoinclusions and psammoma bodies are often visible in smears (see Fig. 18.8) [32,33,34].
Pleomorphic Adenoma
The most common tumor of the lacrimal gland is pleomorphic adenoma [35]. These adenomas are generally well circumscribed on imaging studies. They may indent the sclera or cause bony remodeling but are not invasive in bone. These lesions should be diagnosed by FNA, as more invasive incisions may violate the pseudocapsule and lead to contamination and implantation of tumor cells in adjacent tissues. Pleomorphic adenoma typically harbor both epithelial and mesenchymal components in smears. The epithelial cells may be arranged individually, in sheets, or in clusters. The mesenchymal component consists of a chondromyxoid matrix and associated spindled (myoepithelial) cells [36] (see Fig. 18.9).
Hemangioma and Other Benign Mesenchymal Neoplasms
Hemangioma is more of a clinical and radiological rather than a cytological diagnosis. Mesenchymal neoplasm (e.g., schwannoma, lipoma, pleomorphic lipoma) may also involve the orbit as the primary setting [37]. Cytomorphology is similar to those described at other anatomical locations.
Malignant Tumors of Lacrimal Structures
Patients with lacrimal gland malignancy frequently present with swelling of the eyelid, diplopia, and pain. CT shows a soft tissue lesion centered on the lateral orbital margin. Morphologically, malignant tumors arising in the lacrimal gland are similar to those of their salivary gland counterparts. The most common malignancies are adenoid cystic carcinoma, carcinoma ex pleomorphic adenoma, and salivary duct carcinoma.
Adenoid Cystic Carcinoma
FNA smears show numerous basaloid cells with sparse cytoplasm. The cells usually form characteristic “rosettes” by growing around extracellular globules of homogenous basement membrane material (see Fig. 18.10). The stroma is characteristic and shows fingerlike and tubular structures, which are pathognomonic [38].
Other Salivary-Type Carcinomas
Carcinoma ex pleomorphic adenoma, salivary duct carcinoma, and adenocarcinoma not otherwise specified (NOS) may arise in the lacrimal glands [39]. Carcinoma ex pleomorphic adenoma (salivary duct type, mucoepidermoid carcinoma) and primary salivary duct carcinoma show cytological characteristics previously reported (see Fig. 18.11) [40]. Carcinoma NOS may be morphologically nonspecific. Primary mucinous adenocarcinoma may also arise in the lacrimal gland (see Fig. 18.12).
Primary Malignant Neoplasms of the Lacrimal Sac
Primary lacrimal sac tumors are uncommon, among them squamous cell carcinoma is the most common. FNA presents findings similar to those of smears from squamous cell carcinoma in other locations. Smears most often contain cohesive groups and clusters or dispersed moderately pleomorphic tumor cells with irregular nuclei. Necrotic cell fragments, cell debris, and keratin masses may be identified in the background.
Orbital Malignant Tumors Outside Lacrimal Structures
A large spectrum of tumors including olfactory neuroblastoma (see Fig. 18.13), different types of sarcomas, and metastases occur in this location [2, 41]. FNA of many of them yields diagnostic material and in some entities, such as rhabdomyosarcoma (see Fig. 18.14) and other small cell malignancies, makes cellular material accessible for immunocytochemistry and molecular diagnostics. Sinonasal tract malignancies may occasionally present as orbital tumors (see Fig. 18.15).
Orbital metastases usually reflect advanced malignant disease (see Figs. 18.15, 18.16, and 18.17) [42,43,44,45]. Breast, lung, and prostatic adenocarcinomas are the most common primary sites.
Hematolymphoid Lesions
Non-Hodgkin Lymphoma
These may occur in the orbit and can also be related to the lacrimal gland. Lymphomas are primary or metastatic [46,47,48]. FNA has proven to be a very efficient modality to provide diagnostic yield (see Fig. 18.18) and, in the majority of cases in combination with other diagnostic modalities, lead to a diagnosis reliable enough to allow initiation of treatment without further invasive diagnostic procedures [48, 49].
Myeloma
Orbital myeloma is composed of numerous dissociated tumor cells with abundant basophilic cytoplasm, eccentrically placed round nuclei with a prominent wheel-spoke-shaped chromatin pattern and a small nucleolus.
Intraocular Tumors
Transocular FNA is a safe and reliable diagnostic method for suspected intraocular tumors and inflammatory conditions in which noninvasive diagnostic modalities have failed to establish the diagnosis and in which cytological verification of the diagnosis is necessary to institute appropriate treatment [50].
Malignant Melanoma
Transscleral FNA is justified in adult patients when tumor presentation is not characteristic (differential diagnosis between primary and metastatic tumors) or in cases when prognosis is examined [50,51,52]. Similar to other locations, melanomas may show melanin or not (see Fig. 18.19). Cells are spindled, roundish, or epithelioid. Binucleation is common.
Retinoblastoma
Unilateral or bilateral retinoblastomas are intraocular tumors in children. The diagnosis is clinical in combination with a typical ultrasound appearance. Intraocular FNA should be avoided. Usually FNA is used in metastases or orbital recurrences [53,54,55]. Cells are roundish or poorly differentiated with or without rosette formation. Mitotic figures are numerous (see Fig. 18.20). Focal background necrosis is common.
References
Rastogi A, Jain S. Fine needle aspiration biopsy in orbital lesions. Orbit. 2001;20:11–23.
Agrawal P, Dey P, Lal A. Fine-needle aspiration cytology of orbital and eyelid lesions. Diagn Cytopathol. 2013;41:1000. (Epub ahead of print).
Koss GL, Woyke S, Olszewski W. Cytologic interpretation and histological bases. In: Aspiration biopsy. New York: Igaku-Shoin; 1992. p. 659–77.
Krzystolik Z, Roslawska A, Bedner E. The cytological, immunocytochemical and molecular genetic analysis in diagnosis of the neoplasms of the eye, eye adnexa and orbit. Doc Ophthalmol. 1994;88:155–63.
Nassar DL, Raab SS, Silverman JF, Kennerdell JS, Sturgis CD. Fine-needle aspiration for the diagnosis of orbital hematolymphoid lesions. Diagn Cytopathol. 2000;23:314–7.
Tani E, Seregard S, Rupp G, Söderlund V, Skoog L. Fine-needle aspiration cytology and immunocytochemistry of orbital masses. Diagn Cytopathol. 2006;34:1–5.
Klijanienko J, El-Naggar AK, Servois V, Rodriguez J, Desjardins L, Schlienger P, et al. Histologically similar, synchronous or metachronous, lacrimal salivary-type and parotid gland tumors: a series of 11 cases. Head Neck. 1999;21:512–6.
Helsel JC, Bardales RH, Mukunyadzi P. Fine-needle aspiration biopsy cytology of malignant neoplasms of the sinonasal tract. Cancer. 2003;99:105–12.
Char DH, Miller T, Kroll S. Orbital metastases: diagnosis and course. Br J Ophthalmol. 1997;81:386–90.
Goldberg RA, Rootman J, Cline RA. Tumors metastatic to the orbit: a changing picture. Surv Ophthalmol. 1990;35:1–24.
Valenzuela AA, Archibald CW, Fleming B, Ong L, O’Donnell B, Crompton JJ, et al. Orbital metastasis: clinical features, management and outcome. Orbit. 2009;28:153–9.
Kennerdell JS, Slamovits TL, Dekker A, Johnson BL. Orbital fine-needle aspiration biopsy. Am J Ophthalmol. 1985;99:547–51.
Henderson JW, Farrow GM, Garrity JA. Orbital tumors. New York: Raven; 1994.
Cangiarella JF, et al. Fine needle aspiration cytology of orbital masses. Acta Cytol. 1996;40:1205–11.
Westman-Naeser S, Naeser P. Tumours of the orbit diagnosed by fine needle biopsy. Acta Ophthalmol. 1978;56:969–76.
Bessiere E. Aspiration biopsy and tumors of the orbit. Bull Soc Ophtalmol Fr. 1959;4:343–7. [In French]
Zeppa P, Tranfa F, Errico ME, Troncone G, Fulciniti F, Vetrani A, et al. Fine needle aspiration (FNA) biopsy of orbital masses: a critical review of 51 cases. Cytopathology. 1997;8:366–72.
O’Hara BJ, Ehya H, Shields JA, Augsburger JJ, Shields CL, Eagle RC Jr. Fine needle aspiration biopsy in pediatric ophthalmic tumors and pseudotumors. Acta Cytol. 1993;37:125–30.
Solo S, Siddaraju N, Srinivasan R. Use of fine needle cytology in the diagnosis of orbital and eyelid mass lesions. Acta Cytol. 2009;53:41–52.
Calle R, Zajdela A, Haye C, Schlienger P. Primary malignant lymphoid tumors of the orbit, eye and adnexa oculi. Treatment and prognosis based on the site of the tumor and its histological type [article in French]. Bull Cancer. 1971;58:329–49.
Zajdela A, Vielh P, Schlienger P, Haye C. Fine-needle cytology of 292 palpable orbital and eyelid tumors. Am J Clin Pathol. 1990;93:100–4.
Wiktorin ACH, Dafgård Kopp EME, Tani E, Söderén B, Allen RC. Fine-needle aspiration biopsy in orbital lesions: a retrospective study of 225 cases. Am J Ophthalmol. 2016;166:37–42.
Glasgow BJ, Layfield LJ. Fine-needle aspiration biopsy of orbital and periorbital masses. Diagn Cytopathol. 1991;7:132–41.
Das DK, Das J, Bhatt NC, Chachra KL, Natarajan R. Orbital lesions. Diagnosis by fine needle aspiration cytology. Acta Cytol. 1994;38:158–64.
Liu D. Complications of fine needle aspiration biopsy of the orbit. Ophthalmology. 1985;92:1768–71.
Sturgis CD, Silverman JF, Kennerdell JS, Raab SS. Fine-needle aspiration for the diagnosis of primary epithelial tumors of the lacrimal gland and ocular adnexa. Diagn Cytopathol. 2001;24:86–9.
Dhaliwal U, Arora VK, Singh N, Bhatia A. Clinical and cytopathologic correlation in chronic inflammations of the orbit and ocular adnexa: a review of 55 cases. Orbit. 2004;23:219–25.
Kuruba SL, Prabhakaran VC, Nagarajappa AH, Biligi DS. Orbital aspergillus infection diagnosed by FNAC. Diagn Cytopathol. 2011;39:523–6.
Char DH, Miller T. Orbital pseudotumor. Fine-needle aspiration biopsy and response to therapy. Ophthalmology. 1993;100:1702–10.
Majumdar K, Tyagi I, Saran RK, Kumar S, Gondal R. Multicentric extranodal Rosai Dorfman disease—a cytological diagnosis, with histological corroboration. Acta Cytol. 2012;56:214–8.
Kamal S, Kumar S, Goel R, Bodh SA, Kumar R, Bansal S, et al. Rosai-dorfman with bilateral involvement of lacrimal sac as extranodal disease. Orbit. 2012;31:132–3.
Islam MN, Amin MS, Dipi RM, Khan NA. Comparison of computed tomographic and cytopathological findings in the evaluation of adult orbital mass. Mymensingh Med J. 2013;22:75–9.
Gupta N, Kaur J, Rajwanshi A, Nijhawan R, Srinivasan R, Dey P, et al. Spectrum of orbital and ocular adnexal lesions: an analysis of 389 cases diagnosed by fine needle aspiration cytology. Diagn Cytopathol. 2012;40:582–5.
Mehrotra R, Kumar S, Singh K, Tandon MP, Singh M. Fine-needle aspiration biopsy of orbital meningioma. Diagn Cytopathol. 1999;21:402–4.
Lakhey M, Thakur SK, Mishra A, Rani S. Pleomorphic adenoma of lacrimal gland: diagnosis based on fine needle aspiration cytology. Indian J Pathol Microbiol. 2001;44:333–5.
Kopp ED, Sahlin S, Tani E, Skoog L, Seregard S. Fine-needle aspiration biopsy in lacrimal gland pleomorphic adenoma. Eye. 2010;24:386.
Dulani S, Diagavane S, Lele S, Gaurkhede H. A bilobed schwannoma in roof of orbit: a rare case report. Case Rep Ophthalmol Med. 2012;2012:139241.
Malberger E, Gdal-On M. Adenoid cystic carcinoma of the orbit diagnosed by means of aspirative cytology. Ophthalmologica. 1985;190:125–7.
Lelli GJ Jr, Yang GC. Large cell carcinoma of the lacrimal gland diagnosed by fine needle aspiration biopsy. Orbit. 2011;30:291–2.
Klijanienko J, Vielh P, Batsakis JD, et al. Salivary gland tumours, monographs in clinical cytology, vol. 15. Basel: Karger; 2000.
Das DK, Das J, Kumar D, Bhatt NC, Banot K, Natarajan R. Leiomyosarcoma of the orbit: diagnosis of its recurrence by fine-needle aspiration cytology. Diagn Cytopathol. 1992;8:609–13.
Pitts J, Chang CH, Mavrikakis I, Shaikh A, Rootman J. Hepatocellular carcinoma presenting as orbital bone metastasis. Ophthal Plast Reconstr Surg. 2008;24:477–9.
Heerema A, Sudilovsky D. Mucinous adenocarcinoma of the ovary metastatic to the eye: report of a case with diagnosis by fine needle aspiration biopsy. Acta Cytol. 2001;45:789–93.
Kopelman JE, Shorr N. A case of prostatic carcinoma metastatic to the orbit diagnosed by fine needle aspiration and immunoperoxidase staining for prostatic specific antigen. Ophthalmic Surg. 1987;18:599–603.
Khurana AK, Ahluwalia BK, Gupta S, Rajan C, Arora BB. Bilateral proptosis due to metastatic Ewing’s sarcoma of the orbit: fine needle aspiration cytology (FNAC) and histopathology of a case. Indian J Ophthalmol. 1992;40:15–7.
Bernardini F, Bazzan M. Lymphoproliferative disease of the orbit. Curr Opin Opthalmol. 2007;18:398–401.
Subramanian R, Solo S, Mishra MM, Murugan P, Siddaraju N, Basu D, et al. Fine needle aspiration cytology of primary lymphoid lesions of the orbit: report of four cases. Acta Cytol. 2007;51:417–20.
Wolska-Szmidt E, Jakubowska A, Krzystolik K, Chosia M. Fine needle aspiration biopsy and molecular analysis in differential diagnosis of lymphoproliferative diseases of the orbit and eye adnexa. Pol J Pathol. 2004;55:51–7.
Chosia M, Wolska-Szmidt E. Is it possible to diagnose lymphoproliferative lesions by fine needle aspiration biopsy? [Article in Polish]. Klin Ocz. 2005;107:555–9.
Shields JA, Shields CL, Ehya H, Eagle RC Jr, De Potter P. Fine-needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick lecture. Ophthalmology. 1993;100:1677–84.
Bagchi K, Giri A, Sarkar R, Das S, Nag S. Fine needle aspiration biopsy in the diagnosis of intraocular and extra-ocular mass lesions. J Indian Med Assoc. 2010;108:457–9.
Eide N, Walaas L. Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review. Acta Ophthalmol. 2009;87:588–601.
Longmuir SQ, Syed NA, Boldt HC. Diffuse anterior retinoblastoma without retinal involvement. Ophthalmology. 2010;117:2034–8.
Das DK, Das J, Chachra KL, Natarajan R. Diagnosis of retinoblastoma by fine-needle aspiration and aqueous cytology. Diagn Cytopathol. 1989;5:203–6.
Gündüz K, Müftüoglu O, Günalp I, Unal E, Taçyildiz N. Metastatic retinoblastoma clinical features, treatment, and prognosis. Ophthalmology. 2006;113:1558–66.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Klijanienko, J., Bartuma, K., Domanski, H.A. (2019). Orbit and Ocular Adnexa. In: Domanski, H. (eds) Atlas of Fine Needle Aspiration Cytology. Springer, Cham. https://doi.org/10.1007/978-3-319-76980-6_18
Download citation
DOI: https://doi.org/10.1007/978-3-319-76980-6_18
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-76979-0
Online ISBN: 978-3-319-76980-6
eBook Packages: MedicineMedicine (R0)