Differential Diagnosis

An enlarging lesion at the site of a previously treated tumor likely represents renewed growth of an incompletely eradicated initial tumor rather than the development of a new pathologic entity. Exceptions are infrequent but those in the following list need to be considered:

These alternative diagnoses must be excluded before prognosis is addressed and therapy is chosen. Neurodiagnostic imaging usually permits accurate prediction of the diagnosis. Generally, recurrent tumors have imaging features similar to those of the original lesion. A recurrent malignant glioma will likely have central low intensity, rim enhancement, and hypointense surround on enhanced T1-weighted magnetic resonance imaging (MRI). In some cases, however, attention to subtle differences may be required: a more spherical, sharply demarcated shape may suggest abscess rather than recurrent malignant glioma; and a diffuse, irregularly marginated pattern of surrounding edema may indicate radiation necrosis rather than recurrent tumor.

Two scenarios, malignant progression and radiation effects, often pose particular diagnostic difficulty. In each case, alternative diagnoses are often impossible to distinguish using current imaging modalities alone. Thus, biopsy for histologic evaluation and confirmation may be necessary.

Malignant Progression

The first scenario is the renewed growth of a low grade tumor. When low grade gliomas regrow after therapy, approximately half remain nonanaplastic, but the other 50% have progressed to a more malignant form.³ Molecular analyses have delineated genetic correlates of this progression.⁴ Enlarging low grade tumors will usually resemble the original tumor on imaging studies. When progression in grade has occurred, the new tumor may also resemble the old one, especially if the original tumor enhanced with contrast. Enhancement is highly predictive of likelihood of recurrence; low grade enhancing tumors are 6–8 times more likely to recur than nonenhancing ones.³ Most commonly, new malignant growth in a previously nonenhancing glioma enhances and thus is readily identified. In one study, only 30% (16/42) of low-grade tumors enhanced initially, but 92% (22/24) enhanced at recurrence.³ Occasionally, an enlarging malignant focus may not enhance. It might, however, be apparent as a region of hypermetabolism on a 2-deoxyglucose or 11-C methionine PET study, or have an increased rate of enhancement on a dynamic MRI scan, increased activity on a dual-isotope, single-photon emission computerized tomogram (SPECT), or increased choline signal on magnetic resonance spectroscopy (MRS).^5–7 The differential specificity of each of these new modalities is approximately 80% to 90%. Usually, however, histologic analysis after biopsy or resection is warranted to verify malignant transformation.⁸

Radiation Effects

The second scenario that causes diagnostic difficulty is renewed enlargement of a tumor mass following radiation. Often, CT and MR imaging inadequately distinguish recurrent tumor from radiation-induced enlargement. Usually only large, very malignant tumors grow sufficiently fast to show significant enlargement during, or within 3 months of completing, a course of radiation. When this does occur, the prognosis is particularly poor.⁹

Radiation can cause tumor enlargement in three ways:¹ through an early reaction, occurring during or shortly after irradiation, which is likely to be edema;² through an early delayed reaction arising a few weeks to a few months after radiation which involves edema and demyelination; and³ through a late delayed reaction that occurs 6 to 24 months after radiation and reflects radiation-induced necrosis.¹⁰ Regional teletherapy to a dose of 60 Gy is the current standard radiation treatment for most gliomas.¹¹ Although these doses have a low risk of inducing radiation necrosis, regional early and early delayed effects are relatively common. In most cases, tissue swelling represents edema and is transient. Acute symptoms from early and early delayed effects of radiation usually respond quickly to a short course of corticosteroids. The low density, T1 hypointense, T2 hyperintense regions of edema correspond to the area irradiated. Chronically, these volumes of brain will demonstrate parenchymal atrophy, enlargement of subarachnoid spaces, and ex vacuo ventricular dilatation. Dementia with apathy, inanition, and memory loss and decline in fine motor control are the clinical correlates. In the absence of new tumor growth, enhancement on CT and MRI beyond the initial resection margin is infrequent; when it does occur, it is patchy, irregularly marginated, and it can be distinguished from the more focal appearance of recurrent tumor.

In contrast, the late delayed effect of radiation-induced necrosis appears at about the time malignant tumors might be expected to recur.¹² It is thus more likely to be mistaken for recurrent tumor growth. The risk of radiation necrosis increases with the volume of tissue treated, the dose delivered, and the fraction size.¹³ Radiation necrosis following fractionated treatment to doses less than 70 Gy is rare, but it is much more common following brachytherapy or radiosurgery, which deliver high doses of radiation to relatively small volumes over a short time period.^12,14,15 A common protocol for brachytherapy is a 50- to 60-Gy boost (to 60 Gy of regional external beam radiotherapy) to a 0- to 5-cm tumor delivered over approximately 1 week. The radiosurgery equivalent is a 10- to 20-Gy boost to a 0- to 3-cm diameter tumor delivered in less than 1 hour.¹⁶ Necrosis is radiographically and pathologically evident in almost all cases and symptomatic in about half.

Whether it arises from higher doses of fractionated radiotherapy, brachytherapy, or radiosurgery, radiation necrosis is often difficult to distinguish from recurrent tumor. It forms a ring contrast-enhancing mass that resembles a malignant tumor. It has a CT hypodense, T1 hypointense, T2 hyperintense center; an enhancing annular region; and a hypodense, T1 hypointense, T2 hyperintense surround. The surround corresponds to edema that strikingly radiates along white matter tracts. The similarity of this appearance to that of recurrent tumors and the time course of its occurrence frequently necessitates additional measures to differentiate radiation-induced necrosis from recurrent tumor. A variety of functional neurodiagnostic imaging techniques attempt to distinguish between these two possibilities. These include PET scans, SPECT studies, cerebral blood volume mapping, and MRS. Regions of high activity are thought to distinguish recurrent tumor from relatively metabolically inactive and hypovascular radiation necrosis.⁶ Although specificity in differentiating tumor from radiation necrosis of up to 100% has been claimed, in many cases these studies are inconclusive and the diagnosis is revealed either by the clinical course or by analysis of a pathology specimen.

When an enlarging mass, which is either recurrent tumor, radiation necrosis, or both, becomes symptomatic, corticosteroid therapy is required.¹⁷ Up to half the patients receiving brachytherapy and radiosurgery for a malignant glioma develop symptoms that either prove refractory to corticosteroids or require debilitating long-term steroid use.^12,18,19 Surgery for resection of an enlarging, symptomatic mass is needed in 20% to 40% of cases following brachytherapy or radiosurgery of a malignant glioma. At reoperation for presumed radiation necrosis following focal radiation treatment of a malignant glioma, necrosis without tumor was found in 5% of cases, tumor alone in 29%, and a mixture of radiation necrosis and tumor in 66%.¹² In almost all cases, the tumor that is seen is of reduced viability.^20,21

Recurrence after Surgery

Surgery may fail because of anatomic considerations, pathologic features, or errors in judgment or technique. The involvement of critical structures may limit the initial resection: involvement of the optic pathways, diencephalon, internal capsule, brain stem, or eloquent cortex by a glioma often precludes complete removal. Tumor recurrence, despite removal of all macroscopically evident tumor, can occur if there is microscopic infiltration of adjacent structures. Even low grade cerebral gliomas are usually infiltrative. Anaplastic astrocytomas characteristically are widely invasive. Finally, errors in judgment, such as preoperatively underestimating the amount of tumor that can be safely removed or intraoperatively failing to remove tumor that was targeted, result in potentially resectable tumor being left as a nidus of regrowth.

Recurrence after Radiation

Radiation therapy may fail because of inadequate targeting, underutilization of tolerable dose, or radiation resistance of the tumor cells. Proximity to critical anatomical structures can also limit maximal allowable radiation dosage. Furthermore, the correlations between imaging abnormality and tumor extent are incomplete. Pathologic studies have shown that individual tumor cells can be found throughout and even beyond CT hypodense and MRI T2 hyperintense areas of malignant glioma.^23,24 For each individual case, the extent of brain invasion from the contrast-enhancing margin of a malignant glioma is incompletely known. The choice of field size for irradiation of such lesions is difficult and relies as much on the trade-off between target volume and tolerable dose as on the accurate delineation of tumor boundaries. Failure to include an adequate annulus of tissue about the tumor to accommodate imaging uncertainty and technical error may leave tumor cells incompletely irradiated.

Even if the maximal dose tolerated by infiltrative surrounding brain is delivered, tumor cells may remain viable. Hypoxic, nonproliferating cells and tumor stem cells are particularly radioresistant; with time or change in the physiologic conditions following therapy, re-entry of cells into the cell cycle permits the proliferation that results in clinically apparent tumor recurrence.^25,26 Analysis of patterns of failure demonstrates that, even with maximal tolerable doses of photon radiation of 70 to 80 Gy, almost all malignant astrocytomas fail centrally.²⁷ A study of high dose fractionated proton irradiation following radical resection of glioblastomas showed the following:¹ a dose between 80 and 90 Gy is sufficient to prevent tumor regrowth;² outside of this high dose volume, tumor regrows, usually in areas receiving between 60 and 70 Gy;³ enlargement of the high dose volume to include more peripheral areas is likely to induce unacceptably high levels of symptomatic radiation-related necrosis.²⁸

Recurrence after Chemotherapy

Chemotherapy fails as a result of inadequate drug delivery, toxicity, or cell resistance. The blood–brain barrier is deficient in the contrast-enhancing region of the tumor, but surrounding brain usually has an intact blood–brain barrier; lipid-insoluble drugs thus have limited access to tumor cells infiltrating peripheral regions. The margin between drug efficacy and neurotoxicity, bone marrow suppression, pulmonary injury, and gastrointestinal side-effects is often narrow. Non-cycling cells and tumor stem cells are resistant to cell-cycle specific drugs, and potentially vulnerable cells often rapidly develop biochemical means of resistance to chemotherapeutic agents.^25,26,29

Even if these therapies significantly reduce the tumor burden, the patient’s immune response may be rendered ineffective by chemotherapy and by the tumor’s secretion of factors antagonistic to immune function, such as IL-10, prostaglandin E2, and transforming growth factor (TGF)-beta 2, and its expression of apoptosis-inducing molecules, such as Fas ligand (FasL) and galectin-1.³⁰ Each of these limitations of each component of multimodality therapy may contributes to failure to prevent tumor regrowth. At the time of tumor recurrence, consideration of these reasons for failure is essential to assessment of prognosis and to the choice of subsequent therapy.

Residual Tumor

Radiologic demonstration of residual tumor after initial treatment may be consistent with preoperative goals and expectations; the prognosis would be that originally formulated. If, however, residual tumor is identified unexpectedly, the prognosis may need to be altered. The prognostic import of residual tumor is best seen in the relationship between extent of resection and likelihood of tumor recurrence.

Cytoreductive surgery is a fundamental part of the treatment of most systemic malignancies.³¹ In most cases, there is a strong relationship between the extent of resection and outcome. For gliomas, correlation between extent of resection or, more significantly, size of residual tumor, and outcome measures, such as interval to tumor progression and survival, has been strongly suggested by retrospective and prospective series, but not by randomized clinical trials.³² More recently, one study, reported a significant survival advantage when 98% or greater resection is achieved.³³

Correlation of survival with extent of resection for low grade gliomas has been suggested by retrospective uncontrolled reviews and comparisons with historical controls.^3,34–36 One study of 461 adult patients with low grade cerebral gliomas found that gross total surgical removal correlated with length of survival.³⁷ Another reported median survival duration of 7.4 years following maximal surgical resection. The median survival of a subgroup patients with hemispheric tumors compared favorably (10 years vs. 8 years) with that of a comparable series treated with biopsy and radiation alone.^3,35 Additional studies have demonstrated that extensive resection of low grade gliomas delays tumor recurrence.^36,38

For high grade gliomas, the correlations between the extent of resection at the initial operation and¹ the time to tumor recurrence and² the duration of patient survival have been disputed.³⁹ Historical reports and reviews of large series have noted the association of survival and extent of resection for both astrocytomas and oligodendrogliomas.^11,40–43 Extensive reviews of the literature, however, have failed to locate randomized, controlled clinical trials comparing survival after biopsy with that after radical resection of malignant gliomas.^44,45 Nevertheless, the benefit of surgical cytoreduction has been strongly suggested by the following findings:

Although less than ideal, the data that exist for gliomas and experience with tumors outside the central nervous system suggest the benefit of cytoreduction when a near-total removal (2 log reduction of tumor cell number) of a glial tumor can be achieved. Thus, failure to identify and remove readily accessible tumor mass at an initial operation might warrant reoperation before regrowth occurs.

Recurrent Tumor

Regrowth of tumors after an initial response (diminution or stability) to surgery and radiation therapy is ominous. This is particularly true if the growth is more rapid or more infiltrative than that of the original tumor. Such growth often exhibits changes in the basic biology of the tumor that make it less responsive to subsequent therapy. A short interval between initial treatment and recurrence of symptoms often indicates rapid regrowth and a poor prognosis. Factors to be considered in estimating prognosis include the biology of the tumor (its pathology, growth rate, and invasiveness), its resectability, its prior response to radiation and chemotherapy, and the age and performance status of the patient.⁵⁸ Estimates of the recurrent tumor’s size, growth rate, invasiveness, and location must be made in assessing its potential for causing both neurologic deficit and death. Reappearance of a slowly growing, well-demarcated frontal convexity oligodendroglioma with deletions of chromosomes 1p and 19q in a middle-aged patient of good neurologic condition after a 10-year interval of postsurgical quiescence clearly carries a prognosis very different from that of diffuse diencephalic spread of a glioblastoma multiforme in an elderly patient with a poor performance status 3 months after treatment with surgery, radiation, and chemotherapy.⁵⁹

Therapy of Recurrent Gliomas

The choice of therapy of a recurrent glioma is based on a comparison of the natural history of the regrowing tumor with the risk–benefit ratio of potential therapies. Recurrent gliomas warrant aggressive multimodality therapy if the patient is in good neurologic and general medical condition and therapeutic options offer a realistic chance for significant improvement in neurologic status or extension of survival.⁶⁰

Patterns of Recurrence of Gliomas

When gliomas recur, most do so locally. Historically, more than 80% of recurrent glioblastoma multiforme arose within 2 cm of the original margin of contrast-enhancing tumor.^61,62 In one series, over 90% of glioma cases showed recurrence at the original tumor location, while 5% developed multiple lesions after treatment.⁶³ In another study of 36 patients with malignant gliomas receiving 70 to 80 Gy of fractionated radiation, 32 (89%) had central (at least 95% of the recurrent tumor within the volume receiving at least 95% of the maximum dose) or in-field (at least 80% of tumor within this highest dose volume) recurrence, and 3 (8%) had marginal recurrence. Only one (3%) fell predominantly outside the high dose range. Seven patients had multiple sites of recurrence, but only one had a large recurrence outside the high dose volume.²⁷ This tendency to recur locally is a function of tumor cell distribution. There is a gradient of tumor cell density in which tumor cell number decreases rapidly at increasing distances from the contrast-enhancing rim of solid tumor. Thus, although individual tumor cells spread through the brain at great distances from the primary site, there are so many more cells locally that the odds favor local reaccumulation of tumor mass.^23,24

Factors contributing to the likelihood of local recurrence include the following:

As tumor cell proliferation resumes at the initial tumor site, cells again spread rapidly and diffusely. Tumor cell proliferation resumes at distant sites as a result of the influx of these new, mitotically active cells or the renewed growth of cells that spread before the initial treatment.⁶³ Biologic therapeutic agents may also affect the pattern of recurrence; recent experience with bevacizumab (Avastin) suggests that tumors treated with this inhibitor of VEGF are more likely to recur as diffusely infiltrative lesions distant from the original site of tumor.⁶⁴ Consequently, treatments targeting local recurrence alone will, at best, be briefly palliative. Treatment of tumor recurrence thus usually involves a combination of modalities aimed at both local and distant disease.

Epidemiology of Recurrent Glioblastoma

The heterogeneity in defining recurrence and the variability of treatment algorithms employed at different institutions result in a vague profile of recurrent glioblastoma multiforme.⁶⁵ In a multi-center trial of reoperation for resection and placement of cavitary biodegradable BCNU-wafer in 222 patients with recurrent glioblastoma and a Karnofsky Performance Score of at least 60, the median interval from initial diagnosis to tumor recurrence was 12 months.⁶⁶ Among a cohort of 301 patients with GBM, 223 patients had tumor recurrence at a median interval from initial diagnosis of 4.9 months;⁶⁷ 64% of these had a Karnovsky Performance Score greater than 70 at the time of recurrence.

Glioblastoma recurrence is demonstrated on imaging obtained in routine surveillance or in response to new or recurring symptoms. In a questionnaire-based study of patients with recurrent glioblastoma or anaplastic astrocytoma and a KPS >70, self-reported symptoms included fatigue, uncertainty about the future, motor difficulties, drowsiness, communication difficulties, and headache.⁶⁸ While most symptoms likely reflected tumor recurrence, confounding factors such as radiation necrosis and steroid treatment may have contributed to generalized fatigue, and pain and uncertainty about the future may have resulted from the diagnosis alone, independent of current tumor status. Incoordination, weakness, visual loss, and pain were reported more frequently by patients with recurrent glioblastoma than by those with anaplastic astrocytoma, providing evidence that more aggressive disease will cause greater neurological deficit.

Therapy of Recurrent Malignant Glioma

Choice of therapy for a recurrent glioma must consider the tumor’s current and previous histology, previous treatment, and location and the patient’s age, medical and neurologic conditions, and preferences. An enlarging lesion that was originally a low grade glioma should undergo biopsy (stereotactically or, if resection is anatomically feasible, by open craniotomy) to confirm histology (Fig. 10-2). If the tumor remains low grade and a large part of the lesion can be resected without inflicting significant neurologic deficit, it should be removed; if previously irradiated to significantly less than maximal tolerable dose, the tumor bed and surrounding area should receive fractionated radiotherapy. The longer the interval since the initial radiotherapy, the higher the dose that can be given safely at recurrence. If the tumor is inaccessible to surgery, radiation alone should be prescribed. If a low grade tumor previously irradiated to a maximal tolerable dose recurs as a low grade glioma, it should be resected, if possible. If it is inaccessible, stereotactically delivered focal radiation is an attractive option.^69,70

FIGURE 10-2 Recurrent glioma. Decisions in the management of a recurrent tumor should consider grade, resectability, and prior therapy. N, neurologic; reg rad, regional fractionated radiation therapy; focal rad/boost, stereotactic radiosurgery, brachytherapy, or radiotherapy; small, focal, less than 10 cm³, radiographically demarcated; CTx, chemotherapy; ST, stereostatic; XRTx, radiotherapy.