Fig. 7.1
Macroscopic features of squamous cell carcinoma of the uterine cervix (most specimens are opened at the 12 o’clock position with scissors). (a) Radical hysterectomy after previous conization procedure. Note the ulceration within the cervix (asterisk). There is no visible tumor, so the ecto- and endocervix should be completely processed. (b) Radical hysterectomy (total mesometrial resection (TMMR) technique) with a small ulcerated tumor between 3 and 10 o’clock. (c) Large polypoid exophytic carcinoma with circumferential growth. (d) Large ulcerated carcinoma involving the whole circumference of the cervix. (e) Ectocervix with a small polypoid and ulcerated carcinoma between 6 and 12 o’clock. (f) Frontal cut of a radical hysterectomy (same case as pictured in (e) confined to the cervix. (g) Radical hysterectomy (TMMR technique) with a large mostly endophytic growth tumor (barrel-shaped) with smooth outer appearance of the ectocervix. (h) Radical hysterectomy (TMMR technique) in pregnancy and small carcinoma confined to the cervix. (i) Magnetic resonance imaging (MRI) of a large cervical SCC (Courtesy of Dr. Gudrun Borte, University Hospital of Leipzig). (j) Radical hysterectomy (TMMR technique) from the same patient pictured in (i) with a bulky ulcerated carcinoma
Regardless of screening strategies, about one fourth of patients present with advanced stage disease (FIGO ≥IIIA; [32, 91]). In this cohort, bleeding disturbances may become more continuous and may be accompanied by malodorous discharge. Because of its embryonal development, cervical cancer preferentially grows within the parametria/mesometria [36], which causes obstruction of the ureter by narrowing the lumen or direct infiltration resulting in flank pain or even renal failure. Infiltration of the pelvic tissues may provoke pain, frequently within the pelvis or leg, caused by organ obstruction, local inflammatory response, and infiltration of the perineurium or lumbosacral nerve ganglia. Additionally, pedal edema may occur due to lymphatic and venous obstruction and may indicate pelvic lymph node involvement.
Macroscopic Appearances (Fig. 7.1)
SCC may be located in the ecto- or endocervix. The principal macroscopic appearance is that of an exophytic or endophytic growth, with or without superficial ulceration. A primarily endocervical localization may produce a barrel-shaped appearance. Deep stromal invasion results in a hard consistency. In locally advanced cases, infiltration of the resected vaginal cuff may be present, and involvement of the adjacent para-/mesometrial tissue may be palpable. Macroscopically, there are no differences between the different histological types (adenocarcinoma versus squamous cell versus neuroendocrine carcinomas).
Microscopic Appearances
Histopathological Tumor Types
There are several variants of SCC of the uterine cervix [103, 113], some of which cause diagnostic challenges or show prognostic importance as discussed under individual subheadings below. The WHO classification defines the following subtypes of SCC [108]:
Keratinizing SCC
Non-keratinizing SCC
Papillary SCC
Basaloid SCC
Warty-type SCC
Verrucous SCC
Squamotransitional SCC
Papillary SCC
Lymphoepithelioma-like SCC
The International Collaboration on Cancer Reporting (ICCR) recommends that subtyping of cervical SCC is not required, as this does not influence treatment decisions [50].
Non-keratinizing SCC
Non-keratinizing SCCs (7.2) are the most common, composed of polygonal squamous cells without keratinization [108]. The cells grow in anastomosing cords or nests with a round, angulated, or spiky appearance. The cells are oval to polygonal, often with an eosinophilic cytoplasm; cell borders may be indistinct and are sometimes prominent with intercellular bridges. The nuclei may be uniform with a coarse and granular chromatin with or without nucleoli but may display considerable pleomorphism. The mitotic count is variable. As seen in other carcinomas and in adenocarcinoma of the uterine cervix [96], there exist different patterns of invasion [40, 47] which may represent different degrees of tumor cell dissociation (Fig. 7.3). There is typically a peritumoral stromal response, which may vary with different invasive patterns. Many tumors are accompanied by peritumoral inflammatory response (Figs. 7.2 and 7.3), which is more often seen in tumors with a fingerlike pattern of infiltration. Tumors with spray-like pattern of invasion on the other hand may show a strong peritumoral desmoplastic response (Figs. 7.2 and 7.3). The cell size is variable; earlier classification separated a large cell non-keratinizing SCC from a small cell variant [93]. The use of the term “small cell” non-keratinizing SCC in the pathology report is not recommended [108] to avoid confusion with small cell neuroendocrine carcinoma, a subtype associated with very poor prognosis [29]. In rare instances SCC may be mixed with a true small cell neuroendocrine carcinoma [29, 40]; the majority of mixed neuroendocrine carcinomas being associated with adenocarcinoma [29, 40].
Fig. 7.2
Morphological spectrum of non-keratinizing and keratinizing squamous cell carcinoma (SCC). (a) Colposcopy-guided biopsy containing a non-keratinizing SCC, (b) low-power view of a non-keratinizing SCC with fingerlike pattern of invasion and strong peritumoral desmoplastic reaction and weak inflammatory response, (c) high-power view of a non-keratinizing SCC with fingerlike pattern of invasion without peritumoral desmoplastic reaction but moderate inflammatory response, (d) low-power view of a non-keratinizing SCC with mixed fingerlike and spray-like patterns of invasion and without peritumoral inflammatory response but strong desmoplastic reaction, (e) high-power view of a non-keratinizing SCC with peritumoral retraction artifacts, (f) inked resection margin of a hysterectomy specimen. The distance between the leading edge of the tumor and the margin is marked by a double-headed arrow; (g) example of keratinizing form of high-grade intraepithelial lesion involving an endocervical gland (h) keratinizing SCC
Fig. 7.3
Growth patterns and peritumoral stromal alterations (stromal remodeling) of squamous cell carcinoma of the uterine cervix: (a) closed or pushing pattern of invasion with cohesive tumor growth with well-delineated but infiltrating borders and “pushing” margins with a weak peritumoral inflammatory response, (b) fingerlike growth pattern with trabecular tumor growth in solid cords and cell groups with rounded edges, accompanied by a strong peritumoral inflammatory response with lymphocytes. Note that the inflammatory response is peritumoral and not intratumoral as seen in lymphoepithelioma-like carcinomas (see Fig. 7.7), (c) spray-like pattern with tumor growth in very small groups of infiltrating cells with sharpened tips with a strong peritumoral desmoplastic stromal reaction but no inflammatory response
On occasion, non-keratinizing SCC may show a deceptive “CIN 3-like” pattern, comprising islands of atypical squamous epithelial cells with well-circumscribed edges and a central luminal space filled with debris or occasionally keratin [3] (Fig. 7.4). These may be misdiagnosed as CIN 3 involving crypts. Features useful in distinction are the extent beyond the crypt field in the adjacent cervix, the presence of usual infiltration in other areas, and/or the presence of a mass lesion. The distinction is important as under-recognition can result in undertreatment, and there has been a report of a case with an unusual and late pattern of recurrence [121].
Fig. 7.4
(a) SCC invading in a pattern resembling CIN 3: the invasive islands have rounded edges with peripheral palisading but extend deeper than the crypt field, (b) conventional invasion comprising cells with eosinophilic cytoplasm forming islands with irregular edges is also present
Since non-keratinizing SCC represents the commonest histological subtype of cervical SCC and shows no special morphology, in the authors’ opinions, this may be designated as SCC, not otherwise specified (NOS).
Keratinizing SCC
Keratinizing SCC (Fig. 7.2h) is less common than its non-keratinizing counterpart. This is characterized by morphological evidence of keratinization in the form of keratin pearls or intracytoplasmic keratinization. The cells and nuclei are usually larger and hyperchromatic with a coarse chromatin and lack easily seen nucleoli. There may be a correlation with ectocervical localization and the keratinizing form of CIN (Fig. 7.2g). It is possible, as in vulval carcinomas, that keratinization may indicate HPV-independent SCC [12].
Basaloid SCC
Basaloid SCC (Fig. 7.5) is HPV related [30] and composed of nests of immature small oval cells with scanty cytoplasm and dark nuclei, resembling cells seen in CIN 3 and showing brisk mitotic activity. Some cytoplasmic keratinization may occur but keratin pearls are not seen. The majority of tumors demonstrate geographical or comedo-like necrosis. Because of its aggressive behavior [30], the WHO classification considers basaloid SCC as a high-grade tumor (grade 3; [108]). Immunohistochemically, basaloid SCCs are positive for p16, cytokeratin 34βE12, and, sometimes, neuroendocrine markers, but negative for TTF-1 [30, 68]. The main differential diagnosis is with small cell neuroendocrine carcinoma (SCNEC). Immunohistochemically, SCNEC shows positivity for p16, neuroendocrine markers, and TTF-1 but is negative for cytokeratin 34βE12 [29, 30, 39, 40, 68].
Fig. 7.5
Basaloid neoplasms of the uterine cervix (a, b) adenoid basal cell carcinoma: proliferation of cords and bands of bland-appearing basaloid cells with central gland formation. (c, d) Basaloid squamous cell carcinoma: nests of immature basal-type cells with peripheral palisading accompanied by comedo-like necrosis, some pleomorphic cells (arrows) and focal keratinization (asterisks)
Adenoid basal carcinoma (ABC; Fig. 7.5) of the cervix is composed of small, monomorphic, basaloid cells that are p16 positive, forming rounded nests or cords. Some adenoid formations may be seen containing necrotic debris. Contrary to basaloid SCC, there is no geographic/comedo necrosis and low mitotic activity. The tumors may be associated with another carcinoma subtype. Pure ABCs have a favorable prognosis [5], while mixed tumors share the prognostic outcome of the non-ABC component.
Verrucous SCC
Verrucous SCC is a distinct type of highly differentiated SCC which is similar morphologically to its much more common vulval counterpart. This has a favorable prognosis [17, 31] and is distinguished from keratinizing SCC by the absence of nuclear atypia and destructive stromal invasion. The tumor characteristically shows a pushing border and a hyperkeratotic undulating surface, resembling condyloma and condylomatous SCC (see next).
Warty/Condylomatous SCC
Squamotransitional/Transitional and Papillary SCC
Squamotransitional/transitional SCCs have a papillary architecture with fibrovascular cores covered by cells resembling CIN 3/HSIL [56, 57]. Rare cases of pure transitional cell carcinoma have been reported [1] that are indistinguishable from their urological counterparts. However, most of these tumors represent malignant squamous elements. The evidence relating transitional cell metaplasia of the uterine cervix [83, 119] and squamotransitional SCC is controversial.
Papillary SCCs consist of fibrovascular papillae with different thickness, covered by an epithelium representing CIN 3-like morphology. They differ from warty SCC by the lack of Bowenoid morphology and from squamotransitional SCC by their more overt squamous differentiation.
Squamotransitional and papillary SCC can be diagnostically challenging in small biopsies because invasion may not be seen within the stroma included in the slender fibrovascular cores present in biopsies, and sampling of deeper tissues is precluded by the papillary surface of the tumor (Fig. 7.6). The typical appearance with papillary architecture and small fibrovascular cores covered by CIN 3-like squamous epithelium favors the diagnosis of this cancer subtype, which should be raised even if stromal invasion is not seen. Correlation with the clinical appearance of a visible (papillary-exophytic) tumor of the uterine cervix is helpful. In doubtful cases re-biopsy or even conization may be necessary to establish the diagnosis of invasive carcinoma [56, 82]. Regardless of the sometimes superficial infiltration of squamotransitional and papillary SCC, the tumor should be staged according to the whole tumor size [2]. Because of its rarity, the prognostic impact of squamotransitional and papillary SCC is controversial [2, 22].
Fig. 7.6
Papillary squamous cell carcinoma of the uterine cervix. Cervical curettage specimen containing fragmented tissue 1.5 cm in diameter from a 69-year-old postmenopausal patient. The radical hysterectomy specimen contained a 2.4 × 1.9 × 2 cm well-differentiated papillary squamous cell carcinoma staged pT2b pN0 (0/36) MX L0 V0 Pn0, R0. (a) Fragmented tumor tissue with thin papillae resembling papillary noninvasive urothelial carcinoma. (b, c) Papillae covered by epithelium similar to high-grade squamous intraepithelial lesion. No invasion can be seen
In the authors’ opinion, squamotransitional and papillary SCC should be regarded as a single category of (non-keratinizing) SCC with a papillary growth pattern, for several reasons. Firstly, both tumors morphologically differ only by the presence/degree of squamous differentiation, which is almost always CIN 3-like and challenging to grade; furthermore it may be more relevant to grade the deeper infiltrative component. Secondly, mixed forms have been reported, and it is likely that these terms are used interchangeably [56]. Thirdly, they share HPV 16-mediated etiology with other types of SCC [6, 22]. Fourthly, they share diagnostic difficulties in relation to sampling and recognition as above; a common term would encourage recognition and alert the pathologist and clinician. Fifthly, this would remove the potential for confusion with origin from the urogenital tract. Finally and most importantly, their separation has no therapeutic implications.
Lymphoepithelioma-Like SCC
Lymphoepithelioma-like SCC (Fig. 7.7) bears a striking resemblance to its nasopharyngeal counterpart. This is a very rare tumor with high-grade morphology but a more favorable prognosis than keratinizing SCC, NOS [72, 110]. It is composed of ill-defined islands of undifferentiated squamous cells, associated with a marked lymphocytic, sometimes eosinophil-rich, infiltrate surrounding and infiltrating the tumor islands [80, 98]. The tumor cells have poorly defined cell borders, eosinophilic cytoplasm, and uniform vesicular nuclei with prominent nucleoli. The tumors are HPV related with no association to EBV infection [13, 98].
Fig. 7.7
Lymphoepithelioma-like carcinoma of the uterine cervix. (a) Poorly delineated islands of poorly differentiated squamous cells, accompanied by dense lymphocytic infiltration peri- and intratumoral (compare to Fig. 7.3b, non-keratinizing squamous cell carcinoma with strong peritumoral inflammatory response). (b) Strong p16 immunostaining of the tumor cells. (c) The lymphocytic infiltrate shows positive staining for leukocyte common antigen (LCA)
Main Differential Diagnoses of SCC
Some of the lesions that may cause diagnostic problems in colposcopy-guided biopsies are listed below. Useful immunohistochemical markers in this setting are summarized in Table 7.1.
Cytokeratins | PAX-8 | p16 | GATA-3 | p63 | LCA | Desmin | Myogenin | HMB-45, melan-A | |
|---|---|---|---|---|---|---|---|---|---|
Tumors with a “squamous appearance” | |||||||||
SCC non-keratinizing | +ve for: CK 7, CK 5/6, CK 17, pan-CK | + | +a | −/+d | + | − | − | − | − |
TCC (bladder) | +ve for: pan-CKs CK 7, CK 20, CK 5/6 | + | +/− | + | + | − | − | − | − |
AC and ASQ G3 | +ve | + | + | − | − | − | − | − | − |
Glassy cell CX | +ve | + | + | − | − | − | − | − | − |
Large cell NECb | +/− | ?? | + | − | −/+ | − | − | − | − |
Malignant melanomac | +/− (CK 7 –ve) | − | +/− | − | − | − | − | − | + |
ETT | + (esp. CK 18) | ?? | − | + | + | − | − | − | − |
Ductal breast cancerd | +ve (CK 18) | − | −/+ | +/− | −/+ | − | − | − | − |
Tumors with a small round blue cell appearance | |||||||||
Lymphoma | − | − | − | − | − | − | − | − | − |
Non-keratinizing SCCe | +ve, see above | + | + | −/+d | + | − | − | − | − |
Small cell NECb | −/+ | +/− | + | − | − | − | − | − | − |
Embryonal RMS | − | ?? | − | − | − | − | + (cytoplasmic) | + (nuclear) | − |
Lobular breast cancerd | + | − | −/+ | +/− | − | − | − | − | − |
Lesions Mimicking Invasive Disease (Fig. 7.8)
Tangential cutting of (immature) metaplastic squamous epithelium and decidual change of cervical stroma. Both lesions have no nuclear atypia and low levels of mitotic activity. p16 is negative and decidual cells are positive for vimentin.
Squamous epithelial hyperplasia with pseudoinvasion is a lesion that most commonly occurs within the ectocervix and represents a reactive change; this harbors no nuclear atypia, shows low mitotic activity, and is negative for p16.
Placental site nodule (PSN) may mimic a squamous lesion because of its eosinophilic appearance and sometimes marked (regressive) nuclear pleomorphism. The intermediate trophoblastic cells of PSN are positive for CK 8/18 and GATA-3 as well as HPL, whereas CIN and SCC are negative. p16 may show focal patchy positivity in PSN as opposed to block staining.
CIN 3 with extensive endocervical gland involvement can be mimicked by a rare but challenging pattern of invasion in SCC and is discussed in the paragraph of the morphologic appearance of non-keratinizing SCC (see above).
Fig. 7.8
Morphological mimics of early stromal invasion in SCC, (a) pseudoinvasion by elongated and thickened squamous epithelium protruding into the cervical stroma. Note the well-defined basal cell layer and the absence of cellular pleomorphism, (b) pseudoinvasion due to reserve cell hyperplasia and immature squamous cell metaplasia within an endocervical crypt showing squamous metaplasia, (c) extensive involvement of endocervical glands by CIN 3 mimicking invasive disease; note the round and smooth outline of the squamous islands without any stromal response, (d) higher magnification of c shows residual glandular epithelium at the tip of the endocervical gland, (e–g) stromal decidualization in pregnancy mimicking invasive SCC; decidualized cells are negative for p16 but positive for vimentin, (h) placental site nodule mimicking fragments of non-keratinizing SCC
Differential Diagnosis of Invasive Lesions
Transitional cell carcinoma (TCC) of the urinary bladder may invade the uterine cervix and may mimic non-keratinizing SCC. Without knowledge of clinical history, the diagnosis may be challenging. TCCs are positive for p63 and GATA-3 and may show p16 expression (which is in general not diffuse and strong as in cervical HPV-related SCC). Low molecular weight cytokeratins (e.g., CK 34β-E12) may not be helpful because these are positive in SCC.
Poorly differentiated adeno- or adenosquamous carcinoma of the uterine cervix can be distinguished by its negativity for p63. Sometimes adenocarcinomas demonstrate PAS-positive secretions; very focal PAS positivity may occur in SCC.
Glassy cell carcinoma (Fig. 7.9) is a poorly differentiated variant of adenosquamous carcinoma characterized by cells with sharp cytoplasmic margins, eosinophilic cytoplasm with “ground-glass” appearance, and large nuclei containing prominent eosinophilic nucleoli. Many tumors show a dense peritumoral inflammatory response containing numerous eosinophils, which is uncommon in SCC. The tumors are positive for p16, cytokeratins, and MUC-2 but negative for p63.
Large cell neuroendocrine carcinomas (Fig. 7.10) have a diffuse, organoid trabecular, or cord-like pattern, similar to the fingerlike pattern of invasion of SCC, and are composed of cells that have abundant eosinophilic cytoplasm, large nuclei, and prominent nucleoli. The majority of tumors show areas of dirty tumor necrosis within the infiltrating tumor cell nests, a pattern not generally seen in SCC. The majority, but not all, of tumors express neuroendocrine markers and may be positive for p63 [74]. TTF-1 is not uncommonly positive.
Malignant melanoma (MM) should always be included in the differential diagnosis in any unusual looking tumor, especially those with prominent eosinophilic nucleoli. Primary MM within the cervix is exceedingly rare. The presence of melanin pigment and immunostains for CK 7, p16, and melanocytic markers may aid diagnosis.
Gestational trophoblastic disease may involve the uterine cervix, and particularly epithelioid trophoblastic tumor (ETT) may mimic SCC (Fig. 7.11). ETT is characterized by islands of relatively monomorphic cells with generally abundant eosinophilic cytoplasm and areas of eosinophilic geographic necrosis [69]. Among the tumor cells, there are small-sized vessels with normal-appearing vessel walls. ETT is positive for cytokeratins, especially CK 18 and GATA-3, HPL, inhibin, and cyclin E, but is negative for p16 and neuroendocrine and melanocytic markers. It should be noted that p63 stains positive in SCC as well as ETT and is therefore not useful in distinction. The Ki-67 labeling index is about 10–15% and tends to be much higher in SCC.
Metastatic ductal carcinoma of the breast may mimic SCC [89]. Clinical data and the use of GATA-3, mammaglobin, and GCDFP-15 may be helpful. Some breast cancers are positive for p16 [102] and for p63 [112].
Stratified mucin-producing carcinoma (“invasive SMILE”) represents a recently described variant of adenocarcinoma [62, 87] that may provoke some differential diagnostic problems with glassy cell and poorly differentiated SCC. The tumor cells infiltrate the cervical stroma in the form of nests of stratified, columnar cells with bland, round to ovoid nuclei without prominent nucleoli. A distinct pattern of peripheral nuclear palisading is present in the majority of cases [62]. Some neutrophilic and eosinophilic infiltration may surround the infiltrative tumor nests. Mucicarmine and/or PAS staining may highlight mucin production. Morphologic evidence of squamous differentiation in the form of keratinization or intercellular bridges is not present. Tumor cells stain diffusely positive with p16.
Fig. 7.9
Glassy cell carcinoma. (a, b) Infiltrating cords and bands of large cells with prominent nucleoli and basophilic pale cytoplasm. Peri- and intratumoral infiltrate rich in eosinophils. (c, d) Tumor cells are positive for CK 5/6 with peripheral staining and show positivity for p16
Fig. 7.10
Neuroendocrine carcinomas of the uterine cervix, (a, b) large cell neuroendocrine carcinoma with large islands of cells with scanty cytoplasm but pleomorphic nuclei with some nuclear molding. Within the tumor cell islands, there is comedo-like necrosis, (c) positive staining for p16 in a large cell neuroendocrine carcinoma, (d) small cell neuroendocrine carcinoma composed of small cells with scanty cytoplasm infiltrating the endocervical stroma. The inset shows positive staining for p16
Fig. 7.11
Gestational trophoblastic disease involving the cervix, (a, b) gestational choriocarcinoma within the endocervical stroma surrounded by hemorrhagic necrosis. Note the syncytiotrophoblastic giant cells (c, d) epithelioid trophoblastic tumor mimicking non-keratinizing SCC with infiltrative islands of monomorphic cells, surrounded by pale eosinophilic necrosis. Tumor cells are monomorphic without mitotic figures. There is no peritumoral stromal remodeling
Tumors with a Small Round Blue Cell Appearance
As mentioned above, non-keratinizing SCC may be composed of small cells and should not be misinterpreted as the following lesions. For immunohistochemical differential diagnoses, see Table 7.1.
Small cell neuroendocrine carcinomas (Fig. 7.12) may show small areas of dirty tumor necrosis within the infiltrating tumor cell nests. The majority, but not all, of tumors express neuroendocrine markers, with CD56 and synaptophysin being the most sensitive. p63 is almost always negative. TTF-1 is not uncommonly positive and does not help to exclude a pulmonary primary.
Lymphomas may primarily or secondarily occur within the cervix [59] and should be included within the differential diagnosis. They are negative for epithelial markers and p16, but positive for lymphoid markers.
Embryonal rhabdomyosarcoma affects women in their second and third decades. These present as polypoid lesions with small round or spindle cells with hyperchromatic dense nuclei. The cells typically show subepithelial condensation (cambium layer). Tumor cells are positive for vimentin and myogenic markers but negative for cytokeratins and p16.
Rarely metastatic lobular breast cancer may involve the uterine cervix with a small round blue cell appearance [89]. As mentioned above, clinical data and the use of GATA-3, mammaglobin, E-cadherin and GCDFP-15 may be helpful in the differential diagnosis.
Fig. 7.12
Mixed squamous and small cell neuroendocrine carcinoma of the uterine cervix. (a) Foci of squamous epithelium within infiltrating small cells with dark blue nuclei and scanty cytoplasm, (b) both components stain positive for p16
Diagnostic Immunohistochemistry in SCC
There is a wide range of low and high molecular weight cytokeratin (CK) expression in SCC [105]. Broad-spectrum cytokeratins, such as AE 1/3, MNF 116, and Pan Plus as well as CK 5/6, CK 7, and CK 17, are positive in SCC [11]. Nearly all SCCs are positive for p40 and p63 [118] and for p16 [86]. The majority, but not all, of SCCs are positive for the Müllerian marker PAX-8 [63]. The main differential diagnoses and helpful immunohistochemical stains are summarized in Table 7.1.
Diagnosis and Measurement of Superficially Invasive Squamous Cell Carcinoma
Invasive squamous cell carcinoma (SCC) is a lethal disease with a high death toll worldwide, justifying its treatment by radical measures. Cervical screening, designed to prevent cervical cancer through detection of precancerous changes, leads to detection of minimally invasive cases, before they are symptomatic or clinically apparent, which may not require radical treatment. Various terms have been used in the past to describe such cases including “early stromal invasion” and “microinvasive carcinoma,” and there have been many different staging proposals. Despite these attempts various terms have been used imprecisely and inconsistently, and the measurement and staging of low-volume disease continues to be problematic, with potential for overtreatment and undertreatment of individual cases. The use of imprecise terms is strongly discouraged in favor of universally recommended terms and staging systems [34].
Recently there has been a concerted effort to unify the terminology and reporting parameters of all HPV-related lower anogenital tract squamous lesions, in recognition that these have similar biology and management implications [19]. This project, termed the Lower Anogenital Squamous Terminology (LAST) project, included a working group that focused on defining criteria for superficially invasive squamous cell carcinoma (SISCCA), aiming to clearly delineate cases that can be managed conservatively from those requiring radical treatment. The group identified 1863 publications and drew data from 194, most of which related to cervical disease. They concluded that the definition of SISCCA differed for different anogenital sites and that for the cervix SISCCA corresponds to FIGO stage IA1. The presence of vascular invasion and the pattern of invasion do not influence the FIGO stage of cervical carcinoma. Conservative options are not recommended for FIGO stage IA2 and beyond.
Diagnosis of Stromal Invasion
In low-volume disease, stromal invasion may be obvious, but is sometimes subtle. Features that may be helpful in identifying stromal invasion are listed below:
Small, angulated buds of atypical squamous epithelial cells with a more differentiated or “hypermature” appearance (Fig. 7.13); this phenomenon, termed “paradoxical” differentiation, is believed to result through an epithelial-mesenchymal transition(EMT)-like mechanism whereby invading cells acquire mesenchymal phenotypic and functional alterations that facilitate invasiveness. Immunohistochemistry for EMT-related markers such as cyclin D1 has been put forward to facilitate diagnosis of stromal invasion but must be interpreted with caution.
Invasive buds may be seen in continuity with surface epithelium or gland crypts involved by high-grade cervical intraepithelial neoplasia/squamous intraepithelial lesion (CIN/SIL), and these may be single or multiple.
Alternatively they may be detached from any epithelium, at least in the plane of sectioning, and seen as discrete islands.
Irrespective of whether they are attached or separate, their “hypermature” appearance is characterized by more abundant eosinophilic cytoplasm than that in the cells within the CIN/SIL from which they arise.
Nuclei are paler than those of the neighboring high-grade CIN/SIL, tend to be more vesicular and pleomorphic, and may contain nucleoli; in some cases nuclei may appear to be blander than those in the adjacent CIN/SIL.
Unlike the orderly basal palisade of high-grade CIN/SIL, these islands exhibit altered and haphazard nuclear polarity.
Absence or loss of a sharply defined surrounding basement membrane may facilitate recognition; this may be aided by immunohistochemistry for laminin or collagen IV.
Dyskeratosis may be present.
Characteristically there is a stromal reaction, which may be inflammatory, edematous, or desmoplastic; this may be difficult to discern if the adjacent CIN/SIL is also surrounded by an intense inflammatory reaction.
There are different patterns of stromal invasion, such as a “spray bud” pattern (which comprises tiny nests of hypermature squamous cells), a confluent pattern, and a pattern with invasive “tongues”; these patterns do not independently influence prognosis over and above invasive depth.
Fig. 7.13
Stromal invasion characterized by “paradoxical maturation”; cells with abundant eosinophilic cytoplasm form nests with irregular edges and a surrounding inflammatory reaction; adjacent noninvasive epithelium shows regular borders and consists of cells with scanty cytoplasm, a basaloid appearance, and darker, monotonous nuclei
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