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Case report: A giant calcified uterus, likely due to benign leiomyoma
International Journal of Paleopathology 10 (2015) 51–57
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International Journal of Paleopathology journal homepage: www.elsevier.com/locate/ijpp
Case report: A giant calcified uterus, likely due to benign leiomyoma Garrard Cole a , Carolyn Rando a,∗ , Lucy Sibun b , Tony Waldron a a b
UCL Institute of Archaeology, London, UK Archaeology South–East, UCL Institute of Archaeology, London, UK
a r t i c l e
i n f o
Article history: Received 24 February 2015 Received in revised form 12 May 2015 Accepted 25 May 2015 Keywords: Leiomyoma Differential diagnosis Enlarged uterus Post-medieval england Neoplasm Calcification
a b s t r a c t During the 2011 excavation of the site of St. Michael’s Litten, in Chichester, England, a female skeleton, dating to the post-Medieval period (1550–1850), with a large, unidentified pelvic mass was uncovered. The mass measured 16.4 H × 19.0 W × 24.3 L and was 66 cm in its greatest circumference; it weighed 3.32 kg. The skeleton presented with established osteoporosis and was estimated to be of an advanced age. The analytic methodology used to evaluate the mass was based on that of Kramar et al. (1983). Considering the results of these analyses, and through an extensive search of the relevant medical, historical and archaeological literature, it was determined that this mass was likely a neoplasm of reproductive origin, and was further defined as a calcified uterus containing a number of leiomyomas. To date, this is the largest of its kind ever found archaeologically. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Material and methods
In 2011, Archaeology SouthEast, the Field Unit of the UCL Institute of Archaeology, excavated a cemetery in Chichester, West Sussex, England, known as St. Michael’s Litten; the cemetery was in use from the early 12th century (Morgan, 1992) until its closure in 1850. At the time of excavation the land was in use as a car park. The remains of 1730 individuals were recovered, dating from the medieval and post-medieval periods (roughly 1100–1850 C.E.). It was not possible to date closely more than a small number, such as those that were in family vaults or were named. The post-medieval skeleton that is the subject of the present paper was recovered from the base of excavations in the centre of the site, and thus probably belongs to an earlier phase (the postmedieval period in the UK ranges from 1550 to 1850, with this specimen likely dating to pre-1700). The outstanding feature of the skeleton was the presence of a large mass that was apparently resting within the pelvis (Fig. 1).
2.1. The skeleton The skeleton was relatively complete but in a poor state of preservation, the bones fragmentary and friable. The biological profile was therefore determined using the auricular surface stage for age and cranial morphology/metric analysis for sex (Buikstra and Ubelaker, 1994; Bass, 2005); these analyses suggested that the skeleton was likely that of an elderly female. Additionally, it was evident that the individual had established osteoporosis. The skeleton presented with wedge fractures of one unidentifiable thoracic vertebra and of the fourth and fifth lumbar vertebrae and she had a Singh index of 1 (most severe stage; Singh et al., 1972). The cortices of the long bones were considerably thinned, as were the vertebrae and the sacrum, the latter having a healed horizontal fracture on the anterior surface (between S2 and S3). 2.2. The mass
∗ Corresponding author at: UCL Institute of Archaeology, 31–34 Gordon Square, London WC1H 0PY, UK. Tel.: +44 (0)20 7679 4780. E-mail address: [email protected] (C. Rando). http://dx.doi.org/10.1016/j.ijpp.2015.05.003 1879-9817/© 2015 Elsevier Inc. All rights reserved.
The mass was roughly ovoid in shape, the posterior surface relatively straight in relation to the sacrum and lumbar spine. The inferior portion narrowed and would have fitted exactly into the true pelvis. There was a break in the outer shell of the mass where it seemed to fit against the anterior border of the pelvic rim. This revealed a nodular interior, the nodules of which were loosely adherent. The upper part of the mass swelled upwards and forwards out of the pelvis and would certainly have been apparent during life, mimicking a pregnancy (Fig. 2).
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Fig. 1. Skeleton ESC11 3786 in situ. Note the poor state of the remains and the obvious presence of a huge mass in the pelvic area. There were no associated grave goods found with the individual; the skeleton was buried in a simple shroud-type inhumation.
The mass measured 16.4 H × 19.0 W × 24.3 L cm and was 66 cm in its greatest circumference; it weighed 3.32 kg, that is, approximately the weight of a full term infant. The whole mass was encapsulated in a solid outer shell marked by large vascular channels and a few irregular openings into the interior. It was possible to insert a probe deep inside the mass through some of the vascular foramina.
low speed diamond saw and polished using 6 and 3 m polishing paste. The polished surface was then carbon coated; microscopic analysis was carried out at 15 kV acceleration voltage and variable pressure. The energy dispersive X-ray (EDX) instrument attached to the SEM was used to determine the elemental spectrum of the specimens. Subsequently to the SEM analysis, the polished specimen was used for thin section analysis. The carbon coat was removed by polishing and the specimen reduced to thin sections about 60 m thick using an Isomet diamond saw and polishing paste as described above. The section was mounted on standard glass slides using thin cyanoacrylate adhesive. The extreme hardness of the calcified specimens caused buckling of the thin section so a normal slide was used as a cover rather than the usual coverslip. The sections were examined using a Leica DM EP microscope operating in plane-polarised light (PPL) and cross-polarised light (XPL) modes. The software package QCapture Pro 6.0 was used to control the attached digital camera. A Leica Laborlux 12 POL microscope with a reflected UV attachment was used for autofluorescence (AF) analysis. This microscope was operated in reflected mode using a 420–490 nm exciting filter and a 520 nm suppression filter. Once all the tests were complete, the mass was half-sectioned (using a high power circular saw mounted with a water-cooled diamond blade) along the sagittal plane through its maximum length. 3. Results
2.3. Methods The analytical methodology was derived from that of Kramar et al. (1983); this was updated appropriately considering recent advancements in technology. The aim behind each of the analyses listed below was to determine the inherent composition of the mass; specifically, whether the changes were of osseous origin or the result of calcification – crucial creating an appropriate differential and eventual potential diagnosis of the mass. A computer-aided tomography (CT) scan was carried out on a 64-MDCT Lightspeed VCT (GE Healthcare; helical mode at 50 kV and 149 mA) to visualise the internal composition of the mass. Two samples were taken for testing, a nodule from the exposed interior at the lower frontal area, and a section from a sheet of material from the same exposed area. These were investigated using an XTek micro-computed tomography (CT) unit operated (50 kV and 45 A). Both CT and CT data were imported into 3DSlicer (Slicer 4.3; open-source) for image processing and visualisation. A Hitachi S3400 environmental scanning electron microscopy (SEM) was used (secondary electron and backscattered electron modes) to examine prepared and unprepared surfaces of both specimens. The unprepared material was a surface produced by a fine 60 tip saw followed by sanding with 1200 grit emery paper. The prepared material was similarly cut then embedded in a single clear Logitech 301 resin block. The block was then cut using an Isomet
The CT scan showed a complex structure, the relatively smooth outer shell was extremely dense and of variable thickness, up to the few millimetres (Fig. 3). The majority of the interior consisted of a collection of nodules of varying size, together with numerous voids and several high-density sheets. There was no obvious internal anatomical structure to the various components. Several small irregular shaped openings were observed in the outer shell coupled via irregularly shaped channels to interior voids. The largest of these was located in the upper right quadrant, probably marking the point of entry of major blood vessels. The CT scan showed that both the nodule and the sheet had a relatively uniformly opaque interior. The internal view revealed by sectioning is shown in Fig. 4. The outer shell seemed to be harder than the interior. The cut surface was initially a dark orange colour and some of the sections nodules showed a black interior. The orange colour lightened noticeably as the material dried out. The large central darker brown region was physically separate and could be lifted out of the central void. The difference in colour seen is due to drying out during the photographic session. The analysed specimens were hard and the material sufficiently dense to take a polish similar to polished marble. Photographs of unpolished sections embedded in epoxy resin are shown in Fig. 5a and b. The nodule and planar sheet has noticeably different struc-
Fig. 2. Lateral (a) and inferio-anterior (b) perspectives of the tumour.
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Fig. 3. GE Lightspeed CT scan imagery. (a) Anterior–posterior mid-section view showing a random irregular nodular pattern with a thin sclerotic outer shell (dashed arrow) encompassing the whole specimen in this view. There are three linear high density regions (solid arrow) in the upper right quadrant. These presumably represent in-situ examples of the planar sheet sampled in subsequent testing. (b) Medio-lateral with anterior to the left. This shows the presence of a large void towards the posterior of the specimen with a relatively uniformly organized nodular zone towards its base. A nodular focus (dashed arrow) is visible to the lower posterior of the specimen. The large irregular gap (solid arrow) on the mid anterior margin marks where the specimen rested on the superior ramii of the pelvis.
The different internal structures of the nodule and the sheet are further reflected in the XPL images (Fig. 5e and f). Both specimens show birefringence but the sheet has uniform extinction over the entire sample whereas the nodule has regions of different extinction, giving a patchy appearance that varies irregularly with rotation. The AF images (Fig. 5g and h) show a yellow and green response typical of phosphates (Macphail and Goldberg, 2010). The difference in internal structure is again clearly shown; the nodule with a whorled pattern and the sheet with a laminar structure.
4. Discussion
Fig. 4. The tumour after sectioning. The harder outer shell can be clearly visualised here, along with the central void area. The lobular nature of the mass can also be appreciated from this view.
Table 1 EDX composition (%) of nodule and calcified sheet (carbon coated specimens). Element
Nodule
Sheet
Carbon Oxygen Calcium Phosphorus Ca/P ratio
40.1 41.3 11.0 7.5 1.47
41.5 30.8 11.3 7.4 1.53
tures. The nodule shows an irregular structure with apparently random zones of different colour and there is a suggestion of a whorled fibrous component present. The planar sheet has a more uniform structure with a laminated outer layer over a less regular core. Using the SEM there was no internal structure consistent with bone and no vascular channels were found in either specimen. The nodule showed a variation in density when viewed at high magnification in BSED mode (Fig. 5c and d) and large irregular channels were seen ranging from approximately 4 to 33 m in width and with higher density, whiter shells. The interior was marked by numerous blacker, lower density whorled structures that appeared to have been sectioned both longitudinally and transversely; they were 0.5–1 m in width. Irregular taphonomic cracks had propagated through the specimen independent of any internal structure. The EDX analysis of carbon coated specimens (Table 1) showed a similar chemical composition, the presence of oxygen, calcium and phosphorus being consistent with a calcium phosphate compound. No osseous structure was apparent.
The data obtained from the tests carried out on the mass provide a consistent description of it composition. It is clearly a large calcified mass with no evidence of osseous change. The small nodule analysed shows a whorled pattern, characteristic of a leiomyoma (Martin, 1897). The sheet shows multiple layers of calcification over a presumed soft tissue, and highly vascular core. 4.1. Differential diagnosis In trying to determine the pathogenesis of the tumour, thirtyfour possibilities were initially considered. Taking the results of the CT scans, the histology, and the inspection of the internal structure, we discarded twenty-six of these, leaving seven for further consideration. These were restricted to those occurring within or around the female reproductive system, as this is almost certainly the origin of the mass. The short list comprises: osteosarcoma of the ovary, osteosarcoma of the uterus, leiomyoma, leiomyosarcoma, cystadenofibroma, ovarian fibroma, and diffusely enlarged uterus with calcification. 4.1.1. Osteosarcoma of the ovary, or the uterus Although osteosarcomas are the most common primary malignant bone tumours, they are rare with few cases reported (Yeasmin et al., 2009; Fadare et al., 2007; Vyas et al., 2006). Both forms considered here have a universally poor prognosis; the tumour progresses rapidly with a short clinical duration, and is often fatal (Yeasmin et al., 2009). Osteosarcomas are most frequently observed in women of menopausal age, mean of mid-fifties, although the age of onset can range from 14 to 80 (Fadare et al., 2007); the age range is slightly skewed towards older women in the case of uterine osteosarcomas, with a mean age of onset in the mid-sixties and a range of 41–82 (Su et al., 2002). The size of the tumours varies from 5 to 27 cm; histologically, osteosarcomas have visible osteons with bone formation and focal calcification apparent radiographically and at autopsy (Crum et al., 1980; Hirakawa et al., 1988; Hardisson
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Fig. 5. This figure shows the data for the nodule (left column) and planar sheet (right column) for the four analytic methods (visible light microscopy, SEM imaging, XPL microscopy and autofluorescence microscopy). The visible light microscopy data of the polished embedded specimens (a and b) shows clearly the difference in internal structure of the nodule and planar sheet. The nodule (a) has a chaotic distribution of randomly oriented clusters of fine fibrils, both parallel to and perpendicular to the plane of examination. This is consistent with the distribution of muscle tissue in a leiomyoma nodule. The planar sheet (b) shows a more ordered structure with laminar layers encompassing a core of possibly calcified soft tissue. The high magnification SEM image of the nodule (c) shows the random disordered nature of the fibrils within larger similarly disordered bundles. In contrast, the bulk of the planar sheet (d) shows a uniform appearance, apart from disordered taphonomic changes around the margin of the specimen. The XPL images (e and f) clearly distinguish the random fibrous structure of the nodule (e) from the laminar structure of the sheet (f). The blue light autofluorescence images show a string yellow/green response for both the nodule (g) and the sheet (h). This suggests the bulk material forming the specimens is of a similar nature. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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et al., 2001; Lin et al., 2002; Su et al., 2002; Fadare et al., 2007; Vyas et al., 2006; Yeasmin et al., 2009).
4.1.2. Ovarian fibromas Fibromas are the most common tumour of the ovary, the most common sex-cord tumour in general, and are associated with Meig’s syndrome (Leung and Yuen, 2006). They are generally benign but can cause problems with fertility and excessive retention of fluids within abdominal/thoracic cavities (Outwater et al., 1997). Fibromas may be large on presentation (upwards of 25 cm) but average around 6 cm. They appear as solid masses on radiography, non-homogenous and with focal calcifications; on gross inspection they are whorled and lobular, with solid density and areas of calcification (Wright et al., 2003; de Souza et al., 2005; Leung and Yuen, 2006).
4.1.3. Ovarian cystadenoma Cystadenomas, serous epithelial tumours, account for approximately 25% of all ovarian tumours (Hayes et al., 2008). They are similar to fibromas in their presentation with tough fibrous tissue as the essential component, and are usually benign (Seidman and Mehrotra, 2005). Typically, calcifications are not observed and they tend to be smaller than fibromas (Hayes et al., 2008).
4.1.4. Leiomyoma These are the most common type of pelvic tumour, occurring in between 20 and 40% of women in their reproductive years. Despite the fact that they are commonly referred to as uterine fibroids, they do not arise from fibrous tissue, but rather from the smooth cells of the uterus (Casillas et al., 1990; Stewart, 2001; Wilde and Scott-Barrett, 2009). Although benign, leiomyomas are a primary indication for hysterectomy, and can cause abnormal uterine bleeding, pressure and pain in the pelvic region, and reproductive problems (Stewart, 2001). They are, like most benign tumours of the reproductive system, more often observed in post-menopausal women (Walker and Stewart, 2005; Wilde and Scott-Barrett, 2009). The size of leiomyomas is variable, from 10 mm to greater than 20 cm (Walker and Stewart 2005), however, larger masses can quickly outstrip their blood supply and may degenerate, which can be followed by calcification (Robboy et al., 2000; Wilde and Scott-Barrett, 2009). Radiographically, they present with low signal intensity on MRI and as solid, heterogeneous masses (Price et al., 2004; Yamashiro et al., 2007; Kitajima et al., 2010). On gross examination, fibroids are bulky and irregular (often lobular), with larger masses presenting with necrotic centres (Price et al., 2004; Tok et al., 2006; Yamashiro et al., 2007).
4.1.5. Leiomyosarcoma Aggressive, often terminal malignant tumours, uterine sarcomas account for up to 6% of all malignant tumours of the uterus (Sahdev et al., 2001; Kido et al., 2003; Rha et al., 2003). Leiomyosarcomas represent approximately 40–50% of uterine sarcomas, and can arise from pre-existing leiomyomas (Sahdev et al., 2001). As with their benign counterparts, they are more common in postmenopausal women, but the average age at presentation tends to be older (Robboy et al., 2000; Tanaka et al., 2004). On X-ray, leiomyosarcomas appear as large, heterogeneous masses, with areas of haemorrhage and cystic necrosis (Sahdev et al., 2001; Rha et al., 2003). They are generally soft in consistency, as compared with leiomyomas, which tend to be harder and more rubbery (Robboy et al., 2000; Wang et al., 2011). Focal calcifications can be present, although they are not commonly reported (see Shintaku and Sekiyama, 2004 and Takeuchi et al., 2014 for exceptions).
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4.1.6. Enlarged uterus In addition to neoplasms, there are other conditions that can create an enlarge uterus (a comprehensive review can be found in Kido et al., 2003), many of which are related to hormones, or pregnancy/birth. However, these conditions tend not to cause calcification (or ossification), although this is not outside the realm of possibility.
4.2. Historical and archaeological evidence Having considered the differential described above it seems most likely that the tumour described here is a calcified uterus containing a number of leiomyomas, most of which are contained within sheets of calcified material. There have been eight previous reports of calcified leiomyomas in the paleopathological literature (Table 2), with the largest, from Nubia, approximately half the size of the present tumour (Strouhal and Jungwirth, 1977). There are many case studies of women with uterine fibroids which confirm that these are very common tumours. In one early study (Kelly and Cullen, 1909), the prevalence in patients at the Johns Hopkins Hospital was found to be 10.0% for white, and 33.8% for ‘coloured’ patients. Calcification was present in 15.5% of cases and the largest specimen found was 27 × 17 × 13 cm, somewhat larger than our tumour (Kelly and Cullen, 1909). Other early clinical studies showed the prevalence of calcification to range from 2.4 to 9.3% but varied considerably with age, 2% in age 30–39, 16% in age 40–50, and 10% in age 60–70 (Torpin et al., 1942; McDonald, 1909). The calcification of leiomyomas arises when the soft tissue mass outgrows its blood supply. It is variable in both form and extent and may result in a calcified shell, a calcified body, or a shell enclosing a body. The specimen described by Strouhal and Jungwirth (1977) appears to have just an outer calcified shell. Nicholson et al. (2001) observed such a shell forming when a patient was treated to control the growth of a fibroid. PVA spheroids were injected into an artery supplying the tumour and a thin calcified shell was generated. There is a specimen held in the Hunterian Museum at the Royal College of Surgeons of England (specimen 519.2) which seems to show calcification without a shell; the tumour described here appears to have both a calcified shell and a calcified body. We cannot know, of course, what the clinical course of our ‘patient’ was, although there can be little doubt that she would have been aware of the presence of the tumour during her lifetime. Arnott described a case in 1840, however, which may suggest a possible outcome, however. The patient was an unmarried woman of 72 who suffered intense abdominal pain after a fall whilst out walking. Arnott examined her 5 h after the incident and noted the presence of a large, hard abdominal mass with no sign of external injury. When questioned about the tumour, the patient said that it had been present for at least thirty years and had caused no problems however. The patient died 34 h after the accident and at autopsy it appeared that the impact of the fall perforated a section of bowel stretched over the tumour, with resultant peritonitis. The tumour was described as hard, with an osseous appearance. It extended out of the pelvis into the abdomen, resembling the uterus in shape and size at the fifth month of gestation. The soft tissue of the uterus had largely disappeared. The posterior portion was reduced through atrophy to a membranous state, which the anterior portion was stretched over the tumour. The tumour was 17.8 cm long and 48.3 cm in circumference and its surface was yellowish-white in colour. When the tumour was half-sectioned it was found to be hard as marble and appeared formed from the agglomeration of several smaller parts.
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Table 2 Characteristics of calcified leiomyomas reported in the paleopathological literature. Maximum dimensions
(mm)
Weight(g) Age of individual(years)
Period
Location
Reference
4700–3490 BC 6th–4th century BC 79 AD 3rd–4th century AD 5th–7th century AD 5th–10th century AD 13th–15th century AD Medieval 16th–18th century AD 16th–18th century AD 16th–18th century AD Post-medieval
Corseaux-sur-Vevey, Switzerland Alfedena, Italy Ercolania, Italy Eqyptian, Nubia Rances, France Sion Sous-les-Scex, France Grenada, Spain Basel, Switzerland Brussels, Belgium Brussels, Belgium Brussels, Belgium Chichester, England
Kramar et al. (1983) Capasso et al. (1994) Capasso (2001) Strouhal and Jungwirth (1977) Baud and Kramar (1990) Baud and Kramar (1990) Jiménez-Brobeil et al. (1992) Scheidegger (1990) Quintelier (2009) Quintelier (2009) Quintelier (2009) This paper
Height Medio-lateral Antero–posterior 56 13 71 123 30 46 61 70 71 53 31 243
52 13 63 105 26 32 48 70 47 47 25 190
45 13 47 80 18 25 48 70 47 47 25 164
∼40 35–45
84
Mature
85 45 8 3320
40–50 35–40 50–60 Mature
5. Conclusions Based on the evidence presented above, the likely diagnosis for this large lobular mass is a calcified uterus containing a number of leiomyomas; an alternative suggestion could be a large leiomyoma with multiple nodules. In either case, this mass represents a benign, slow-growing tumour. No comment can of course be made on whether this mass contributed to the individual’s cause of death (as was described in Arnott, 1840) and it is difficult to know whether it affected her quality of life at all.
Acknowledgements We would like to thank Sandra Bond, Richard McPhail, Patrick Quinn, Kevin Reeves and Aaron Gasparik of the UCL Institute of Archaeology; Robert Speller (Department of Physics, UCL); and Miles Woodhead (Salisbury NHS Trust). We would also like to extend our sincere gratitude to the archaeologists from Archaeology SouthEast for their exceptional job excavating the skeleton. Finally, we would like to thank Editor-in-Chief Professor Jane Buikstra, the associate editor, and our two reviewers for their invaluable comments and suggestions.
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G. Cole et al. / International Journal of Paleopathology 10 (2015) 51–57 Su, M., Tokairin, T., Nishikawa, Y., Yoshioka, T., Takahashi, O., Watanabe, H., Doi, Y., Omori, Y., Yoshioka, T., Sageshima, M., Tanaka, T., Enomoto, K., 2002. Primary osteosarcoma of the uterine corpus: care report and review of the literature. Pathol. Int. 52, 158–163. Takeuchi, K., Sugimoto, M., Yoshida, A., Yamashita, S., Tsujino, T., Nishino, R., 2014. Spontaneous uterine perforation secondary to leiomyosarcoma arising in a uterine leiomyoma. Open J. Obstet. Gynecol. 4, 186–189. Tanaka, Y.O., Nishida, M., Tsunoda, H., Okamoto, Y., Yoshikawa, H., 2004. Smooth muscle tumors of uncertain malignant potential and leiomyosarcomas of the uterus: MR findings. J. Magn. Reson. Imaging 20, 998–1007. Tok, C.H., Bux, S.I., Mohamed, S.I., Lim, B.K., 2006. Degenerated uterine fibroid mimicking hydrometra: fallacy in CT. Biomed. Imaging Interv. J. 2 (4), 1–4. Torpin, R., Pund, E., Peeples, W.J., 1942. The etiologic and pathologic factors in a series of 1741 fibromyomas of the uterus. Am. J. Obstet. Gynecol. 44, 569–574. Vyas, V., Rammah, A.M.A., Ashebu, S.D., Sharaan, G.M., El-Sayed, M., Jarslov, N., El-Khodary, A., 2006. A case report of primary osteosarcoma of the ovary. Int. J. Gynecol. Cancer 16 (1), 349–352.
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Walker, C.L., Stewart, E.A., 2005. Uterine fibroids: the elephant in the room. Science 308 (5728), 1589–1592. Wang, W.L., Soslow, R., Hensley, M., Asad, H., Zannoni, G.F., de Nictolis, M., Branton, P., Muzikansky, A., Oliva, E., 2011. Histopathologic prognostic factors in stage I leiomyosarcoma of the uterus: a detailed analysis of 27 cases. Am. J. Surg. Pathol. 35 (4), 522–529. Wilde, S., Scott-Barrett, S., 2009. Radiological appearances of uterine fibroids. Indian J. Radiol. Imaging 19 (3), 222. Wright, J.D., Powell, M.A., Rader, J.S., Pfeifer, J.D., Huettner, P.C., Merritt, D.F., 2003. Acute abdominal pain with calcified pelvic mass. J. Pediatr. Adolesc. Gynecol. 16, 237–241. Yamashiro, T., Gibo, M., Utsunomiya, T., Murayama, S., 2007. Huge uterine leiomyoma with adenomyotic cysts mimicking uterine sarcoma on MR imaging. Radiat. Med. 25 (3), 127–129. Yeasmin, S., Nakayama, K., Ishibashi, M., Katagiri, A., Iida, K., Manabe, A., Miyazaki, K., 2009. Primary osteosarcoma of ovary. Int. J. Clin. Oncol. 14 (2), 163–166.
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International Journal of Paleopathology journal homepage: www.elsevier.com/locate/ijpp
Case report: A giant calcified uterus, likely due to benign leiomyoma Garrard Cole a , Carolyn Rando a,∗ , Lucy Sibun b , Tony Waldron a a b
UCL Institute of Archaeology, London, UK Archaeology South–East, UCL Institute of Archaeology, London, UK
a r t i c l e
i n f o
Article history: Received 24 February 2015 Received in revised form 12 May 2015 Accepted 25 May 2015 Keywords: Leiomyoma Differential diagnosis Enlarged uterus Post-medieval england Neoplasm Calcification
a b s t r a c t During the 2011 excavation of the site of St. Michael’s Litten, in Chichester, England, a female skeleton, dating to the post-Medieval period (1550–1850), with a large, unidentified pelvic mass was uncovered. The mass measured 16.4 H × 19.0 W × 24.3 L and was 66 cm in its greatest circumference; it weighed 3.32 kg. The skeleton presented with established osteoporosis and was estimated to be of an advanced age. The analytic methodology used to evaluate the mass was based on that of Kramar et al. (1983). Considering the results of these analyses, and through an extensive search of the relevant medical, historical and archaeological literature, it was determined that this mass was likely a neoplasm of reproductive origin, and was further defined as a calcified uterus containing a number of leiomyomas. To date, this is the largest of its kind ever found archaeologically. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Material and methods
In 2011, Archaeology SouthEast, the Field Unit of the UCL Institute of Archaeology, excavated a cemetery in Chichester, West Sussex, England, known as St. Michael’s Litten; the cemetery was in use from the early 12th century (Morgan, 1992) until its closure in 1850. At the time of excavation the land was in use as a car park. The remains of 1730 individuals were recovered, dating from the medieval and post-medieval periods (roughly 1100–1850 C.E.). It was not possible to date closely more than a small number, such as those that were in family vaults or were named. The post-medieval skeleton that is the subject of the present paper was recovered from the base of excavations in the centre of the site, and thus probably belongs to an earlier phase (the postmedieval period in the UK ranges from 1550 to 1850, with this specimen likely dating to pre-1700). The outstanding feature of the skeleton was the presence of a large mass that was apparently resting within the pelvis (Fig. 1).
2.1. The skeleton The skeleton was relatively complete but in a poor state of preservation, the bones fragmentary and friable. The biological profile was therefore determined using the auricular surface stage for age and cranial morphology/metric analysis for sex (Buikstra and Ubelaker, 1994; Bass, 2005); these analyses suggested that the skeleton was likely that of an elderly female. Additionally, it was evident that the individual had established osteoporosis. The skeleton presented with wedge fractures of one unidentifiable thoracic vertebra and of the fourth and fifth lumbar vertebrae and she had a Singh index of 1 (most severe stage; Singh et al., 1972). The cortices of the long bones were considerably thinned, as were the vertebrae and the sacrum, the latter having a healed horizontal fracture on the anterior surface (between S2 and S3). 2.2. The mass
∗ Corresponding author at: UCL Institute of Archaeology, 31–34 Gordon Square, London WC1H 0PY, UK. Tel.: +44 (0)20 7679 4780. E-mail address: [email protected] (C. Rando). http://dx.doi.org/10.1016/j.ijpp.2015.05.003 1879-9817/© 2015 Elsevier Inc. All rights reserved.
The mass was roughly ovoid in shape, the posterior surface relatively straight in relation to the sacrum and lumbar spine. The inferior portion narrowed and would have fitted exactly into the true pelvis. There was a break in the outer shell of the mass where it seemed to fit against the anterior border of the pelvic rim. This revealed a nodular interior, the nodules of which were loosely adherent. The upper part of the mass swelled upwards and forwards out of the pelvis and would certainly have been apparent during life, mimicking a pregnancy (Fig. 2).
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Fig. 1. Skeleton ESC11 3786 in situ. Note the poor state of the remains and the obvious presence of a huge mass in the pelvic area. There were no associated grave goods found with the individual; the skeleton was buried in a simple shroud-type inhumation.
The mass measured 16.4 H × 19.0 W × 24.3 L cm and was 66 cm in its greatest circumference; it weighed 3.32 kg, that is, approximately the weight of a full term infant. The whole mass was encapsulated in a solid outer shell marked by large vascular channels and a few irregular openings into the interior. It was possible to insert a probe deep inside the mass through some of the vascular foramina.
low speed diamond saw and polished using 6 and 3 m polishing paste. The polished surface was then carbon coated; microscopic analysis was carried out at 15 kV acceleration voltage and variable pressure. The energy dispersive X-ray (EDX) instrument attached to the SEM was used to determine the elemental spectrum of the specimens. Subsequently to the SEM analysis, the polished specimen was used for thin section analysis. The carbon coat was removed by polishing and the specimen reduced to thin sections about 60 m thick using an Isomet diamond saw and polishing paste as described above. The section was mounted on standard glass slides using thin cyanoacrylate adhesive. The extreme hardness of the calcified specimens caused buckling of the thin section so a normal slide was used as a cover rather than the usual coverslip. The sections were examined using a Leica DM EP microscope operating in plane-polarised light (PPL) and cross-polarised light (XPL) modes. The software package QCapture Pro 6.0 was used to control the attached digital camera. A Leica Laborlux 12 POL microscope with a reflected UV attachment was used for autofluorescence (AF) analysis. This microscope was operated in reflected mode using a 420–490 nm exciting filter and a 520 nm suppression filter. Once all the tests were complete, the mass was half-sectioned (using a high power circular saw mounted with a water-cooled diamond blade) along the sagittal plane through its maximum length. 3. Results
2.3. Methods The analytical methodology was derived from that of Kramar et al. (1983); this was updated appropriately considering recent advancements in technology. The aim behind each of the analyses listed below was to determine the inherent composition of the mass; specifically, whether the changes were of osseous origin or the result of calcification – crucial creating an appropriate differential and eventual potential diagnosis of the mass. A computer-aided tomography (CT) scan was carried out on a 64-MDCT Lightspeed VCT (GE Healthcare; helical mode at 50 kV and 149 mA) to visualise the internal composition of the mass. Two samples were taken for testing, a nodule from the exposed interior at the lower frontal area, and a section from a sheet of material from the same exposed area. These were investigated using an XTek micro-computed tomography (CT) unit operated (50 kV and 45 A). Both CT and CT data were imported into 3DSlicer (Slicer 4.3; open-source) for image processing and visualisation. A Hitachi S3400 environmental scanning electron microscopy (SEM) was used (secondary electron and backscattered electron modes) to examine prepared and unprepared surfaces of both specimens. The unprepared material was a surface produced by a fine 60 tip saw followed by sanding with 1200 grit emery paper. The prepared material was similarly cut then embedded in a single clear Logitech 301 resin block. The block was then cut using an Isomet
The CT scan showed a complex structure, the relatively smooth outer shell was extremely dense and of variable thickness, up to the few millimetres (Fig. 3). The majority of the interior consisted of a collection of nodules of varying size, together with numerous voids and several high-density sheets. There was no obvious internal anatomical structure to the various components. Several small irregular shaped openings were observed in the outer shell coupled via irregularly shaped channels to interior voids. The largest of these was located in the upper right quadrant, probably marking the point of entry of major blood vessels. The CT scan showed that both the nodule and the sheet had a relatively uniformly opaque interior. The internal view revealed by sectioning is shown in Fig. 4. The outer shell seemed to be harder than the interior. The cut surface was initially a dark orange colour and some of the sections nodules showed a black interior. The orange colour lightened noticeably as the material dried out. The large central darker brown region was physically separate and could be lifted out of the central void. The difference in colour seen is due to drying out during the photographic session. The analysed specimens were hard and the material sufficiently dense to take a polish similar to polished marble. Photographs of unpolished sections embedded in epoxy resin are shown in Fig. 5a and b. The nodule and planar sheet has noticeably different struc-
Fig. 2. Lateral (a) and inferio-anterior (b) perspectives of the tumour.
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Fig. 3. GE Lightspeed CT scan imagery. (a) Anterior–posterior mid-section view showing a random irregular nodular pattern with a thin sclerotic outer shell (dashed arrow) encompassing the whole specimen in this view. There are three linear high density regions (solid arrow) in the upper right quadrant. These presumably represent in-situ examples of the planar sheet sampled in subsequent testing. (b) Medio-lateral with anterior to the left. This shows the presence of a large void towards the posterior of the specimen with a relatively uniformly organized nodular zone towards its base. A nodular focus (dashed arrow) is visible to the lower posterior of the specimen. The large irregular gap (solid arrow) on the mid anterior margin marks where the specimen rested on the superior ramii of the pelvis.
The different internal structures of the nodule and the sheet are further reflected in the XPL images (Fig. 5e and f). Both specimens show birefringence but the sheet has uniform extinction over the entire sample whereas the nodule has regions of different extinction, giving a patchy appearance that varies irregularly with rotation. The AF images (Fig. 5g and h) show a yellow and green response typical of phosphates (Macphail and Goldberg, 2010). The difference in internal structure is again clearly shown; the nodule with a whorled pattern and the sheet with a laminar structure.
4. Discussion
Fig. 4. The tumour after sectioning. The harder outer shell can be clearly visualised here, along with the central void area. The lobular nature of the mass can also be appreciated from this view.
Table 1 EDX composition (%) of nodule and calcified sheet (carbon coated specimens). Element
Nodule
Sheet
Carbon Oxygen Calcium Phosphorus Ca/P ratio
40.1 41.3 11.0 7.5 1.47
41.5 30.8 11.3 7.4 1.53
tures. The nodule shows an irregular structure with apparently random zones of different colour and there is a suggestion of a whorled fibrous component present. The planar sheet has a more uniform structure with a laminated outer layer over a less regular core. Using the SEM there was no internal structure consistent with bone and no vascular channels were found in either specimen. The nodule showed a variation in density when viewed at high magnification in BSED mode (Fig. 5c and d) and large irregular channels were seen ranging from approximately 4 to 33 m in width and with higher density, whiter shells. The interior was marked by numerous blacker, lower density whorled structures that appeared to have been sectioned both longitudinally and transversely; they were 0.5–1 m in width. Irregular taphonomic cracks had propagated through the specimen independent of any internal structure. The EDX analysis of carbon coated specimens (Table 1) showed a similar chemical composition, the presence of oxygen, calcium and phosphorus being consistent with a calcium phosphate compound. No osseous structure was apparent.
The data obtained from the tests carried out on the mass provide a consistent description of it composition. It is clearly a large calcified mass with no evidence of osseous change. The small nodule analysed shows a whorled pattern, characteristic of a leiomyoma (Martin, 1897). The sheet shows multiple layers of calcification over a presumed soft tissue, and highly vascular core. 4.1. Differential diagnosis In trying to determine the pathogenesis of the tumour, thirtyfour possibilities were initially considered. Taking the results of the CT scans, the histology, and the inspection of the internal structure, we discarded twenty-six of these, leaving seven for further consideration. These were restricted to those occurring within or around the female reproductive system, as this is almost certainly the origin of the mass. The short list comprises: osteosarcoma of the ovary, osteosarcoma of the uterus, leiomyoma, leiomyosarcoma, cystadenofibroma, ovarian fibroma, and diffusely enlarged uterus with calcification. 4.1.1. Osteosarcoma of the ovary, or the uterus Although osteosarcomas are the most common primary malignant bone tumours, they are rare with few cases reported (Yeasmin et al., 2009; Fadare et al., 2007; Vyas et al., 2006). Both forms considered here have a universally poor prognosis; the tumour progresses rapidly with a short clinical duration, and is often fatal (Yeasmin et al., 2009). Osteosarcomas are most frequently observed in women of menopausal age, mean of mid-fifties, although the age of onset can range from 14 to 80 (Fadare et al., 2007); the age range is slightly skewed towards older women in the case of uterine osteosarcomas, with a mean age of onset in the mid-sixties and a range of 41–82 (Su et al., 2002). The size of the tumours varies from 5 to 27 cm; histologically, osteosarcomas have visible osteons with bone formation and focal calcification apparent radiographically and at autopsy (Crum et al., 1980; Hirakawa et al., 1988; Hardisson
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Fig. 5. This figure shows the data for the nodule (left column) and planar sheet (right column) for the four analytic methods (visible light microscopy, SEM imaging, XPL microscopy and autofluorescence microscopy). The visible light microscopy data of the polished embedded specimens (a and b) shows clearly the difference in internal structure of the nodule and planar sheet. The nodule (a) has a chaotic distribution of randomly oriented clusters of fine fibrils, both parallel to and perpendicular to the plane of examination. This is consistent with the distribution of muscle tissue in a leiomyoma nodule. The planar sheet (b) shows a more ordered structure with laminar layers encompassing a core of possibly calcified soft tissue. The high magnification SEM image of the nodule (c) shows the random disordered nature of the fibrils within larger similarly disordered bundles. In contrast, the bulk of the planar sheet (d) shows a uniform appearance, apart from disordered taphonomic changes around the margin of the specimen. The XPL images (e and f) clearly distinguish the random fibrous structure of the nodule (e) from the laminar structure of the sheet (f). The blue light autofluorescence images show a string yellow/green response for both the nodule (g) and the sheet (h). This suggests the bulk material forming the specimens is of a similar nature. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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et al., 2001; Lin et al., 2002; Su et al., 2002; Fadare et al., 2007; Vyas et al., 2006; Yeasmin et al., 2009).
4.1.2. Ovarian fibromas Fibromas are the most common tumour of the ovary, the most common sex-cord tumour in general, and are associated with Meig’s syndrome (Leung and Yuen, 2006). They are generally benign but can cause problems with fertility and excessive retention of fluids within abdominal/thoracic cavities (Outwater et al., 1997). Fibromas may be large on presentation (upwards of 25 cm) but average around 6 cm. They appear as solid masses on radiography, non-homogenous and with focal calcifications; on gross inspection they are whorled and lobular, with solid density and areas of calcification (Wright et al., 2003; de Souza et al., 2005; Leung and Yuen, 2006).
4.1.3. Ovarian cystadenoma Cystadenomas, serous epithelial tumours, account for approximately 25% of all ovarian tumours (Hayes et al., 2008). They are similar to fibromas in their presentation with tough fibrous tissue as the essential component, and are usually benign (Seidman and Mehrotra, 2005). Typically, calcifications are not observed and they tend to be smaller than fibromas (Hayes et al., 2008).
4.1.4. Leiomyoma These are the most common type of pelvic tumour, occurring in between 20 and 40% of women in their reproductive years. Despite the fact that they are commonly referred to as uterine fibroids, they do not arise from fibrous tissue, but rather from the smooth cells of the uterus (Casillas et al., 1990; Stewart, 2001; Wilde and Scott-Barrett, 2009). Although benign, leiomyomas are a primary indication for hysterectomy, and can cause abnormal uterine bleeding, pressure and pain in the pelvic region, and reproductive problems (Stewart, 2001). They are, like most benign tumours of the reproductive system, more often observed in post-menopausal women (Walker and Stewart, 2005; Wilde and Scott-Barrett, 2009). The size of leiomyomas is variable, from 10 mm to greater than 20 cm (Walker and Stewart 2005), however, larger masses can quickly outstrip their blood supply and may degenerate, which can be followed by calcification (Robboy et al., 2000; Wilde and Scott-Barrett, 2009). Radiographically, they present with low signal intensity on MRI and as solid, heterogeneous masses (Price et al., 2004; Yamashiro et al., 2007; Kitajima et al., 2010). On gross examination, fibroids are bulky and irregular (often lobular), with larger masses presenting with necrotic centres (Price et al., 2004; Tok et al., 2006; Yamashiro et al., 2007).
4.1.5. Leiomyosarcoma Aggressive, often terminal malignant tumours, uterine sarcomas account for up to 6% of all malignant tumours of the uterus (Sahdev et al., 2001; Kido et al., 2003; Rha et al., 2003). Leiomyosarcomas represent approximately 40–50% of uterine sarcomas, and can arise from pre-existing leiomyomas (Sahdev et al., 2001). As with their benign counterparts, they are more common in postmenopausal women, but the average age at presentation tends to be older (Robboy et al., 2000; Tanaka et al., 2004). On X-ray, leiomyosarcomas appear as large, heterogeneous masses, with areas of haemorrhage and cystic necrosis (Sahdev et al., 2001; Rha et al., 2003). They are generally soft in consistency, as compared with leiomyomas, which tend to be harder and more rubbery (Robboy et al., 2000; Wang et al., 2011). Focal calcifications can be present, although they are not commonly reported (see Shintaku and Sekiyama, 2004 and Takeuchi et al., 2014 for exceptions).
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4.1.6. Enlarged uterus In addition to neoplasms, there are other conditions that can create an enlarge uterus (a comprehensive review can be found in Kido et al., 2003), many of which are related to hormones, or pregnancy/birth. However, these conditions tend not to cause calcification (or ossification), although this is not outside the realm of possibility.
4.2. Historical and archaeological evidence Having considered the differential described above it seems most likely that the tumour described here is a calcified uterus containing a number of leiomyomas, most of which are contained within sheets of calcified material. There have been eight previous reports of calcified leiomyomas in the paleopathological literature (Table 2), with the largest, from Nubia, approximately half the size of the present tumour (Strouhal and Jungwirth, 1977). There are many case studies of women with uterine fibroids which confirm that these are very common tumours. In one early study (Kelly and Cullen, 1909), the prevalence in patients at the Johns Hopkins Hospital was found to be 10.0% for white, and 33.8% for ‘coloured’ patients. Calcification was present in 15.5% of cases and the largest specimen found was 27 × 17 × 13 cm, somewhat larger than our tumour (Kelly and Cullen, 1909). Other early clinical studies showed the prevalence of calcification to range from 2.4 to 9.3% but varied considerably with age, 2% in age 30–39, 16% in age 40–50, and 10% in age 60–70 (Torpin et al., 1942; McDonald, 1909). The calcification of leiomyomas arises when the soft tissue mass outgrows its blood supply. It is variable in both form and extent and may result in a calcified shell, a calcified body, or a shell enclosing a body. The specimen described by Strouhal and Jungwirth (1977) appears to have just an outer calcified shell. Nicholson et al. (2001) observed such a shell forming when a patient was treated to control the growth of a fibroid. PVA spheroids were injected into an artery supplying the tumour and a thin calcified shell was generated. There is a specimen held in the Hunterian Museum at the Royal College of Surgeons of England (specimen 519.2) which seems to show calcification without a shell; the tumour described here appears to have both a calcified shell and a calcified body. We cannot know, of course, what the clinical course of our ‘patient’ was, although there can be little doubt that she would have been aware of the presence of the tumour during her lifetime. Arnott described a case in 1840, however, which may suggest a possible outcome, however. The patient was an unmarried woman of 72 who suffered intense abdominal pain after a fall whilst out walking. Arnott examined her 5 h after the incident and noted the presence of a large, hard abdominal mass with no sign of external injury. When questioned about the tumour, the patient said that it had been present for at least thirty years and had caused no problems however. The patient died 34 h after the accident and at autopsy it appeared that the impact of the fall perforated a section of bowel stretched over the tumour, with resultant peritonitis. The tumour was described as hard, with an osseous appearance. It extended out of the pelvis into the abdomen, resembling the uterus in shape and size at the fifth month of gestation. The soft tissue of the uterus had largely disappeared. The posterior portion was reduced through atrophy to a membranous state, which the anterior portion was stretched over the tumour. The tumour was 17.8 cm long and 48.3 cm in circumference and its surface was yellowish-white in colour. When the tumour was half-sectioned it was found to be hard as marble and appeared formed from the agglomeration of several smaller parts.
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Table 2 Characteristics of calcified leiomyomas reported in the paleopathological literature. Maximum dimensions
(mm)
Weight(g) Age of individual(years)
Period
Location
Reference
4700–3490 BC 6th–4th century BC 79 AD 3rd–4th century AD 5th–7th century AD 5th–10th century AD 13th–15th century AD Medieval 16th–18th century AD 16th–18th century AD 16th–18th century AD Post-medieval
Corseaux-sur-Vevey, Switzerland Alfedena, Italy Ercolania, Italy Eqyptian, Nubia Rances, France Sion Sous-les-Scex, France Grenada, Spain Basel, Switzerland Brussels, Belgium Brussels, Belgium Brussels, Belgium Chichester, England
Kramar et al. (1983) Capasso et al. (1994) Capasso (2001) Strouhal and Jungwirth (1977) Baud and Kramar (1990) Baud and Kramar (1990) Jiménez-Brobeil et al. (1992) Scheidegger (1990) Quintelier (2009) Quintelier (2009) Quintelier (2009) This paper
Height Medio-lateral Antero–posterior 56 13 71 123 30 46 61 70 71 53 31 243
52 13 63 105 26 32 48 70 47 47 25 190
45 13 47 80 18 25 48 70 47 47 25 164
∼40 35–45
84
Mature
85 45 8 3320
40–50 35–40 50–60 Mature
5. Conclusions Based on the evidence presented above, the likely diagnosis for this large lobular mass is a calcified uterus containing a number of leiomyomas; an alternative suggestion could be a large leiomyoma with multiple nodules. In either case, this mass represents a benign, slow-growing tumour. No comment can of course be made on whether this mass contributed to the individual’s cause of death (as was described in Arnott, 1840) and it is difficult to know whether it affected her quality of life at all.
Acknowledgements We would like to thank Sandra Bond, Richard McPhail, Patrick Quinn, Kevin Reeves and Aaron Gasparik of the UCL Institute of Archaeology; Robert Speller (Department of Physics, UCL); and Miles Woodhead (Salisbury NHS Trust). We would also like to extend our sincere gratitude to the archaeologists from Archaeology SouthEast for their exceptional job excavating the skeleton. Finally, we would like to thank Editor-in-Chief Professor Jane Buikstra, the associate editor, and our two reviewers for their invaluable comments and suggestions.
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