| Abstract|| |
Objectives: To study the histological features in uterine STUMP, and atypical leiomyomas (AL), and to correlate with clinical outcome. Materials and Methods: From January 2004 to August 2010, a total of 21 cases were retrieved from records, labeled as STUMP(7), AL (5), AL with low risk of recurrence (2), smooth muscle tumor of low malignant potential (STLMP) (2), and symplastic leiomyoma (5). The slides were reviewed for coagulative tumor cell necrosis (CTCN), hyaline necrosis/ infarction type necrosis, presence and degree of cytological atypia, mitotic activity, epithelioid morphology and myxoid features. The other characteristics (such as size, circumscription, individual tumor cell necrosis), were noted, wherever available. Results: The mean age was 45 years (median 46; range 24-67 yrs). CTCN was seen in 2 cases on examination of additional material; wherein a revised diagnosis of leiomyosarcoma had been given. Infarction type necrosis and individual cell necrosis was seen in 2 and 3 cases, respectively. Mitoses were less than 5/10hpf in all the cases. One of the tumours labeled as STUMP also had concurrent endometrial adenocarcinoma. Follow up: Follow-up was available in 11 cases (52.3%). One patient had died. (cause not known). In 10 patients, the follow-up ranged from 4 to 56 months (mean 20.9 months; median 15 months) nine patients were alive and well. One patient (labeled STLMP) had metastatic liver disease 3 yrs after the primary surgery, at the last follow-up. Conclusions: 1) There is an overlap in using the terminologies as STUMP, AL, AL with low risk of recurrence, AL with low malignant potential. A designation of STUMP does convey a category of borderline malignancy to the gynecological surgeons. Most behave in a benign fashion and follow-up without adjuvant therapy is currently recommended. Critical evaluation of coagulative tumor necrosis is essential. Follow-up remains a challenge in our setting.
Keywords: Atypical leiomyoma, coagulative tumor cell necrosis, smooth muscle tumor of uncertain malignant potential
|How to cite this article:|
Deodhar KK, Goyal P, Rekhi B, Menon S, Maheshwari A, Kerkar R, Tongaonkar H B. Uterine smooth muscle tumors of uncertain malignant potential and atypical leiomyoma: A morphological study of these grey zones with clinical correlation. Indian J Pathol Microbiol 2011;54:706-11
|How to cite this URL:|
Deodhar KK, Goyal P, Rekhi B, Menon S, Maheshwari A, Kerkar R, Tongaonkar H B. Uterine smooth muscle tumors of uncertain malignant potential and atypical leiomyoma: A morphological study of these grey zones with clinical correlation. Indian J Pathol Microbiol [serial online] 2011 [cited 2014 Jul 31];54:706-11. Available from: http://www.ijpmonline.org/text.asp?2011/54/4/706/91500
| Introduction|| |
Uterine smooth muscle tumors of uncertain malignant potential (STUMP) are uncommon tumors. They are unclassifiable by current criteria as unequivocally benign or malignant.
Conventionally, a diagnosis of leiomyosarcoma is made when two of the three criteria are met, namely coagulative tumor cell necrosis (CTCN), diffuse cytological atypia, and mitotic index > 10 MFs/10hpf.
A category of STUMP is used when subtype of smooth muscle differentiation is in doubt i.e., standard versus epithelioid versus myxoid; or other assessments are doubtful i.e., type of necrosis or interpretation of mitotic figures. In these cases, alternative interpretation leads to different diagnosis and hence different follow-up measures, emphasizing the importance of accurate interpretation.
To study the histological features in uterine STUMP, and atypical leiomyomas (AL), and to correlate with clinical outcome.
| Materials and Methods|| |
From January 2004 to August 2010, a total of 27 cases were retrieved from our records, labeled as STUMP or atypical leiomyoma or symplastic leiomyoma (SL). Out of that, three cases had submitted slides twice, one was a mesenteric mass, one retroperitoneal tumor and one was a vaginal polyp. Hence, six cases were not included for this study and a total of 21 cases are included for this study. [Table 1] The slides were reviewed by two authors (KD and PG) for CTCN, hyaline necrosis/ infarction type necrosis, individual cell necrosis, presence and degree of cytological atypia, mitotic activity, epithelioid morphology, and myxoid features. The other characteristics (such as size, circumscription, individual tumor cell necrosis), were noted, wherever available.
| Results|| |
The mean age was 45 yrs (median 46; range 24-67 yrs). Out of these two were broad ligament tumors. Two were pelvic masses, one of which was a recurrence after hysterectomy and the other showed a large mass not separate from uterus.
The information about the size was available in 6 cases; the median size was 10.9 cm.
The cytological atypia was graded as mild, moderate and marked; and also assessed whether it is focal and diffuse. Significant cytological atypia was almost always evident on the low power. The mitotic count was assessed in the most mitotically active area (expressed per 10/hpf) [Figure 1] and [Figure 2]. Specific attempt to measure objective lens diameter was not made. CTCN [Figure 3], [Figure 4] was seen in two cases on examination of additional material; in these, the diagnosis was revised to leiomyosarcoma. Infarction type necrosis was seen in two cases, and individual cell necrosis was seen in three cases [Figure 5], [Figure 6]. The histological findings are tabulated in [Table 2], and the types of necrosis and its outcome are tabulated in [Table 3].
|Figure 1: Atypical leiomyoma, marked nuclear pleomorphism and intranuclear inclusions, (Hematoxylin and eosin, ×400)|
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|Figure 2: Atypical leiomyoma, marked nuclear pleomorphism and mitotic figure. (Hematoxylin and eosin, ×400)|
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|Figure 3: Coagulative tumor cell necrosis (Hematoxylin and eosin, x 100)|
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|Figure 5: Individual tumor cell necrosis with myxoid change. (Hematoxylin and eosin, ×400)|
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|Table 3: Outcome of coagulative tumor cell necrosis, infarction necrosis, individual tumor cell necrosis|
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In one other case labeled as AL, patient developed a sigmoid deposit with features of high grade sarcoma in one month. One of the tumours labeled as STUMP also had concurrent endometrial adenocarcinoma. In 11 cases, immunohistochemistry was done.
Epithelioid morphology was seen in six cases (28.6 %) [Figure 7], [Figure 8]. Out of that, three cases had follow-up from 6, 15 and 19 months each. Three cases were lost to follow-up. Two cases showed focal myxoid areas. [Figure 9] shows an example of infarction type necrosis.
|Figure 7: (a) Epithelioid morphology , (Hematoxylin and eosin, × 40); (b) (Hematoxylin and eosin, × 100), (c) immunopositivity for desmin, (d) immunonegativity for CD10 (c and d: IHC, × 100)|
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Follow up: Follow-up was available in 11 cases (52.3%). One patient had died. (Cause not known)
In 10 other patients, the follow-up was available ranging from 4 to 56months (mean 20.9 months; median 15 months) Nine patients were alive and well. One of the 10 patients, (labeled STLMP) had metastatic liver disease 3 yrs after the primary surgery, at the last follow-up.
| Discussion|| |
The seminal work on problematic uterine smooth muscle neoplasms comes from the study of Bell et al. This forms the basis of our understanding and establish the diagnostic criteria in these tumors. The issue is to evaluate whether any particular morphological finding is able to reliably predict the biological behavior of the tumor. They extensively studied various parameters (such as cellularity, mitotic index, degree and extent of atypia, types of necrosis, tumor uterine interphase, intravascular growth) in 213 patients. Out of three univariate predictors (atypia, mitotic index, and CTCN), they concluded that CTCN comes out as the best separating feature between benign and malignant tumors.
The term 'STUMP' was first used by Kempson in 1973. 
In 1961, Przybora  introduced the term 'leiomyosarcoma in situ' for a group of 15 uterine smooth muscle tumors in which distinct atypical cells including multinucleate giant cells were found within an otherwise simple myoma. , He postulated that leiomyosarcoma in situ is a transitional phase in the development of a fully malignant sarcoma, analogous to carcinoma in situ (this concept has subsequently been disregarded). Further studies with uterine smooth muscle tumors with atypical histological features, including multinucleate tumor giant cells of the symplastic type but without mitotic activity have recognized their clinically benign course. ,
Based on cytological atypia, CTCN and mitoses, Bell et al. divided problematic uterine smooth muscle tumors in five different groups. The STUMP tumors were subdivided in the study by Bell et al. into three groups
- Atypical leiomyoma with low risk of recurrence - diffuse moderate to severe atypia, <10MFs/10hpf and no CTCN
- Atypical leiomyoma but limited experience- focal mod. To severe atypia, <20MFs/10hpf, no CTCN
- Smooth muscle tumor of low malignant potential has CTCN, mitoses less than 10MFs/10hpf, absent to mild nuclear atypia.
The WHO book has used these terminologies which are used as diagnostic categories while coming to diagnosis in the above cases. 
The STUMPs remain a heterogeneous group of rare tumors. Ip et al. in their study described 16 tumors from 11 hospitals between 1992 and 2006.  Ng et al described 18 cases of STUMP and 72 leiomyosarcomas between 1970 and 2006 in their article.
The largest study of uterine STUMP is presented by Guntupalli et al In their study , they used similar criteria for definition of STUMP, and used following four categories
Guntupalli et al. found no significant difference between race/ethnicity, as well as tobacco use status with regards to presence or absence of recurrence.  Whereas, in the study by Toro et al. the incidence of leiomyosarcoma was 1.7 times more in African American women than in Caucasian women. Lumbiganon et al in a multicenter case control study, found that smoking was associated with decrease in the relative risk of developing uterine leiomyoma. Schwartz et al in their study, found that the smoking reduced the risk of developing leiomyosarcoma (odds ratio=0.6).
- Tumor cell necrosis, no atypia, MI<10/10HPF; 2) diffuse atypia, no tumor cell necrosis MI <10/10hpf; 3) no tumor cell necrosis, no atypia,MI>20/10hpf; 4)cellularity/hypercellularity and a MI >4/10hpf; 5) irregular margins or vascular invasion at the periphery of the tumor. In their study, the authors found three cases showed recurrences out of 41 patients. However, in this study, the authors have not depicted any specific histological parameter, to be seen in those cases with recurrence. 
In our study, ethnicity and use of tobacco status has not been recorded. The mean age in our study was 45.5 years, which is comparable to other studies. (Guntupalli et al 43 yrs; Ng et al 44.6 yrs)
There is limited data on whether STUMP tumors are hormone sensitive. 
Perhaps the most important feature in assessing these tumors is recognition of CTCN. Bell et al characterized it by an abrupt transition from viable cells to necrotic cells without an interposed zone of granulation or hyalinised tissue between viable and nonviable cells. Within the necrotic foci, coagulative "ghost" outlines of cells could be seen with preservation of the nuclei to the extent that hyperchromasia and pleomorphism could be noted. Preservation of vascular structures in necrosis/peritheliomatous arrangement is seen. Hemorrhage was uncommon in coagulative necrosis.
A band of paucicellular hyaline collagen seen in between viable and nonviable cells
Uniform pale outline of tissue including blood vessels is seen. The overall pattern of hyaline necrosis suggested previous infarction with 'walling off' or reparative fibrosis.
Hemorrhage can be seen (unlike CTCN) and extensive hyalinization causing thickening of a vessel wall is seen.
The third and less common type of necrosis described is -ulcerative necrosis. This was found in submucosal smooth muscle tumors and was associated with inflammatory reaction on the surface.
Individual tumor cell necrosis does not find much mention in the literature. However, according to Bell et al, individual cell necrosis or pyknosis is seen in all types of smooth muscle tumors and designation of necrosis is not warranted.
In our opinion, it is sometimes difficult to distinguish between hyaline necrosis and CTCN. Early phase of hyaline necrosis may not show collagen deposition, and may show abrupt transition between the viable and nonviable tumor cells. We then found preservation of blood vessels and peritheliomatous tumor cells in CTCN a reliable point in their distinction. Gao et al have suggested that use of trichrome stain may be useful in this separation.
A brief mention about presence of atypical mitoses is required. Bizarre leiomyoma is generally defined as 'a leiomyoma containing giant cells with pleomorphic nuclei and little or no mitotic activity.' Another description in an authoritative book mentions ' a leiomyoma in which pleomorphic tumor giant cells are usually focal and mitoses are often entirely absent; by definition MFs cannot be numerous and abnormal mitotic figures absent. 
In our study cases, 5 cases are labeled as symplastic leiomyoma, 4 of which had less than 1 mitosis /10hpf, and one showed mitoses of 2-3/10hpf. However, one case showed atypical mitotic figures. We still made a diagnosis of symplastic leiomyoma. Is presence of atypical mitotic figures not consistent with this diagnosis?
Interestingly, Przbora noted atypical mitoses in two of their cases. , Downs et al in their study of 24 bizarre leiomyomas, state that they could not exclude atypical mitotic figures in three of their cases. Moreover, abnormal mitotic figures have been depicted in mitotically active leiomyomas. 
In two cases, after asking for and studying more sections we offered a diagnosis of leiomyosarcoma underlining the importance of sampling. [Table 3] We came across hyaline necrosis in two cases.
The body of evidence of diagnosis, natural history, clinical course and optimal management of STUMP remains problematic. Ng et al reported no recurrences in 18 out of 18 cases of STUMP while Guntupalli  showed 3 out of 41 cases of recurrences. Peters WA et al showed 27% of patients had recurrences (but 75% of those who recurred experienced long term survival). Hence, overall, the risk of recurrence appears low and management advice of expectant management sounds reasonable.
A significant difference in staining intensity for ki 67 between leiomyosarcoma and STUMP has been reported.  Other investigators have suggested STUMP that express p16 and p53 may have a greater propensity to recur. 
It is also to be noted that Bell et al. and the literature in general have emphasized that these definitions and groups described above apply to uterine smooth muscle tumors of usual type. The myxoid and epithelioid variety of tumors is excluded.  Hence, practically, in such tumors, one may tend to overcall a tumor as STUMP tumor, which may not be unjustified.
| Conclusions|| |
- A diagnosis of uterine STUMP is a heterogeneous group and encompass entities such as STUMP, AL, AL with low risk of recurrence, AL with low malignant potential. These continue to represent gray areas in diagnostic pathology.
- While we should continue to use these, keeping the sanctity of subtypes mentioned in the literature, the gynecological oncologists are looking for a unifying diagnosis, and low interobserver variability.
- Most behave in a benign fashion, and follow-up without adjuvant therapy (expectant management) is currently recommended.
- Critical evaluation of CTCN is crucial.
- We feel individual tumor cell necrosis should be mentioned. Probably it is part of infarction type necrosis, none the less, should prompt further sampling.
- Correlation of histology with imaging is mandatory; especially if necrosis is not seen on biopsy and is seen on imaging.
- Use of Ki67 and p53 may help stratify the diagnoses on a larger sample size
- Follow-up remains a challenge in our setting.
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Kedar K Deodhar
Department of Pathology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai - 400 012
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
[Table 1], [Table 2], [Table 3]